Neuroprotective Effect for Cerebral Ischemia by Natural Products: A Review

Abstract

Natural products have a significant role in the prevention of disease and boosting of health in humans and animals. Stroke is a disease with high prevalence and incidence, the pathogenesis is a complex cascade reaction. In recent years, it’s reported that a vast number of natural products have demonstrated beneficial effects on stroke worldwide. Natural products have been discovered to modulate activities with multiple targets and signaling pathways to exert neuroprotection via direct or indirect effects on enzymes, such as kinases, regulatory receptors, and proteins. This review provides a comprehensive summary of the established pharmacological effects and multiple target mechanisms of natural products for cerebral ischemic injury in vitro and in vivo preclinical models, and their potential neuro-therapeutic applications. In addition, the biological activity of natural products is closely related to their structure, and the structure-activity relationship of most natural products in neuroprotection is lacking, which should be further explored in future. Overall, we stress on natural products for their role in neuroprotection, and this wide band of pharmacological or biological activities has made them suitable candidates for the treatment of stroke.

Introduction

Stroke is a disease with high prevalence and incidence (Benjamin et al., 2018). Strokes can be divided into two categories: ischemic and hemorrhagic stroke, and over 80% are ischemic stroke (Zhou et al., 2018). Ischemic stroke is a pathological condition characterized by blood vessels occlusion and insufficient of blood supply. Stroke which is one of the most common causes of disability and death worldwide, seriously endangers human health and brings heavy burden to society and family (Donnan et al., 2008; Kalogeris et al., 2016). The pathological mechanism of cerebral ischemia is a complex cascade reaction, and its severity is related to the time of cerebral ischemia and the depth of the ischemic site (Steliga et al., 2020). The occurrence and development of cerebral ischemia included neuron excitotoxicity, mitochondrial dysfunction, neuroinflammatory damage, oxidative stress, etc. It is generally believed that glutamate excitotoxicity, energy metabolism disorder, and Ca²⁺ overload happened within 24 h of the onset of stroke, accompanied by the generation of free radicals (Guo, Li and Wang, 2009; Manzanero, Santro, Arumugam, 2013). Apoptosis and necrosis also occurred within a few hours of ischemia (Wang, C. et al., 2015). In the subacute phase, brain edema and blood-brain barrier (BBB) destruction happened. Endothelial cells, pericytes, astrocytes, etc are activated and inflammatory factors are released, accompanied with the proliferation of reactive glial cells (Stanimirovic and Satoh, 2000; Liebner et al., 2018). There exists endogenous repair in the late stage of cerebral ischemia, and neurogenesis, glial scars, angiogenesis could be observed (Steliga et al., 2020). Therefore, the occurrence and development of stroke is complicated, which makes its treatment very difficult. Tissue plasminogen activator (t-PA) is the only therapeutic medicine for ischemic stroke approved by Food and Drug Administration (FDA). However, t-PA has a restricted time window of 6 h, and delayed t-PA infusion increases the risk of hemorrhagic transformation and carries high mortality (Group 1995; Hacke et al., 2008). Despite constantly increasing understanding of ischemic stroke pathophysiology through laboratory and clinical studies, the treatment strategy is still not ideal. Therefore, there is an urgent medical need to identify new molecules that can provide neuroprotection against cerebral ischemic or ischemic reperfusion (I/R) injury.

Natural products obtained from natural sources, including plants, animals, fungi and microorganisms. Natural products have played an important role in ancient traditional medicine systems, such as Unani, Chinese and Ayurveda which are still in common use today. Natural products are known to exert additive, synergistic or antagonistic effects on the body. With the pharmacology technology developing, the administration forms of natural products are various, which has drawn much attention for the treatment of stroke from drug discovery to drug delivery (Hermann et al., 2019; Long et al., 2020; Williams et al., 2020). The pathogenesis of stroke is a complex cascade reaction, including neuro-inflammatory damage, oxidative stress, mitochondrial dysfunction, neurotoxicity, blood-brain barrier (BBB) disruption, neurovascular unit (NVU) damage and other factors. In recent years, it’s reported that a vast number of natural products have demonstrated beneficial effects on stroke worldwide (Fei et al., 2020). The neuroprotection of natural products has been discovered to modulate activities via multiple targets and signaling pathways with direct or indirect effects on enzymes, such as kinases, receptors and proteins (Bagli et al., 2016). This wide band of pharmacological or biological activities has made them suitable candidates for the treatment of stroke (Cai et al., 2019; Zhang, C. et al., 2020; Zhong et al., 2020). As a requirement of novel drug development for stroke, there is a focus on the neuroprotection of natural products via multi-targets. Hence, we stress on natural products for their role in neuroprotection (Figure 1). This review provides a comprehensive summary of the pharmacological effects and multiple target mechanisms of natural products for cerebral ischemic or I/R injury.

FIGURE 1

Methodology

Database searches using Google scholar, PubMed, and China National Knowledge Internet (CNKI) were conducted until July 2020 to include up to date documented information in the present review. For data mining, the following words were used in the databases mentioned above: neuroprotection, natural product, phytoconstituents, natural products cerebral ischemic injury, natural products cerebral ischemic reperfusion injury, in vivo and in vitro studies for prevention and treatment of stroke. In almost all cases, the original articles or abstracts were obtained and the relevant data was extracted.

Neuroprotective Role of Flavonoids in Ischemic Brain Injury

Flavonoids, a natural bioactive compound found abundant in vegetables, fruits and traditional herbal medicine. Prevention and/or treatment with flavonoids such as baicalin, apigenin, vitexin, quercetin and other flavonoid compounds have shown promising neuroprotective effects against ischemic-induced injury by through increasing neuronal viability, cerebral blood flow and reducing ischemic-related apoptosis (Putteeraj et al., 2018).

Baicalin

Baicalin, mainly derived from the root of Scutellaria baicalensis Georgi, is one kind of a crucial flavonoid (Figure 2A). This medicinal plant is widely distributed in China, Russia, Mongolia, North Korea and Japan, and has the functions of clearing away heat and dampness, purging fire and detoxification (Zhao et al., 2019). In recent years, baicalin has also been found to have a wide range of neuroprotective effects (Liang et al., 2017; Sowndhararajan et al., 2018). Middle cerebral artery occlusion (MCAO) induced cerebral ischemic injury in vivo and oxygen–glucose deprivation (OGD) induced hypoxia injury in vitro were implemented. Baicalin at doses ranging from 50 to 200 mg/kg could significantly improve neurological deficit and reduce infarct volume via inhibiting apoptotic and oxidative pathway, including myeloid cell leukemia 1 (Mcl 1), B-cell lymphoma-2 (Bcl 2), superoxide dismutase (SOD), malondialdehyde (MDA), and so on (Cao et al., 2011; Zheng et al., 2015). Neuroprotective activity was also confirmed in another study. Baicalin could decrease nuclear factor kappa B (NF-κB) p 65 to exert neuroprotection (Xue et al., 2010). In addition, baicalin 100 mg/kg inhibits toll like receptor 2/4 (TLR2/4) signaling pathway in cerebral ischemia rats (Tu et al., 2011). Baicalin down-regulated nucleotide-binding oligomerization domain protein 2 (NOD2) receptor and tumor necrosis factor α (TNF α) expression of neurons with OGD in vitro and cerebral ischemia-reperfusion in vivo (Li, F et al., 2010). These findings suggested baicalin could afford neuroprotection through multiple pathways.

FIGURE 2

Scutellarin and Scutellarein

Scutellarin (Figure 2B) and scutellarein (Figure 2C), is the major active component extracted from Erigeron breviscapus (Vant.) Hand-Mazz, a Chinese herbal medicine (Zhang et al., 2009). Accumulated data have demonstrated the effectiveness and benefits of breviscapine and scutellarin in treating cerebrovascular disease and cardiovascular disease in clinic and in experimental study (Cao et al., 2008; Wang et al., 2015a; Gao et al., 2017). It has demonstrated that scutellarin is benefit to brain injury caused by cerebral ischemia/reperfusion due to its anti-oxidation and anti-inflammatory effects and ability to attenuate neuronal damage (Wang and Ma 2018). Scutellarin could effectively suppress the inflammatory response in activated microglia/brain macrophage in experimentally induced cerebral ischemia, whose underlying mechanism was associated with suppressing the phosphory c-Jun N-terminal kinase (p-JNK) and p-p38 mitogen-activated protein kinase (MAPK), increasing phosphorylation extracellular regulated kinase 1/2 (p-ERK1/2) (Chen H.-L et al., 2020). In MCAO rats given scutellarin 100 mg/kg treatment, neurological scores were significantly improved coupled with a marked decrease in infarct size, which was found that scutellarin had a neuroprotective effect, amplified TNC1 astrogliosis and activated microglia to remodel injured tissue via notch pathway (Fang et al., 2015; Fang et al., 2016). Pretreated with scutellarin 50 or 75 mg/kg has protective effects for cerebral injury through upregulating endothelial nitric oxide synthase (eNOS) expression and downregulating of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and inducible nitric oxide synthase (iNOS) expression (Hu et al., 2005). Another study also proved scutellarin protected against ischemic injury through regulation of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) and connexin 43 to decrease oxidative damage and apoptotic cell death (Sun, J. B. et al., 2018; Zhang et al., 2009). Scutellarin and scutellarein could improve neuronal injury, and scutellarein had better protective effect than scutellarin through improving the Ca²⁺-ATPase and Na⁺, K⁺-ATPase activity in rat cerebral ischemia with bilateral common carotid arteries (BCCAO) (Tang et al., 2014). Scutellarin protects brain from acute ischemic injury probably through its inhibitory effect on the angiotensin-converting enzyme (ACE) and Ang II type 1 receptor (AT1R), also TNF-α, interleukin-6 (IL-6), and interleukin-1β (IL-1β) (Wang et al., 2016).

Apigenin and Vitexin

Apigenin (Figure 2D) is a natural flavonoid and vitexin (Figure 2E) is an apigenin flavone glycoside, which were found in several dietary plant foods as vegetables and fruits, and had a variety of pharmacological effects (Babaei et al., 2020). It has been reported that apigenin and vitexin played a protective role in diseases associated with the oxidative process, such as cardiovascular and neurological disorders (Ayoobi et al., 2017; Che et al., 2020; Li, S. et al., 2017). Angiogenesis is one of the ways to repair brain injury. It’s reported that apigenin could promote cell proliferation, tube formation, and cell migration while inhibiting apoptosis and autophagy by affecting caveolin-1/VEGF, Bcl-2, caspase-3, Beclin-1, and mechanistic target of rapamycin (mTOR) expression. What’s more, apigenin significantly reduced neurobehavioral scores and volume of cerebral infarction while promoting vascular endothelial cell proliferation by upregulating VEGFR2 to affect caveolin-1, VEGF, and eNOS expression in brain tissue of I/R rats (Pang et al., 2018). Vitexin could also play a protective role by suppressing oxidative stress (Cui et al., 2019). In addition, vitexin regulated cell apoptosis and autophagy via MAPK and mTOR/Ulk1 pathway to attenuate cerebral I/R injury (Wang et al., 2015b; Jiang et al., 2018). Apigenin also showed long-term therapeutic effect in cognitive impairments after cerebral I/R injury (Tu et al., 2017). Above all, it suggested apigenin and vitexin had neuroprotective effect through inflammation, angiogenesis, apoptosis and autophagy pathways with multi-targets.

Icariin

Icariin (Figure 2F), an active flavonoid extracted from Epimedium brevicornum Maxim, has been proven to possess a wide range of efficacy including anti-tumor, anti-oxidant, anti-bacterial and anti-inflammatory, etc (Luo et al., 2007; Zhou et al., 2011). It has been also reported to alleviate brain injury and attenuate cognitive deficits (Li, H. et al., 2010; Li et al., 2005). Xiong et al. and Deng et al. found that pretreatment with Icariin and Icariside II, a metabolite of icariin, could decrease neurological deficit score, diminish the infarct volume, and reduce IL-1β and transforming growth factor-β (TGF-β1). Moreover, Icariin suppressed inhibitory κB (IκB)-α degradation and NF-κB activation and up-regulated peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator activated receptor γ (PPARγ) levels in I/R model (Deng et al., 2016; Xiong et al., 2016). Moreover, a study by Mo et al. found that Icariin can inhibit apoptosis and inflammatory in neurons after OGD/R through inositol requiring enzyme 1 (IRE1)- X-Box Binding Protein 1 (XBP1) signaling pathway (Mo et al., 2020).

Quercetin

Quercetin (Figure 2G), is a common flavonoid found in many fruits and vegetables (Lee et al., 2003). It has been reported that quercetin has an anti-oxidative property, anti - inflammation and immunity, anti-cancer, etc (Costa et al., 2016; Li, W. et al., 2016; Shafabakhsh and Asemi 2019; Xu, D. et al., 2019). A study by Jin et al. found that quercetin could increase the expression of ZO-1, Claudin-5, β-catenin, and LEF1, and decrease the expression of MMP-9, GSK-3β and axin to reduce brain edema and BBB leakage and improve BBB dysfunction, which suggested the neuroprotection of quercetin was related to Wnt/β-catenin pathway (Jin et al., 2019). Calcium acts as a second messenger that mediates physiologic functions. It’s reported that quercetin exerted a preventative effect through attenuation of intracellular calcium overload and restoration of down-regulated hippocalcin expression during ischemic injury (Park et al., 2020). Moreover, quercetin alleviated the increasement of protein tyrosine and serine/threonine phosphatase activity, along with the reduction of ERK and Akt phosphorylation in cerebral I/R injury (Wang, Y. Y. et al., 2020). In addition, iso-quercetin protected against oxidative stress and neuronal apoptosis via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB signaling pathway in cerebral ischemic stroke (Dai et al., 2018).

Calycosin

Calycosin (Figure 2H), an isoflavone phytoestrogen isolated from Astragalus membranaceus, is found to possess various potential pharmacological activities, such as, anti-tumorigenesis, anti-oxidation, anti-virus and apoptosis-modulation effects (Chen, J et al., 2015; Wang and Zhao, 2016; Zhao, Y. et al., 2016). It was also demonstrated that calycosin 30 mg/kg could ameliorate both the neurological deficit and infarct volume in experimental cerebral ischemia reperfusion injury, and the mechanism might be attributed to its antioxidant effects (Guo et al., 2012). Post-stroke calycosin 30 mg/kg therapy increased brain-derived neurotrophic factor (BDNF)/TrkB to ameliorate the neurological injury due to switching the microglia from the activated ameboid state to the resting ramified state in ischemic stroke rats (Hsu et al., 2020). Calycosin exhibited a downregulation of dexamethasone-induced Ras-related protein 1 (RASD1), and an upregulation of estrogen receptor (ER)-α and Bcl-2 (Wang, X. et al., 2014). A study by Wang et al. found that calycosin pretreatment for 14 days dramatically upregulated p62, neighbor of BRCA1 gene 1 (NBR1) and Bcl-2, and downregulated TNF-α to ameliorate neurological scores in cerebral I/R rats (Wang, L. et al., 2018).

Neuroprotective Role of Alkaloids in Ischemic Brain Injury

Alkaloids are rated as among the most-investigated plant secondary metabolites with versatile biological activity (Qiu et al., 2014). Recent investigations have pointed out the dynamic role of alkaloids as antibacterial, antidepressant, antioxidant, anti-inflammation (Perviz et al., 2016; Li et al., 2020; Liu et al., 2020; Rosales et al., 2020). Accordingly, alkaloids are emerging as pharmaceutical tools for neuroprotective effects (An et al., 2020). Alkaloids were investigated on neuroprotective effects including berberine, ligustrazine, tetrahydropalmatine and others.

Berberine

Berberine (Figure 3A) is an isoquinoline alkaloid isolated from traditional herbal medicine. It is widely present in the roots, rhizomes, stems or bark of various natural plants, such as Coptis chinensis Franch., Phellodendron chinense Schneid., etc. These plants have been used for thousands of years (Wang et al., 2019a; Fan et al., 2019). Studies have shown that berberine has a variety of pharmacological activities, including anti-microbial, anti-tumor, lowering glucose, lowering cholesterol, anti-inflammatory, antioxidant, immunomodulatory and neuroprotective effects (Asemi et al., 2020; Song et al., 2020). So far, the neuroprotective effect of berberine has been involved (Lin and Zhang 2018). Berberine could improve the survival rate in OGD/R cells and improve the neurological deficiency in cerebral ischemic injury, which was involved in reducing the expression of cleave caspase 3 and up-regulating the expression of p-Bad to inhibit cell apoptosis via TrkB-PI3K/Akt pathway to promote neuron growth (Hu et al., 2012; Chai et al., 2013; Yang et al., 2018a). Other studies also showed berberine 40 mg/kg preconditioning had neuroprotective effects by promoting autophagy, reducing cell apoptosis via PI3K/Akt signaling pathway (Zhang et al., 2016a; Zhang et al., 2016b). In addition, berberine exerted the neuroprotective effects by regulating I/R-induced peripheral lymphocytes early immunoactivation (Song et al., 2012). A study by Zhang et al. found that neuroprotection of early and short-time applying berberine could upregulate p-Akt, p-GSK 3β and phosphor cAMP response element binding protein (p-CREB) and downregulate NF-κB expression to ameliorate BBB permeability in the acute phase of cerebral ischemia (Zhang et al., 2012).

FIGURE 3

Tetramethylpyrazine

Tetramethylpyrazine (Figure 3B), also called ligustrazine, is a kind of alkaloids identified in Ligusticum chuanxiong Hort, which has been used to treat cardiovascular and cerebrovascular diseases for hundreds of years in ancient China (Zhao, X. et al., 2016; Zheng, J. S. et al., 2018). In recent study, Ligusticum chuanxiong Hort and its main active compound ligustrazine have been studied and had anti-inflammatory, anti-oxidant and analgesic effect (Kao et al., 2006; Zou et al., 2018). Tetramethylpyrazine treatment with 20 mg/kg suppressed hypoxia inducible factor-1-alpha (HIF-1α), TNF-α, and activated caspase-3 expression in MCAO-induced brain ischemia in rats (Chang et al., 2007). Tetramethylpyrazine 20 mg/kg inhibited neutrophil activation via elevating nuclear related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression and inhibiting high-mobility group box-1 protein (HMGB1)/toll-like receptor-4 (TLR4), Akt, and ERK pathway following cerebral ischemia rats (Chang et al., 2015). Tetramethylpyrazine analogues were also investigated to induce p-eNOS by activation of PI3K/Akt and TLR-4/NF-κB signaling pathway and regulate the expression of tight junction (TJ) proteins, matrix metalloprotein 9 (MMP-9) and aquaporin 4 (AQP4) under cerebral I/R injury (Yan et al., 2015; Xu et al., 2017; Zhou et al., 2019). The similar finds of PI3K/Akt pathway also were shown in another study (Ding et al., 2019). What’s more, the synergistic effect of drugs has also been shown to have good therapeutic effect. Ligustrazine accompanied with borneol could attenuate I/R injury by downregulating IL-1β, IL-6, and TNF-α, upregulating SOD, GSH-Px and regulating apoptosis and autophagy (Yu, B. et al., 2017; Yu et al., 2016).

Daurinoline

Daurinoline (Figure 3C) is a kind of dibenzyl tetrahydroisoquinoline alkaloid, isolated from menispermum dauricum DC., which has a variety of pharmacological activities, including neuroprotective effect (Zhang et al., 2011). Daurinoline 10 mg/kg and 20 mg/kg could enhance of SOD activity and the ability of scavenging oxygen free radicals (Lan and Lianjun 2020). Daurinoline reduced the level of MDA in brain tissue and increase the activity of SOD to prevent and ameliorated energy metabolism disturbance of cortex and mitochondria of brain induced by repeatedly cerebral ischemia reperfusion (Li and Gong 2004). In addition, daurinoline 5 and 10 mg/kg could inhibit cytochrome c (Cyt-C) release and caspase-3 and caspase- 9 to inhibit neuronal cells apoptosis in the penumbra after cerebral ischemia (Yang et al., 2009).

Levo-tetrahydropalmatine

Levo-tetrahydropalmatine (Figure 3D) are a series of alkaloids, isolated from a Chinese analgesic medicine, called Corydalis yanhusuo W. T. Wang. l-Tetrahydropalmatine, one of its main active ingredients, has been demonstrated to have potent analgesic effects and has been used in Chinese clinical practice for this purpose for many years (Chu et al., 2008; Han et al., 2012; Kang et al., 2016). Recent work showed that l-tetrahydropalmatine suppressed the central excitatory effects of amphetamine (Chang and Lin 2001), and played a protective role against neuronal injury in animal models (Liu et al., 2005; Mantsch et al., 2007; Chen et al., 2012). Levo-tetrahydropalmatine could regulate Src and c-Abl expression to inhibit neuron apoptosis and attenuate BBB injury in cerebral ischemic animals (Mao et al., 2015; Sun, J. B et al., 2018).

Peimine

Peimine (Figure 3E) is a major biologically active component of Fritillaria ussuriensis. Recent studies have shown that isosteroidal alkaloids in Fritillaria had a wide range of pharmacological activities besides its role in cough remedies (Li, J. et al., 2019; Li et al., 2020a; Zhang et al., 2020a; Zhao et al., 2018). It’s also reported that peimine had protective effects on cerebral I/R injury in rats. The mechanism of neuroprotective effect might be related to inhibition of apoptosis, oxidative stress and inflammatory response, reduction of pathological damage and neurological dysfunction through regulation of the PI3K/Akt/mTOR pathway (Guo et al., 2019; Duan et al., 2020).

Neuroprotective Role of Polyphenols and Acids in Ischemic Brain Injury

Polyphenols, a bioactive compound, were found abundant in vegetables, fruits and medical plant. Neuroprotection of polyphenols in medical plants is getting attention in the world. Curcumin, ellagic acid, resveratrol has been extensively studied and show multi-function. They are neuroprotectants, antioxidants, anti-inflammatory and antithrombic agents. It’s reported that the neuroprotective efficacy of these compounds was involved in mitigating brain infarction and global ischemia, improving cerebral blood circulation (Lin 2011).

Curcumin

Curcumin (Figure 3F), a polyphenolic compound extracted from Curcuma longa L., has potential anti-inflammatory, cardiovascular protective effect and neuroprotection. Recent studies demonstrated the neuroprotective effect of curcumin against cerebral ischemic injury through oxidation, apoptosis, autophagy pathways (Eghbaliferiz et al., 2020; Forouzanfar et al., 2020; Ułamek-Kozioł et al., 2020). Rats or mice with cerebral ischemic injury that received curcumin at 10–400 mg/kg exhibited significantly alleviated brain injury. Moreover, a more SOD, GSH-Px and glutathione (GSH) and a lower MDA, NO contents were found in curcumin administrated animals (Thiyagarajan and Sharma 2004; Li. Y. et al., 2016), which suggested the mechanism of curcumin was related to antioxidative activity. In addition, curcumin was proven to suppress the release of inflammatory cytokines via NF-κB, signal transducer and activator of transcription (STAT), Akt/mTOR, ERK signaling pathways (Huang et al., 2018; Li et al., 2015; Mukherjee et al., 2019; Xu, H. et al., 2018). Moreover, Bax, Bcl 2, caspase 3, LC3 II activity and other autophagy and apoptosis cytokines were also reversed by curcumin (Hou et al., 2019; Huang et al., 2018; Wang et al., 2005; Xie, C. J. et al., 2018; Xu, L. et al., 2019; Zhang et al., 2018a). Furthermore, curcumin promoted neuron survival in vitro to exert neuroprotective effects against ischemia injury (Lu et al., 2018; Xie, W. et al., 2018; Zhang, X. et al., 2018).

Resveratrol

Resveratrol (Figure 3G), also named 3,4,5-trihydroxy-trans-stilbene, a natural polyphenolic compound, occurs naturally in grapes and a variety of medicinal plants, and possesses multiple biological activities (Santos et al., 2019; Thapa et al., 2019). The effect of resveratrol on cerebral ischemic injury was also explored. Resveratrol dosage at 10–100 mg/kg marked improved neurological deficiency and protected against cerebral ischemic injury though PI3K/Akt, NF -κB and other pathways (Lei et al., 2020; Simao et al., 2012a; Simao et al., 2012a; Yu, P. et al., 2017). Resveratrol treatment could obviously upregulate nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) to ameliorate oxidative damage in cerebral ischemic injury (Ren et al., 2011; Yang et al., 2018b; Gao et al., 2018). Furthermore, MDA, NO, SOD could be reversed by resveratrol administration (Jie et al., 2020; Tsai et al., 2007; Xu, J. et al., 2018). Silent information regulator 1 (Sirt 1) is a NAD + dependent deacetylase, which plays an important role in cerebral I/R injury (She et al., 2017). It’s reported that resveratrol protected against cerebral ischemic injury by inhibiting NLRP3 inflammasome activation, improving alterations in mitochondrial and glycolytic function through Sirt1 pathway (Della-Morte et al., 2009; Koronowski et al., 2015; He et al., 2017; Koronowski et al., 2017). Moreover, resveratrol could inhibit inflammatory response, including prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, NOS and MMP 9 to alleviate neurological deficits (Candelario-Jalil et al., 2007; Simao et al., 2012b; Wei et al., 2015). In addition, resveratrol could improve brain energy metabolism via inhibiting xanthine oxidase activity and preventing the production of hypoxanthine, xanthine and oxygen radicals (Li et al., 2011). These findings suggested resveratrol could reduce cerebral ischemia injury through multiple pathways.

Ellagic Acid

Ellagic acid (Figure 3H), an important cell protective and antioxidant compound, is a low molecular weight polyphenol derived from several fruits, vegetables and nuts (De Oliveira, 2016). Ellagic acid are recently more taken into accounts since their promising pharmacological effects, such as, anti-inflammation, anti-oxidant and anti-cancer (Ceci et al., 2018; Baradaran Rahimi et al., 2020). In recent study, ellagic acid is investigated as a potential endowed with multi-target pharmacological properties on central nervous system (Alfei et al., 2019). BCCAO was carried out to make global cerebral ischemic injury. Ellagic acid pretreatment with 100 mg/kg could reduce MDA level and restore the heart rate to normal level (Nejad et al., 2015). In addition, ellagic acid 100 mg/kg could activate PI3K/Akt/NOS pathway to alleviate brain injury and protect brain tissue in MCAO model (Kaihua and Jiyu 2020). Furthermore, ellagic acid administration with 10–90 mg/kg could improve brain injury outcomes and increase the proliferation of NSCs through the Wnt/β-catenin signaling pathway (Liu, Q. S. et al., 2017). The upregulation of zonula occludens-1 (ZO-1) and down-regulation of AQP 4 and MMP-9 in injured brain tissues after being treated ellagic acid 10–50 mg/kg (Wang et al., 2019b).

Neuroprotective Role of Glycosides in Ischemic Brain Injury

Asiaticoside

Asiaticoside (Figure 4A) is isolated from Centella asiatica (L.), which has been using as a memory enhancing and psychoactive drug for a long time in Asia (Zheng and Qin 2007). Many studies have shown that C. asiatica indeed has many biological activities in central nervous system (Mook-Jung et al., 1999; Zheng and Qin 2007; Dhanasekaran et al., 2009; Orhan 2012). A report demonstrated asiaticoside showed anti-inflammation effect via inhibiting overactivation of p38 MAPK pathway against cerebral I/R mice (Chen et al., 2014). Another study found asiaticoside showed a protective effect against cerebral I/R injury via the NOD2/MAPK/NF-kB signaling pathway (Zhang et al., 2020b).

FIGURE 4

Salidroside

Salidroside (Figure 4B), the major phenylpropanoid glycoside extract from medicinal Tibetan plant Rhodiola rosea L, has diverse pharmacological activities. Many recent reports and reviews have highlighted that salidroside may exert anti-inflammatory, neuroprotective effects and improve cognitive function (Li, M. et al., 2018; Xu, N. et al., 2019). Salidroside may involve the modulation of monoamine metabolism in the striatum and substantia nigra pars compacta (SNpc), which may be related to the function of the dopaminergic system in the cerebral I/R brain (Zhong et al., 2019). Many studies reported salidroside protected against cerebral I/R injury via PI3K/Akt pathway, accompanying with Nrf2/NF-κB pathway (Wei et al., 2017; Zhang, Y. et al., 2018; Zhang, J. et al., 2019; Zuo et al., 2018). Salidroside exhibited neuroprotective effects against hypoxia/reperfusion injury by activating the SIRT1/FOXO3α pathway (Xu, L. et al., 2018). In addition, salidroside is an effective treatment for ischemic stroke that functions via the fibroblast growth factor 2 (FGF2)-mediated cAMP/PKA/CREB pathway to promote dendritic and synaptic plasticity (Li et al., 2020b). Salidroside treatment reduced the expression of M1 microglia/macrophage markers and increased the exdslbpression of M2 microglia/macrophage markers after stroke and induced primary microglia from M1 phenotype to M2 phenotype (Liu et al., 2018). What’s more, salidroside reduced the markers of endothelial activation and neutrophilic infiltration after I/R injury by inhibition of complement, restoring an anti-inflammatory endothelial phenotype after oxidative stress and inhibiting classical complement activation, in association with anti-apoptotic effects (Wang, Y. et al., 2020).

Neuroprotective Role of Iridoid Glycosides in Ischemic Brain Injury

Iridoid glycosides are special glycosides. Iridoid glycoside exists broadly in plants of many families and has a wide variety of biological activities including purgative, liver protective, anti-microbial, analgesic, antitumor, sedative and anti-inflammatory activities (Ismailoglu et al., 2002). Geniposide, Catalpol and Picroside II were investigated in depth as iridoid glycosides, which had a neuroprotective effect.

Geniposide

Geniposide (Figure 4C), as an iridoid glycoside, was initially isolated from the herb Gardenia jasminoides Ellis (Wang et al., 1992), which has been noted for its variable pharmacological effects, including anti-oxidation, anti-inflammation, and anti-diabetes effects, among others (Koo et al., 2006; Wu et al., 2009). Previous studies showed that geniposide induced neuronal differentiation and attenuated cell injury (Liu et al., 2009; Yin et al., 2010). To date, there were some studies about the cerebral ischemia injury. Geniposide treatment after neonatal hypoxic-ischemia (HI) insult attenuated cell apoptosis, IgG leakage, microgliosis, astrogliosis, pericytes loss and junction protein degradation, which might be through the activation of PI3K/Akt pathway (Liu, F. et al., 2019). Geniposide attenuated inflammatory response by suppressing P2Y14 receptor and downstream ERK1/2 pathway in brain microvascular endothelial cells (BMECs) with OGD (Huang et al., 2017; Li, Y. et al., 2016). What’s more, geniposide in neuroprotection by activating autophagy and inhibiting NLRP3 inflammasome in microglial cells (Fu et al., 2020).

Catalpol

Catalpol (Figure 4D) is the main active component of the radix from Rehmannia glutinosa Libosch, and it belongs to the iridoid monosaccharide glycoside family (Ismailoglu et al., 2002; Zhang et al., 2008), which has pleiotropic protective effects on many diseases, including neurodegenerative diseases (Xia et al., 2012), ischemic stroke (Zhu et al., 2010), metabolic disorders (Zhu et al., 2010) and others. It’s reported that the efficacy of catalpol pretreatment on cerebral I/R injury may be attributed to reduction of free radicals and inhibition of lipid peroxidation and endothelin-1 (ET-1) production (Liu, H. et al., 2014). Additionally, a study by Li et al. found catalpol also exerted the most significant cytoprotective effect on astrocytes by suppressing the production of free radicals and elevating antioxidant capacity (Li et al., 2008). What’s more, catalpol significantly inhibited apoptosis by modulating Bcl-2 and Bax (Li et al., 2006). Catalpol affected angiogenesis via the JAK2/STAT3 signaling pathway and VEGF expression (Dong, W et al., 2016).

Picroside II

Picrorhiza scrophulariflora belongs to the plant family composed of picroside I, II and III, of which picroside II (Figure 4E) is one of the most effective components extracted from the dried rhizome and roots of Picrorhiza kurrooa Royle ex Benth and Picrorhiza scrophulariae flora Pennell (Stuppner and Wagner 1989; Wang et al., 1993). Current researches on picroside II are focused on its neuroprotective, anti-apoptotic, anti-cholestatic, anti-oxidant, anti-inflammation, immunomodulating activities (Cao et al., 2007; Li et al., 2007; He et al., 2009). It has been confirmed that picroside II 25 mg/ml could enhance nerve growth factor - induced PC12 cell axon growth, reduce H₂O₂ induced PC12 cell damage and improve cell survival in vitro (Cao et al., 2007). Picroside II attenuated cerebral I/R injury via inhibiting apoptosis and inflammation, included COX2, TLR4/NF-κB and MEK-ERK1/2 pathway (Guo et al., 2010; Wang, F. et al., 2015; Wang, L. Y. et al., 2015). Picroside II could protect BBB possibly through reducing oxidative stress factors (ROS, NOX2 ROCK, MLCK, and MMP-2) and enhancing BBB function factors, claudin-5 (Zhai et al., 2017). Furthermore, picroside II exerted a neuroprotective effect by inhibiting the mitochondria Cyt C signal pathway and decreasing the permeability of mitochondrial permeability transition pore (mPTP) following I/R injury in rats (Zhang et al., 2017; Li. Q et al., 2018).

Neuroprotective Role of Saponin in Ischemic Brain Injury

Ginsenoside Rg1 (Figure 5A) is the representative components in saponin. Ginsenoside Rg1 is one of the main active ingredients of ginseng (Zhang and Zhao 2014; Chuang et al., 2015). It has been shown that as a small molecular substance, ginsenoside Rg1 easily passes through the blood brain barrier. Moreover, ginsenoside Rg1 could promote stem cell orientation transformation, induce stem cell proliferation and played a neuroprotective role in brain repair (Cheng et al., 2005; Tang et al., 2017; Xie, C. J. et al., 2018). It’s reported that ginsenoside Rg1 could relieve the I/R injury through multiple pathways. Ginsenoside Rg1 could improve neurological injury, regulate BBB disruption and permeability and downregulate AQP 4 and protease-activated receptor-1 (PAR 1) (Zhou et al., 2014; Xie et al., 2015). Ginsenoside Rg1 alleviated oxidative stress after I/R through inhibiting miR-144 activity and subsequently promoting the Nrf2/ARE pathway (Chu et al., 2019). What’s more, a study by Li et al. found that ginsenoside Rg1 may exert its neuroprotective action on cerebral I/R injury through the activation of PPARγ signaling (Li et al., 2017). In addition, it’s also shown that ginsenoside Rg1 treatment obviously decreased cell apoptosis, while the transplanted cells could be differentiated into neurons and glial cells, which also improved cerebral ischemia (Bao et al., 2015). Other studies showed that ginsenoside Rg1 40 mg/kg was attributed to a decrease in ubiquitinated aggregates and a suppression of the inflammatory response and increased in the expression of BDNF in the hippocampal CA1 region after I/R insult (Wang, Y. et al., 2018; Zheng et al., 2019).

FIGURE 5

Astragaloside IV

Astragaloside IV (Figure 5B) is a triterpenoid saponin existing in the root of Astragalus membranaceus. Astragaloside IV also has a variety of pharmacological effects, such as anti-inflammatory, anti-cancer, anti-fibrosis, anti-oxidation stress, immunomodulatory through multiple signals (Ren et al., 2013; Zhang, X. et al., 2019). Meanwhile, it showed that astragaloside IV could inhibit neuroinflammation by reducing BBB permeability and lymphocyte infiltration, and played a neuroprotective role through mitochondrial pathway, antioxidant, anti-inflammatory and anti-apoptotic effects (Costa et al., 2018; Song et al., 2018), which mainly regulated JNK3, FAS, FasL, caspase-8, Bid, caspase-3 and cyto C, p62, Bax/Bcl-2, LC3II/LC3I (Li et al., 2019; Liu et al., 2013; Yin et al., 2020; Zhang, J. et al., 2019). In addition, astragaloside IV could also inhibit neutrophil adhesion related molecules (TNF-a, NF κB, IL-1β, etc.) to play an anti-inflammatory role, and had neuroprotective effect on cerebral I/R injury (Li et al., 2012).

Neuroprotective Role of Terpenoids in Ischemic Brain Injury

Andrographolide

Andrographolide (Figure 5C), a labdane diterpene lactone, is the most active and important constituent isolated from the leaves of Andrographis paniculata (Burm. f.) Nees (Acanthaceae) (Coon and Ernst 2004). Recent studies demonstrated that andrographolide possesses anticancer, anti-inflammatory and hepatoprotective activities, also neuroprotective effect (Negi et al., 2008; Bao et al., 2009). Andrographolide reduced NOX2 and iNOS expression possibly by modulating PI3K/AKT-dependent NF- κB and HIF-1 α activation, which mediated the protective effect in the cerebral I/R mice (Chern et al., 2011). Studies by Yen et al. found andrographolide could play an important role to cerebral endothelial cells (CECs). Furthermore, andrographolide increased Nrf2/HO-1 expression through p38 MAPK regulation, which provided protection against I/R injury (Yen et al., 2013; Yen et al., 2016).

Ginkgolides

Ginkgolide B (Figure 5D) were one of ten kinds of diterpene lactone compounds, which were isolated from Ginkgo biloba leaves. It’s reported that exact of Ginkgo biloba had a broad range of pharmacological effects, such as anti-inflammation, antioxidant, anti-depressant (Chen, C et al., 2017; Hu et al., 2018; Jin, G et al., 2014; Ran et al., 2014; Saini et al., 2014; Wan et al., 2016). Ginkgolides B upregulated the levels of antioxidant proteins through Akt/Nrf2 pathway to protect neurons from oxidative stress injury (Liu, Q. et al., 2019). In addition, ginkgolide B improved neurological function by promoting the proliferation and differentiation of neural stem cells in rats with cerebral I/R injury (Zheng et al., 2018b).

Borneol

Borneol (Figure 5E) is a terpene and bicyclic organic compound, a resin from Cinnamomum camphora (L.) Presl, a traditional Chinese medicine (Yin et al., 2017; Zheng et al., 2018a). As a traditional Chinese medicine, borneol has been used for thousands of years in the treatment of cardiovascular and cerebrovascular diseases. Modern pharmacological studies have shown that borneol had anti-inflammatory, antioxidant stress, anti-apoptosis and other pharmacological effects (Almeida et al., 2013). Borneol protected against cerebral I/R injury through multifunctional cytoprotective pathways, involving in the alleviation of intracellular ROS and iNOS/NO pathway, inhibition of inflammatory factor and depression of caspase-related apoptosis. Additionally, the inhibition of IκBα/NF-κB pathway might play a significant role in the neuroprotection of borneol (Liu et al., 2011). Another study by Dong et al. found that borneol could alleviate cerebral ischemic injury, most likely executed via anti-apoptosis and anti-inflammation effects and maintenance of the BBB stability and TJs to comprehensively improve NVU function (Dong et al., 2018). Additionally, the protection of OGD induced BMECs by tetramethylpyrazine phosphate and borneol combination involved anti-oxidation, apoptosis inhibition, and angiogenesis (Yu et al., 2019).

Neuroprotective Role of Other Compounds in Ischemic Brain Injury

Emodin

Emodin (Figure 5F), 1,3,8-trihydroxy-6-methylanthraquinone, is a naturally occurring anthraquinone derivative and an active component from Polygonum multiflorum Thunb. Rheum palmatum L. etc, which have been used widely in Asia in treatment of multiple diseases (Dong, X. et al., 2016). Emodin has been demonstrated to possess a wide spectrum of pharmacological effects, such as anti-viral, anti-bacterial, anti-allergic, anti-osteoporotic, immunosuppressive, neuroprotective activities (Dong, W. et al., 2016; Leung et al., 2020; Xue et al., 2020). In fact, the neuroprotective effect of Polygonum multiflorum Thunb was first published in 2000 (Gu et al., 2000) and the neuroprotective effect of emodin was published in 2005 when its ability to interfere with the release of glutamate was identified as a method of neuroprotection (Gu et al., 2005). Additionally, emodin might afford a significant neuroprotective effect against glutamate-induced apoptosis through the critical role including Bcl-2/Bax, active caspase-3, p-Akt, p-CREB, and mature BDNF for potent neuroprotective effects of emodin to subsequently enhance behavioral function in cerebral ischemia (Ahn et al., 2016). Another study by Leung et al. found emodin had neuroprotective effects against I/R or OGD injury both in vitro and in vivo, which may be increase Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppress activated-caspase 3 levels through activating ERK1/2 pathway (Leung et al., 2020).

Cordycepin

Cordycepin (Figure 5G) is a derivative of nucleoside adenosine and one of the main active components of Cordyceps sinensis, which is mainly distributed in Europe, North America and Asia (Tuli et al., 2013; Wang, Y. et al., 2015). Cordycepin has a variety of pharmacological activities, such as anti-inflammatory, anti-tumor, antioxidant, anti-inflammatory microorganism, anti-hyperlipidemia, anti-hepatotoxicity, anti-depressant and neuroprotective activities (Ryu et al., 2014; Wang et al., 2015a; Qin et al., 2019). It was shown that cordycepin had an important neuroprotective effect on hypoxic injury by improving the electrophysiological function of neurons (Chen, K. et al., 2017; Liu, Z. B et althogenesis of lesions (Liu, G. et al., 2015). It is confirmed that cordycepin could significantly reduce glutamic acid and aspartic acid, increase SOD activity and down-regulate MDA and MMP-3 to alleviate cerebral ischemic injury or hypoxia injury, suggesting cordycepin could inhibit oxidative damage to exert neuroprotection (Hwang et al., 2008; Cheng et al., 2011). Cordycepin regulated adenosine A1 receptor to improve long-term potentiation formation and neuronal survival through p38/JNK/ERK pathway in BCCAO model and glutamate-induced HT22 neuronal cell death (Dong et al., 2019; Jin, M. L et al., 2014).

Polysaccharides

Polysaccharides are considered to have a wide range of pharmacological effects, such as scavenging free radicals, immune regulation, anti-tumor, anti-oxidation, anti-viral, anti-inflammatory, lowering blood sugar, anti-depression, liver protection, etc (Jin et al., 2012; Kwok et al., 2019; Fang et al., 2020). Panax notoginseng polysaccharide is a kind of heteroglycan derived from the medicinal plant Panax notoginseng, which could increase the ratio of Bcl-2/Bax and reduce caspase-3 in cerebral ischemic brain tissue (Jia et al., 2014). What’s more, it could enhance GSH-Px, SOD activity and IL 10 level, while downregulate MDA, TNF-α, IL-1β level to reduce cerebral infarction size and cell apoptosis to afford neuroprotective effect (Jia et al., 2014; Sy et al., 2015). Angelica polysaccharide is the main active ingredient of Angelica sinensis (Oliv.) Diels, which could also enhance the activities of SOD, GSH and GSH-PX, and reduce MDA, IL-1β, TNF-α and NF-κB in cerebral ischemia-reperfusion injury rats (Yan and Xie, 2018; Dai et al., 2020), in addition, enhance angiopoietin 1, angiopoietin 2, VEGF to promote angiogenesis (Hu et al., 2006; Li, J. et al., 2019). Ginkgo biloba polysaccharides could also play a neuroprotective effect by inhibiting oxidative stress and inflammation to improve neurological deficits in cerebral ischemic animals (Yang et al., 2013). Black fungus polysaccharide is the main active ingredient of Auricularia auricula (L.ex Hook.) Underw in China. Studies have found that fungus polysaccharides could reduce the production of ROS, MDA, and NO in rats with acute or chronic cerebral ischemia injury, enhance the activity of SOD and played an anti-oxidant effect. In addition, it can inhibit neuronal apoptosis and improve cerebral ischemia-reperfusion injury. (Lu et al., 2010; Qian and Min 2010; Ye et al., 2010). Fucose is a marine sulfated polysaccharide extracted from brown algae and some marine invertebrates (Apostolova et al., 2020; Oliveira et al., 2020). Experimental studies have shown that fucose can significantly reduce the levels of pro-inflammatory factors IL-1β, IL-6, MPO and TNF-α in cerebral ischemia model animals, reduce the levels of oxidative stress-related proteins SOD and MDA, and could also regulate cell apoptosis via inhibiting the MAPK pathway to play a neuroprotective effect in cerebral ischemia reperfusion study (Che et al., 2017). Other studies have shown that fucose could also play a neuroprotective effect by inhibiting neuronal apoptosis, glial cell activation and anti-oxidative stress properties (Ahn et al., 2019; Kim et al., 2019). Codonopsis pilosula polysaccharide is a kind of polysaccharide extracted from Codonopsis pilosula. Studies have shown that Codonopsis pilosula polysaccharide could reduce LDH, NO and MDA, increase the content of AChE, SOD and GSH-Px, and inhibit the expression of Beclin-1 to regulate autophagy in the cerebral ischemia-reperfusion injury model (Chen, W. et al., 2015; Ma et al., 2019). It could also inhibit the expression of GFAP protein (Li. S. et al., 2018). Codonopsis pilosula polysaccharides can also reduce the expression of Bax, up-regulate the expression of Bcl-2 and inhibit apoptosis to exert neuroprotective effects through mediating the Nrf2/HO-1 pathway (Ma et al., 2019). Lycium barbarum polysaccharide, astragalus polysaccharide, aloe polysaccharide, yam polysaccharide, etc. also have a certain protective effect on cerebral ischemia (Ge et al., 2017; Liu, H. et al., 2014; Lu et al., 2012; Peng et al., 2019; Wang, Y. et al., 2014; Yan and Zhou, 2012).

Structure-Activity Relationship Between Natural Products and Neuroprotection

Many studies have confirmed the neuroprotective effect of natural products on cerebral ischemia and clarified its preliminary mechanism of action. Different natural products have different mechanisms of anti-cerebral ischemia, which are closely related to the different structures of the compounds. Figure 6 shows the mechanism of cerebral ischemia and the role of different types of natural products in this process. The research on the structure-activity relationship of the biological activity of natural products is mainly related to the basic nucleus of the compound, the number and position of double bonds, and the position of functional groups. They have a great influence on the biological activity of the compound (Aljahdali et al., 2020; Zhou et al., 2021). The flavonoids are based on 2-phenylchromone as the skeleton, which has ortho-dihydroxyl in the structure. The hydroxyl substituent on the basic skeleton is the key functional group for scavenging oxygen free radicals. At the same time, a conjugated system is also the key active site to scavenging oxygen free radicals (Chen et al., 2013). Therefore, flavonoids have unique advantages in scavenging free radicals and inhibiting lipid peroxidation. In addition, flavonoids had anti-inflammatory effects. It is believed that when the C-5 and 7 positions of the A ring of flavonoids have hydroxyl groups at the same time, they will affect the secretion process, mitosis and cell interactions of cells, and then produce strong anti-inflammatory effect (Ying and Chi, 2007).

FIGURE 6

Alkaloids are quite different in structure. For example, berberine has a methylenedioxy ring structure and is the main functional group for anti-bacterial and hypoglycemic activity (Han et al., 2020; Wu and Fang, 2020). This may also be the key structure of its antioxidant effect, which needs further research to confirm. Ligustrazine has a simple structure and a wide range of pharmacological effects. Use it as a lead compound to synthesize various derivatives, which has a variety of biological activities (Wang et al., 2013), and the derivative is more stable than ligustrazine, such as ligustrazine hydrochloride injection has better curative effect in the treatment of ischemic cerebrovascular disease (Li and Zhang, 2020; You et al., 2020). Dauricine is a kind of bisbenzyltetrahydro isoquinoline alkaloid. It has a phenolic hydroxyl group and a conjugated system that is easy to form hydrogen bonds. It may be similar to flavonoids and is considered to be a key structure for antioxidant effects. Studies have shown that phenolic acids have a strong antioxidant effect, which is due to the existence of carboxyl, carbonyl and other structures (Bialecka-Florjanczyk et al., 2018; Wang, Y. et al., 2019). Glycoside components are compounds formed by non-sugar substances and sugars or sugar derivatives, which have the active characteristics both sugar substances and non-sugar substances. For example, flavonoid glycosides and flavonoid aglycones have anti-oxidative biological activity (Xue et al., 2001; Gao et al., 2008; Shao et al., 2013). In addition, most studies believe that glycoside compounds mainly exerted neuroprotective effects by improving the body’s immunity (Brito-Arias, 2007). Iridoid glycosides are a special glycoside chemical. The core of iridoid glycosides is hemiacetal-enether cyclopentane, which is an important structural basis. Anti-oxidant stress is the manifestation of its biological activity (Wang et al., 2019a). Some studies also believe that the double bond on the cyclopentane in iridoid glycosides, the C-11 substituent, and the way of forming the bond after ring opening also have important effects on the anti-inflammatory activity (Mao et al., 2019). For example, loganin, morroniside, and sorgenin all contain several electron-donating groups-hydroxyl groups. The hydroxyl groups release hydrogen atoms and combine with free radicals to block the chain reaction mediated by reactive oxygen species and reduce the body's oxidative stress. Stimulus levels, which weaken the phosphorylation of inflammatory signal pathway related factors, thereby inhibiting the inflammatory response, improving insulin resistance and liver damage (Li et al., 2014). Studies believe that tetracyclic triterpene saponins are the leading compounds for the treatment of neurological diseases, and can show strong neurological activity after proper structural modification and modification. Among them, C-7 and C-9 of lanolin triterpenoids The diene bond connected at the position may be the key group for nerve extension promoting activity (Liu, Y. et al., 2015). The research on the structure-activity relationship of tetracyclic triterpenes is mainly focused on the study of the binding sites related to the action of NMDAR antagonists, indicating that the structural modification and optimization of its aglycon and side chain sugar groups can obtain a new type of neuroactive monomer with high efficiency and low toxicity drug. Tetracyclic triterpene dammarane compounds as NMDAR antagonists will be an effective way to treat neurological diseases (Lee et al., 2006; Ryoo et al., 2020). Studies believe that ginkgolides can improve cerebral blood circulation and energy metabolism through specific inhibition of PAFR, and show a good market prospect in the prevention and treatment of cardiovascular and cerebrovascular diseases. The main differences in their effects are: the number and positions of hydroxyl groups contained in ginkgolides are different, PAF and ginkgolide ligands can be combined, and the introduction of benzyl derivatives at position C-10 is more beneficial for antagonistic activity; In addition, the presence of C, D ring and tert-butyl group also plays an important role in activity (Hui et al., 2013). Some scholars have studied the structure-activity relationship of andrographolide and found that the position of the double bond determines the anti-inflammatory effect of andrographolide and its derivatives, and the anti-inflammatory effects of compounds with double bonds in the ring are stronger than those with double bonds outside the ring (Tian et al., 2015). As a natural component of polycarbonyl and polyhydroxyl groups, emodin can coordinate and chelate with the zinc ions of type IV collagenase to inactivate type IV collagenase, thereby preventing type IV collagenase (MMP-2, MMP- 9) degradation of basement membrane and extracellular matrix of normal tissue cells, play a role in anti-invasion and anti-metastasis (Wang, 2006). As a nucleoside antibiotic, cordycepin has a good application prospect in regulating immunity and scavenging free radicals (Lee et al., 2020).

In summary, the activity of natural products has an important relationship with the structure of the substance itself. The active functional groups of natural products are the key to their functions. Moreover, the bioavailability of many natural products is very low, which limits their use, the structural modifications, changes in dosage forms or improvements in pharmacokinetic parameters can improve their bioavailability. Because the pathogenesis of cerebral ischemia is complex, and cascade reactions occur cross-over. The anti-cerebral ischemia effects of individual natural products are often weak. Therefore, a full understanding of the mechanism of the cerebral ischemia cascade can provide the possibility for the development of specific mechanisms or targeted compounds, and the combined use of different natural products to play a multi-target neuroprotective effect may be a promising therapy. However, it is very important to combine animal models with clinical practice (Ma et al., 2020). Choose appropriate experimental models according to actual conditions to provide a solid foundation for the clinical transformation of natural products.

Conclusions and Outlook

Stroke is one of the most common causes of disability and death worldwide, seriously endangers human health and brings heavy burden to society and family. Till now, there is no effective therapy which is available for the treatment of cerebral ischemia. Recombinant plasminogen activator is the only medicament utilized clinically and its use is restricted due to short therapy time windows and the risk of bleeding. Natural products from plants have been used to treat the cure of numerous disorders through the previous practice of therapeutics (Fan et al., 2020; Li Y. et al., 2017; Savopoulos et al., 2009; Chen, S. et al., 2020). Nowadays, many attempts have been made to explore the neuroprotective effects of natural products with the advance of technology. Hence, this review summarizes recent studies on the biological activities and mechanisms of recognized compounds for cerebral ischemia injury prevention or/and treatment (Table 1). Through the literatures, three aspects should be noted with special focus. First, multiple types of natural products, including flavonoids, alkaloids, saponin, terpene, iridoid glycosides, polyphenols and others, are proven to have a definite effect on cerebral ischemia injury. In fact, the clinical efficacy still requires further confirmation and to study. Second, animal models and cell experiments were used to investigate the neuroprotective effect of natural product on cerebral ischemia injury. Animal models including MCAO, BCCAO and other occlusion methods were used to induce cerebral ischemia injury. Due to the diversity of brain cells, a variety of cell lines are used in the study of neurological diseases, for example, HT22, BV2, BMEC and others. Due to the limitations of cell models, the neuroprotective effects of many natural products in cell models still need to be verified by in vivo experiments. Third, most of the compounds show neuroprotective effects through multiple targets or signaling pathways. These natural products work by comprehensive regulation, inhibiting excitotoxicity, influencing free radicals, anti-apoptosis, impairing blood-brain barrier disruption, anti-inflammation, influencing astrocytic activation and proliferation. The mechanism by which natural products has multiple targets and diverse signaling pathways. Therefore, natural products would be very valuable when seeking novel therapeutic agents for stroke.

In conclusion, this review summarizes that the facts are comprehensive and deeply informative about the neuroprotective activities of natural products in vitro and in vivo experiment. For prophylactic and therapeutic management of stroke, they are promising candidates. Therefore, this review would provide as a reference for current advances in the study on natural products for neuroprotection.

References

• 1

  AhnJ. H.ShinM. C.KimD. W.KimH.SongM.LeeT. K.et al (2019). Antioxidant properties of fucoidan alleviate acceleration and exacerbation of hippocampal neuronal death following transient global cerebral ischemia in high-fat diet-induced obese gerbils. Int. J. Mol. Sci.20, 114. 10.3390/ijms20030554

  • CrossRef
  • Google Scholar

• 2

  AhnS. M.KimH. N.KimY. R.ChoiY. W.KimC. M.ShinH. K.et al (2016). Emodin from polygonum multiflorum ameliorates oxidative toxicity in HT22 cells and deficits in photothrombotic ischemia. J. Ethnopharmacology188, 13–20. 10.1016/j.jep.2016.04.058

  • CrossRef
  • Google Scholar

• 3

  AlfeiS.TurriniF.CatenaS.ZuninP.GrilliM.PittalugaA. M.et al (2019). Ellagic acid a multi-target bioactive compound for drug discovery in CNS? A narrative review. Eur. J. Med. Chem.183, 111724. 10.1016/j.ejmech.2019.111724

  • CrossRef
  • Google Scholar

• 4

  AljahdaliA. Z.FosterK. A.O'DohertyG. A. (2020). Synthesis and biological study of the phomopsolide and phomopsolidone natural products. Chem. Commun.56, 12885–12896. 10.1039/d0cc04069j

  • CrossRef
  • Google Scholar

• 5

  AlmeidaJ. R.SouzaG. R.SilvaJ. C.SaraivaS. R.JúniorR. G.QuintansJde. S.et al (2013). Borneol, a bicyclic monoterpene alcohol, reduces nociceptive behavior and inflammatory response in mice. Sci. World J.2013, 808460. 10.1155/2013/808460

  • CrossRef
  • Google Scholar

• 6

  AnJ.ChenB.KangX.ZhangR.GuoY.ZhaoJ.et al (2020). Neuroprotective effects of natural compounds on LPS-induced inflammatory responses in microglia. Am. J. Transl. Res.12, 2353–2378.

  • Google Scholar

• 7

  ApostolovaE.LukovaP.BaldzhievaA.KatsarovP.NikolovaM.IlievI.et al (2020). Immunomodulatory and anti-inflammatory effects of fucoidan: a review. Polymers (Basel)12. 2338. 10.3390/polym12102338

  • CrossRef
  • Google Scholar

• 8

  AsemiZ.BehnamM.PourattarM. A.MirzaeiH.RazaviZ. S.TamtajiO. R. (2020). Therapeutic potential of berberine in the treatment of glioma: insights into its regulatory mechanisms. Cell Mol. Neurobiol.11, 23. 10.1007/s10571-020-00903-5

  • CrossRef
  • Google Scholar

• 9

  AyoobiF.ShamsizadehA.FatemiI.VakilianA.AllahtavakoliM.HassanshahiG.et al (2017). Bio-effectiveness of the main flavonoids of Achillea millefolium in the pathophysiology of neurodegenerative disorders- a review. Iran J. Basic Med. Sci.20, 604–612. 10.22038/IJBMS.2017.8827

  • CrossRef
  • Google Scholar

• 10

  BabaeiF.MoafizadA.DarvishvandZ.MirzababaeiM.HosseinzadehH.Nassiri-AslM. (2020). Review of the effects of vitexin in oxidative stress-related diseases. Food Sci. Nutr.8, 2569–2580. 10.1002/fsn3.1567

  • CrossRef
  • Google Scholar

• 11

  BagliE.GoussiaA.MoschosM. M.AgnantisN.KitsosG. (2016). Natural compounds and neuroprotection: mechanisms of action and novel delivery systems. In Vivo30, 535–547. 10.1002/9780470134931.ch3

  • CrossRef
  • Google Scholar

• 12

  BaoC.WangY.MinH.ZhangM.DuX.HanR.et al (2015). Combination of ginsenoside Rg1 and bone marrow mesenchymal stem cell transplantation in the treatment of cerebral ischemia reperfusion injury in rats. Cell Physiol. Biochem.37, 901–910. 10.1159/000430217

  • CrossRef
  • Google Scholar

• 13

  BaoZ.GuanS.ChengC.WuS.WongS. H.KemenyD. M.et al (2009). A novel antiinflammatory role for andrographolide in asthma via inhibition of the nuclear factor-κb pathway. Am. J. Respir. Crit. Care Med.179, 657–665. 10.1164/rccm.200809-1516oc

  • CrossRef
  • Google Scholar

• 14

  Baradaran RahimiV.GhadiriM.RamezaniM.AskariV. R. (2020). Antiinflammatory and anti-cancer activities of pomegranate and its constituent, ellagic acid: evidence from cellular, animal, and clinical studies. Phytotherapy Res.34, 685–720. 10.1002/ptr.6565

  • CrossRef
  • Google Scholar

• 15

  BenjaminE. J.ViraniS. S.CallawayC. W.ChamberlainA. M.ChangA. R.ChengS.et al (2018). Heart disease and stroke statistics-2018 update: a report from the American heart association. Circulation137, e67–e492. 10.1161/CIR.0000000000000558

  • CrossRef
  • Google Scholar

• 16

  Bialecka-FlorjanczykE.FabiszewskaA.ZieniukB. (2018). Phenolic acids derivatives - biotechnological methods of synthesis and bioactivity. Curr. Pharm. Biotechnol.19, 1098–1113. 10.2174/1389201020666181217142051

  • CrossRef
  • Google Scholar

• 17

  Brito-AriasM. (2007). Synthesis and characterization of glycosides. Berlin, Germany: Springer Science+Business Media.

  • Google Scholar

• 18

  CaiD.QiJ.YangY.ZhangW.ZhouF.JiaX.et al (2019). Design, synthesis and biological evaluation of diosgenin-amino acid derivatives with dual functions of neuroprotection and angiogenesis. Molecules24, 113. 10.3390/molecules24224025

  • CrossRef
  • Google Scholar

• 19

  Candelario-JalilE.de OliveiraA.GräfS.BhatiaH. S.HüllM.MuñozE.et al (2007). Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide-activated primary rat microglia. J. Neuroinflammation4, 25. 10.1186/1742-2094-4-25

  • CrossRef
  • Google Scholar

• 20

  CaoW.LiuW.WuT.ZhongD.LiuG. (2008). Dengzhanhua preparations for acute cerebral infarction. Cochrane Database Syst. Rev.11, CD005568. 10.1002/14651858.CD005568.pub2

  • CrossRef
  • Google Scholar

• 21

  CaoY.LiuJ. W.YuY. J.ZhengP. Y.ZhangX. D.LiT.et al (2007). Synergistic protective effect of picroside II and NGF on PC12 cells against oxidative stress induced by H2O2. Pharmacol. Rep.59, 573–579. 10.7324/japs.2019.90403

  • CrossRef
  • Google Scholar

• 22

  CaoY.MaoX.SunC.ZhengP.GaoJ.WangX.et al (2011). Baicalin attenuates global cerebral ischemia/reperfusion injury in gerbils via anti-oxidative and anti-apoptotic pathways. Brain Res. Bull.85, 396–402. 10.1016/j.brainresbull.2011.05.002

  • CrossRef
  • Google Scholar

• 23

  CeciC.LacalP. M.TentoriL.De MartinoM. G.MianoR.GrazianiG. (2018). Experimental evidence of the antitumor, antimetastatic and antiangiogenic activity of ellagic acid. Nutrients10, 1756. 10.3390/nu10111756

  • CrossRef
  • Google Scholar

• 24

  ChaiY.-S.HuJ.LeiF.WangY.-G.YuanZ.-Y.LuX.et al (2013). Effect of berberine on cell cycle arrest and cell survival during cerebral ischemia and reperfusion and correlations with p53/cyclin D1 and PI3K/Akt. Eur. J. Pharmacol.708, 44–55. 10.1016/j.ejphar.2013.02.041

  • CrossRef
  • Google Scholar

• 25

  ChangC.-K.LinM.-T. (2001). DL-Tetrahydropalmatine may act through inhibition of amygdaloid release of dopamine to inhibit an epileptic attack in rats. Neurosci. Lett.307, 163–166. 10.1016/s0304-3940(01)01962-0

  • CrossRef
  • Google Scholar

• 26

  ChangC.-Y.KaoT.-K.ChenW.-Y.OuY.-C.LiJ.-R.LiaoS.-L.et al (2015). Tetramethylpyrazine inhibits neutrophil activation following permanent cerebral ischemia in rats. Biochem. Biophys. Res. Commun.463, 421–427. 10.1016/j.bbrc.2015.05.088

  • CrossRef
  • Google Scholar

• 27

  ChangY.HsiaoG.ChenS.-h.ChenY.-c.LinJ.-h.LinK.-h.et al (2007). Tetramethylpyrazine suppresses HIF-1?, TNF-?, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats. Acta Pharmacologica Sinica28, 327–333. 10.1111/j.1745-7254.2007.00514.x

  • CrossRef
  • Google Scholar

• 28

  CheD. N.ChoB. O.KimJ. S.ShinJ. Y.KangH. J.JangS. I. (2020). Luteolin and apigenin attenuate LPS-induced astrocyte activation and cytokine production by targeting MAPK, STAT3, and NF-kappaB signaling pathways. Inflammation43, 1716–1728. 10.1007/s10753-020-01245-6

  • CrossRef
  • Google Scholar

• 29

  CheN.MaY.XinY. (2017). Protective role of fucoidan in cerebral ischemia-reperfusion injury through inhibition of MAPK signaling pathway. Biomolecules Ther.25, 272–278. 10.4062/biomolther.2016.098

  • CrossRef
  • Google Scholar

• 30

  ChenC.LiuX.-P.JiangW.ZengB.MengW.HuangL.-P.et al (2017). Anti-effects of cordycepin to hypoxia-induced membrane depolarization on hippocampal CA1 pyramidal neuron. Eur. J. Pharmacol.796, 1–6. 10.1016/j.ejphar.2016.12.021

  • CrossRef
  • Google Scholar

• 31

  ChenH.-L.JiaW.-J.LiH.-E.HanH.LiF.ZhangX.-L. -N.et al (2020). Scutellarin exerts anti-inflammatory effects in activated microglia/brain macrophage in cerebral ischemia and in activated BV-2 microglia through regulation of MAPKs signaling pathway. Neuromol Med.22, 264–277. 10.1007/s12017-019-08582-2

  • CrossRef
  • Google Scholar

• 32

  ChenJ.LinC.YongW.YeY.HuangZ. (2015). Calycosin and genistein induce apoptosis by inactivation of HOTAIR/p-Akt signaling pathway in human breast cancer MCF-7 cells. Cel Physiol. Biochem.35, 722–728. 10.1159/000369732

  • CrossRef
  • Google Scholar

• 33

  ChenK.SunW.JiangY.ChenB.ZhaoY.SunJ.et al (2017). Ginkgolide B suppresses TLR4-mediated inflammatory response by inhibiting the phosphorylation of JAK2/STAT3 and p38 MAPK in high glucose-treated HUVECs. Oxid Med. Cel Longev2017, 9371602. 10.1155/2017/9371602

  • CrossRef
  • Google Scholar

• 34

  ChenS.YinZ.-J.JiangC.MaZ.-Q.FuQ.QuR.et al (2014). Asiaticoside attenuates memory impairment induced by transient cerebral ischemia-reperfusion in mice through anti-inflammatory mechanism. Pharmacol. Biochem. Behav.122, 7–15. 10.1016/j.pbb.2014.03.004

  • CrossRef
  • Google Scholar

• 35

  ChenW.TangY.LiuL.JiaoY. (2015). Influence of Codonopsis pilosula polysaccharide on brain Tissues,Oxygen free radicals and beclin-1 level of rats with ischemia-reperfusion. Mil. Med. J. South China29, 886–888+923. 10.1016/j.carbpol.2012.07.062

  • CrossRef
  • Google Scholar

• 36

  ChenY.-J.LiuY.-L.ZhongQ.YuY.-F.SuH.-L.ToqueH. A.et al (2012). Tetrahydropalmatine protects against methamphetamine-induced spatial learning and memory impairment in mice. Neurosci. Bull.28, 222–232. 10.1007/s12264-012-1236-4

  • CrossRef
  • Google Scholar

• 37

  ChenY.LongX.PanS.AnX.ChenS. L. (2013). Advances in pharmacodynamic mechanisms and SAR studies of flavonoids. Chin. J. Exp. Trad. Med. Formulae19, 337–344. 10.1201/9781420041781.ch29

  • CrossRef
  • Google Scholar

• 38

  ChengY.ShenL.-h.ZhangJ.-t. (2005). Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacologica Sinica26, 143–149. 10.1111/j.1745-7254.2005.00034.x

  • CrossRef
  • Google Scholar

• 39

  ChengZ.HeW.ZhouX.LvQ.XuX.YangS.et al (2011). Cordycepin protects against cerebral ischemia/reperfusion injury in vivo and in vitro. Eur. J. Pharmacol.664, 20–28. 10.1016/j.ejphar.2011.04.052

  • CrossRef
  • Google Scholar

• 40

  ChenS.ChenH.DuQ.ShenJ. (2020). Targeting myeloperoxidase (MPO) mediated oxidative stress and inflammation for reducing brain ischemia injury: potential application of natural compounds. Front. Physiol.11 (undefined), 433. 10.3389/fphys.2020.00433

  • CrossRef
  • Google Scholar

• 41

  ChernC.-M.LiouK.-T.WangY.-H.LiaoJ.-F.YenJ.-C.ShenY.-C. (2011). Andrographolide inhibits PI3K/AKT-dependent NOX2 and iNOS expression protecting mice against hypoxia/ischemia-induced oxidative brain injury. Planta Med.77, 1669–1679. 10.1055/s-0030-1271019

  • CrossRef
  • Google Scholar

• 42

  ChuH.JinG.FriedmanE.ZhenX. (2008). Recent development in studies of tetrahydroprotoberberines: mechanism in antinociception and drug addiction. Cel Mol Neurobiol28, 491–499. 10.1007/s10571-007-9179-4

  • CrossRef
  • Google Scholar

• 43

  ChuS.-f.ZhangZ.ZhouX.HeW.-b.ChenC.LuoP.et al (2019). Ginsenoside Rg1 protects against ischemic/reperfusion-induced neuronal injury through miR-144/Nrf2/ARE pathway. Acta Pharmacol. Sin40, 13–25. 10.1038/s41401-018-0154-z

  • CrossRef
  • Google Scholar

• 44

  ChuangJ.-H.TungL. C.LinY. (2015). Neural differentiation from embryonic stem cellsin vitro: an overview of the signaling pathways. Wjsc7, 437–447. 10.4252/wjsc.v7.i2.437

  • CrossRef
  • Google Scholar

• 45

  CoonJ. T.ErnstE. (2004). Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med.70, 293–298. 10.1055/s-2004-818938

  • CrossRef
  • Google Scholar

• 46

  CostaI. M.Vieira LimaF.FernandesL.NorraraB.NetaF.AlvesR.et al (2018). Astragaloside IV supplementation promotes A neuroprotective effect in experimental models of neurological disorders: a systematic review. Curr. Neuropharmacol.17, 648–665. 10.2174/1570159X16666180911123341

  • CrossRef
  • Google Scholar

• 47

  CostaL. G.GarrickJ. M.RoquèP. J.PellacaniC. (2016). Mechanisms of neuroprotection by quercetin: counteracting oxidative stress and more. Oxid Med. Cel Longev11, 2986796. 10.1155/2016/2986796

  • CrossRef
  • Google Scholar

• 48

  CuiY.-h.ZhangX.-q.WangN.-d.ZhengM.-d.YanJ. (2019). Vitexin protects against ischemia/reperfusion-induced brain endothelial permeability. Eur. J. Pharmacol.853, 210–219. 10.1016/j.ejphar.2019.03.015

  • CrossRef
  • Google Scholar

• 49

  DaiY.ZhangH.ZhangJ.YanM. (2018). Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NF-κB pathway. Chemico-Biol. Interact.284, 32–40. 10.1016/j.cbi.2018.02.017

  • CrossRef
  • Google Scholar

• 50

  DaiZ.ZhuY.WangZ. (2020). Effects of Angelica polysaccharides on the expression of IL-1β, TNF-α, NF-κB in rats with cerebral ischemia reperfusion injury. Chin. Trad. Patent Med.42, 2176–2178. 10.1016/b978-0-12-374530-9.00013-9

  • CrossRef
  • Google Scholar

• 51

  de OliveiraM. R. (2016). The effects of ellagic acid upon brain cells: a mechanistic view and future directions. Neurochem. Res.41, 1219–1228. 10.1007/s11064-016-1853-9

  • CrossRef
  • Google Scholar

• 52

  Della-MorteD.DaveK. R.DeFazioR. A.BaoY. C.RavalA. P.Perez-PinzonM. A. (2009). Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience159, 993–1002. 10.1016/j.neuroscience.2009.01.017

  • CrossRef
  • Google Scholar

• 53

  DengY.XiongD.YinC.LiuB.ShiJ.GongQ. (2016). Icariside II protects against cerebral ischemia-reperfusion injury in rats via nuclear factor-κB inhibition and peroxisome proliferator-activated receptor up-regulation. Neurochem. Int.96, 56–61. 10.1016/j.neuint.2016.02.015

  • CrossRef
  • Google Scholar

• 54

  DhanasekaranM.HolcombL. A.HittA. R.TharakanB.PorterJ. W.YoungK. A.et al (2009). Centella asiatica extract selectively decreases amyloid β levels in hippocampus of Alzheimer’s disease animal model. Phytother. Res.23, 14–19. 10.1002/ptr.2405

  • CrossRef
  • Google Scholar

• 55

  DingY.DuJ.CuiF.ChenL.LiK. (2019). The protective effect of ligustrazine on rats with cerebral ischemia-reperfusion injury via activating PI3K/Akt pathway. Hum. Exp. Toxicol.38, 1168–1177. 10.1177/0960327119851260

  • CrossRef
  • Google Scholar

• 56

  DongT.ChenN.MaX.WangJ.WenJ.XieQ.et al (2018). The protective roles of L- borneolum, D- borneolum and synthetic borneol in cerebral ischaemia via modulation of the neurovascular unit. Biomed. Pharmacother.102, 874–883. 10.1016/j.biopha.2018.03.087

  • CrossRef
  • Google Scholar

• 57

  DongW.XianY.YuanW.HuifengZ.TaoW.ZhiqiangL.et al (2016). Catalpol stimulates VEGF production via the JAK2/STAT3 pathway to improve angiogenesis in rats' stroke model. J. Ethnopharmacology191, 169–179. 10.1016/j.jep.2016.06.030

  • CrossRef
  • Google Scholar

• 58

  DongX.FuJ.YinX.CaoS.LiX.LinL.et al (2016). Emodin: a review of its pharmacology, toxicity and pharmacokinetics. Phytother. Res.30, 1207–1218. 10.1002/ptr.5631

  • CrossRef
  • Google Scholar

• 59

  DongZ.-S. -W.CaoZ.-P.ShangY.-J.LiuQ.-Y.WuB.-Y.LiuW.-X.et al (2019). Neuroprotection of cordycepin in NMDA-induced excitotoxicity by modulating adenosine A1 receptors. Eur. J. Pharmacol.853, 325–335. 10.1016/j.ejphar.2019.04.015

  • CrossRef
  • Google Scholar

• 60

  DonnanG. A.FisherM.MacleodM.DavisS. M. (2008). Stroke. The Lancet371, 1612–1623. 10.1016/s0140-6736(08)60694-7

  • CrossRef
  • Google Scholar

• 61

  DuanJ.KangK.HuangC.-r.ChenL.-g.WanW.-f.PengT.-m.et al (2020). Protective effect of peimine on cerebral ischemia-reperfusion injury in rats. Chin. J. New Drugs Clin. Rem39, 240–246. 10.3724/sp.j.1008.2010.00238

  • CrossRef
  • Google Scholar

• 62

  EghbaliferizS.FarhadiF.BarretoG. E.MajeedM.SahebkarA. (2020). Effects of curcumin on neurological diseases: focus on astrocytes. Pharmacol. Rep.72, 769–782. 10.1007/s43440-020-00112-3

  • CrossRef
  • Google Scholar

• 63

  FanD.LiuL.WuZ.CaoM. (2019). Combating neurodegenerative diseases with the plant alkaloid berberine: molecular mechanisms and therapeutic potential. Cn17, 563–579. 10.2174/1570159x16666180419141613

  • CrossRef
  • Google Scholar

• 64

  FanQ.ZhouJ.WangY.XiT.MaH.WangZ.et al (2020). Chip-based serum proteomics approach to reveal the potential protein markers in the sub-acute stroke patients receiving the treatment of Ginkgo Diterpene Lactone Meglumine Injection. J. Ethnopharmacol.260, 112964. 10.1016/j.jep.2020.112964

  • CrossRef
  • Google Scholar

• 65

  FangJ.WangZ.WangP.WangM. (2020). Extraction, structure and bioactivities of the polysaccharides from Ginkgo biloba: a review. Int. J. Biol. Macromol.162, 1897–1905. 10.1016/j.ijbiomac.2020.08.141

  • CrossRef
  • Google Scholar

• 66

  FangM.YuanY.LuJ.LiH. E.ZhaoM.LingE.-A.et al (2016). Scutellarin promotes microglia-mediated astrogliosis coupled with improved behavioral function in cerebral ischemia. Neurochem. Int.97, 154–171. 10.1016/j.neuint.2016.04.007

  • CrossRef
  • Google Scholar

• 67

  FangM.YuanY.RangarajanP.LuJ.WuY.WangH.et al (2015). Scutellarin regulates microglia-mediated TNC1 astrocytic reaction and astrogliosis in cerebral ischemia in the adult rats. BMC Neurosci.16, 84. 10.1186/s12868-015-0219-6

  • CrossRef
  • Google Scholar

• 68

  FeiF.SuN.LiX.FeiZ. (2020). Neuroprotection mediated by natural products and their chemical derivatives. Neural Regen. Res.15, 2008–2015. 10.4103/1673-5374.282240

  • CrossRef
  • Google Scholar

• 69

  ForouzanfarF.ReadM. I.BarretoG. E.SahebkarA. (2020). Neuroprotective effects of curcumin through autophagy modulation. IUBMB Life72, 652–664. 10.1002/iub.2209

  • CrossRef
  • Google Scholar

• 70

  FuC.ZhangX.LuY.WangF.XuZ.LiuS.et al (2020). Geniposide inhibits NLRP3 inflammasome activation via autophagy in BV-2 microglial cells exposed to oxygen-glucose deprivation/reoxygenation. Int. Immunopharmacol.84, 106547. 10.1016/j.intimp.2020.106547

  • CrossRef
  • Google Scholar

• 71

  Group T. N. I. O. N. D. A. S. r.-P. S. S. ( 1995). Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med., 333, 1581–1587.10.1056/NEJM199512143332401

  • CrossRef
  • Google Scholar

• 72

  GaoJ.ChenG.HeH.LiuC.XiongX.LiJ.et al (2017). Therapeutic effects of breviscapine in cardiovascular diseases: a review. Front. Pharmacol.8, 289. 10.3389/fphar.2017.00289

  • CrossRef
  • Google Scholar

• 73

  GaoR.ZhaoX.ZhengY.LiuC. (2008). Study on immune function of soy isoflavone glycoside and aglycon. Cereals Oils, 14, 43–44. 10.1007/springerreference_135032

  • CrossRef
  • Google Scholar

• 74

  GaoY.FuR.WangJ.YangX.WenL.FengJ. (2018). Resveratrol mitigates the oxidative stress mediated by hypoxic-ischemic brain injury in neonatal rats via Nrf2/HO-1 pathway. Pharm. Biol.56, 440–449. 10.1080/13880209.2018.1502326

  • CrossRef
  • Google Scholar

• 75

  GeJ. B.LuH. J.SongX. J.LiM.ChenD. D.WuF. (2017). [Protective effects of LBP on cerebral ischemia reperfusion injury in mice and mechanism of inhibiting NF-κB, TNF-α, IL-6 and IL-1β]. Zhongguo Zhong Yao Za Zhi42, 326–331. 10.19540/j.cnki.cjcmm.20161222.016

  • CrossRef
  • Google Scholar

• 76

  GuJ.-W.HasuoH.TakeyaM.AkasuT. (2005). Effects of emodin on synaptic transmission in rat hippocampal CA1 pyramidal neurons in vitro. Neuropharmacology49, 103–111. 10.1016/j.neuropharm.2005.02.003

  • CrossRef
  • Google Scholar

• 77

  GuJ.ZhangX.FeiZ.WenA.QinS.YiS. (2000). [Rhubarb Extracts in Treating Complications of Severe Cerebral Injury]. Chin. Med. J.113 (6), 529–531.

  • Google Scholar

• 78

  GuoC.TongL.XiM.YangH.DongH.WenA. (2012). Neuroprotective effect of calycosin on cerebral ischemia and reperfusion injury in rats. J. Ethnopharmacology144, 768–774. 10.1016/j.jep.2012.09.056

  • CrossRef
  • Google Scholar

• 79

  GuoS.LiJ.XiaoS. (2019). Effects of peimine a on inflammatory response and autophagy in mice with cerebral ischemia-reperfusion injury. Chin. J. Gerontol.39, 5347–5350. 10.5353/th_b5328058

  • CrossRef
  • Google Scholar

• 80

  GuoY.XuX.LiQ.LiZ.DuF. (2010). Anti-inflammation effects of picroside 2 in cerebral ischemic injury rats. Behav. Brain Functions6, 43. 10.1186/1744-9081-6-43

  • CrossRef
  • Google Scholar

• 81

  GuoZ.-H.LiF.WangW.-Z. (2009). The mechanisms of brain ischemic insult and potential protective interventions. Neurosci. Bull.25 (3), 139–152. 10.1007/s12264-009-0104-3

  • CrossRef
  • Google Scholar

• 82

  HackeW.KasteM.BluhmkiE.BrozmanM.DávalosA.GuidettiD.et al (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med.359, 1317–1329. 10.1056/nejmoa0804656

  • CrossRef
  • Google Scholar

• 83

  HanY.LiuH.LiK.WangT.GeX. (2020). Research progress on antifungal activity of berberine and synthesis of its molecular probes. Chem. World61, 83–91. 10.31830/2348-7542.2019.107

  • CrossRef
  • Google Scholar

• 84

  HanY.ZhangW.TangY.BaiW.YangF.XieL.et al (2012). l-Tetrahydropalmatine, an active component of Corydalis yanhusuo W.T. Wang, protects against myocardial ischaemia-reperfusion injury in rats. PLoS One7, e38627. 10.1371/journal.pone.0038627

  • CrossRef
  • Google Scholar

• 85

  HeL. J.LiangM.HouF. F.GuoZ. J.XieD.ZhangX. (2009). Ethanol extraction of Picrorhiza scrophulariiflora prevents renal injury in experimental diabetes via anti-inflammation action. J. Endocrinol.200, 347–355. 10.1677/joe-08-0481

  • CrossRef
  • Google Scholar

• 86

  HeQ.LiZ.WangY.HouY.LiL.ZhaoJ. (2017). Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. Int. Immunopharmacol.50, 208–215. 10.1016/j.intimp.2017.06.029

  • CrossRef
  • Google Scholar

• 87

  HermannD. M.Popa-WagnerA.KleinschnitzC.DoeppnerT. R. (2019). Animal models of ischemic stroke and their impact on drug discovery. Expert Opin. Drug Discov.14, 315–326. 10.1080/17460441.2019.1573984

  • CrossRef
  • Google Scholar

• 88

  HouY.WangJ.FengJ. (2019). The neuroprotective effects of curcumin are associated with the regulation of the reciprocal function between autophagy and HIF-1α in cerebral ischemia-reperfusion injury. Dddt13, 1135–1144. 10.2147/dddt.s194182

  • CrossRef
  • Google Scholar

• 89

  HsuC.-C.KuoT.-W.LiuW.-P.ChangC.-P.LinH.-J. (2020). Calycosin preserves BDNF/TrkB signaling and reduces post-stroke neurological injury after cerebral ischemia by reducing accumulation of hypertrophic and TNF-α-containing microglia in rats. J. Neuroimmune Pharmacol.15, 326–339. 10.1007/s11481-019-09903-9

  • CrossRef
  • Google Scholar

• 90

  HuJ.ChaiY.WangY.KheirM. M.LiH.YuanZ.et al (2012). PI3K p55γ promoter activity enhancement is involved in the anti-apoptotic effect of berberine against cerebral ischemia-reperfusion. Eur. J. Pharmacol.674, 132–142. 10.1016/j.ejphar.2011.11.014

  • CrossRef
  • Google Scholar

• 91

  HuQ.ShenP.BaiS.DongM.LiangZ.ChenZ.et al (2018). Metabolite-related antidepressant action of diterpene ginkgolides in the prefrontal cortex. Ndt14, 999–1011. 10.2147/ndt.s161351

  • CrossRef
  • Google Scholar

• 92

  HuX.-m.ZhouM.-m.HuX.-m.ZengF.-d. (2005). Neuroprotective effects of scutellarin on rat neuronal damage induced by cerebral ischemia/reperfusion. Acta Pharmacol. Sinica26, 1454–1459. 10.1111/j.1745-7254.2005.00239.x

  • CrossRef
  • Google Scholar

• 93

  HuX.LiaoW.YangW.JiangC.ZhouQ.ChenM.et al (2006). Effect of Angelica polysaccharide on the expression of angiopoietin after the ischemic brain injury in rats. Chin. J. Rehabil. Med.11, 204–206+230. 10.26226/morressier.57d034cfd462b80292383365

  • CrossRef
  • Google Scholar

• 94

  HuangB.ChenP.HuangL.LiS.ZhuR.ShengT.et al (2017). Geniposide attenuates post-ischaemic neurovascular damage via GluN2A/AKT/ERK-dependent mechanism. Cel Physiol. Biochem.43, 705–716. 10.1159/000480657

  • CrossRef
  • Google Scholar

• 95

  HuangL.ChenC.ZhangX.LiX.ChenZ.YangC.et al (2018). Neuroprotective effect of curcumin against cerebral ischemia-reperfusion via mediating autophagy and inflammation. J. Mol. Neurosci.64, 129–139. 10.1007/s12031-017-1006-x

  • CrossRef
  • Google Scholar

• 96

  HuiA.WuZ.YuanY.ZhouA.PanJ. (2013). Progress in synthesis and antagonistic activities towards PAFR and GlyR of ginkgolide derivatives and analogs. Chin. J. Org. Chem.33, 1263–1272. 10.6023/cjoc201209028

  • CrossRef
  • Google Scholar

• 97

  HwangI.LimS.YooK.-Y.LeeY.KimH.KangI.-J.et al (2008). A Phytochemically characterized extract of Cordyceps militaris and cordycepin protect hippocampal neurons from ischemic injury in gerbils. Planta Med.74, 114–119. 10.1055/s-2008-1034277

  • CrossRef
  • Google Scholar

• 98

  IsmailogluU. B.SaracogluI.HarputU. S.Sahin-ErdemliI. (2002). Effects of phenylpropanoid and iridoid glycosides on free radical-induced impairment of endothelium-dependent relaxation in rat aortic rings. J. Ethnopharmacol.79, 193–197. 10.1016/s0378-8741(01)00377-4

  • CrossRef
  • Google Scholar

• 99

  JiaD.DengY.GaoJ.LiuX.ChuJ.ShuY. (2014). Neuroprotective effect of Panax notoginseng plysaccharides against focal cerebral ischemia reperfusion injury in rats. Int. J. Biol. Macromol.63, 177–180. 10.1016/j.ijbiomac.2013.10.034

  • CrossRef
  • Google Scholar

• 100

  JiangJ.DaiJ.CuiH. (2018). Vitexin reverses the autophagy dysfunction to attenuate MCAO-induced cerebral ischemic stroke via mTOR/Ulk1 pathway. Biomed. Pharmacother.99, 583–590. 10.1016/j.biopha.2018.01.067

  • CrossRef
  • Google Scholar

• 101

  JieL.YuR.YueC.JingL.QinX.QinY. (2020). Effects of resveratrol on microglia polarization after oxygen glucose deprivation/reoxygenation injury in vitro. Acta Anatomica Sinica51, 320–325. 10.16098/j.issn.0529-1356.2020.03.002

  • CrossRef
  • Google Scholar

• 102

  JinM.ZhaoK.HuangQ.XuC.ShangP. (2012). Isolation, structure and bioactivities of the polysaccharides from Angelica sinensis (Oliv.) Diels: a review. Carbohydr. Polym.89, 713–722. 10.1016/j.carbpol.2012.04.049

  • CrossRef
  • Google Scholar

• 103

  JinZ.KeJ.GuoP.WangY.WuH. (2019). Quercetin improves blood-brain barrier dysfunction in rats with cerebral ischemia reperfusion via Wnt signaling pathway. Am. J. Transl Res.11, 4683–4695. 10.1002/brb3.1911/v2/review1

  • CrossRef
  • Google Scholar

• 104

  JinGHeX. R.ChenL. P. (2014). The protective effect of ginko bilboa leaves injection on the brain dopamine in the rat model of cerebral ischemia/reperfusion injury. Afr. Health Sci.14, 725–728. 10.4314/ahs.v14i3.31

  • CrossRef
  • Google Scholar

• 105

  JinM. L.ParkS. Y.KimY. H.OhJ.-I.LeeS. J.ParkG. (2014). The neuroprotective effects of cordycepin inhibit glutamate-induced oxidative and ER stress-associated apoptosis in hippocampal HT22 cells. Neurotoxicology41, 102–111. 10.1016/j.neuro.2014.01.005

  • CrossRef
  • Google Scholar

• 106

  KaihuaZ.JiyuL. (2020). Neuroprotective effect of ellagic acid on cerebral ischemia-reperfusion injury in rats based on PI3K/Akt/NOS pathway. Chin. J. Pract. Nervous Dis.23,33–39. 10.1007/s12031-020-01703-8

  • CrossRef
  • Google Scholar

• 107

  KalogerisT.BainesC. P.KrenzM.KorthuisR. J. (2016). Ischemia/reperfusion. Compr. Physiol.7, 113–170. 10.1002/cphy.c160006

  • CrossRef
  • Google Scholar

• 108

  KangD. W.MoonJ. Y.ChoiJ. G.KangS. Y.RyuY.ParkJ. B.et al (2016). Antinociceptive profile of levo-tetrahydropalmatine in acute and chronic pain mice models: role of spinal sigma-1 receptor. Sci. Rep.6, 37850. 10.1038/srep37850

  • CrossRef
  • Google Scholar

• 109

  KaoT.-K.OuY.-C.KuoJ.-S.ChenW.-Y.LiaoS.-L.WuC.-W.et al (2006). Neuroprotection by tetramethylpyrazine against ischemic brain injury in rats. Neurochem. Int.48, 166–176. 10.1016/j.neuint.2005.10.008

  • CrossRef
  • Google Scholar

• 110

  KimH.AhnJ. H.SongM.KimD. W.LeeT.-K.LeeJ.-C.et al (2019). Pretreated fucoidan confers neuroprotection against transient global cerebral ischemic injury in the gerbil hippocampal CA1 area via reducing of glial cell activation and oxidative stress. Biomed. Pharmacother.109, 1718–1727. 10.1016/j.biopha.2018.11.015

  • CrossRef
  • Google Scholar

• 111

  KooH.-J.LimK.-H.JungH.-J.ParkE.-H. (2006). Anti-inflammatory evaluation of gardenia extract, geniposide and genipin. J. Ethnopharmacology103, 496–500. 10.1016/j.jep.2005.08.011

  • CrossRef
  • Google Scholar

• 112

  KoronowskiK. B.DaveK. R.SaulI.CamarenaV.ThompsonJ. W.NeumannJ. T.et al (2015). Resveratrol preconditioning induces a novel extended window of ischemic tolerance in the mouse brain. Stroke46, 2293–2298. 10.1161/strokeaha.115.009876

  • CrossRef
  • Google Scholar

• 113

  KoronowskiK. B.KhouryN.SaulI.LorisZ. B.CohanC. H.Stradecki-CohanH. M.et al (2017). Neuronal SIRT1 (silent information regulator 2 homologue 1) regulates glycolysis and mediates resveratrol-induced ischemic tolerance. Stroke48, 3117–3125. 10.1161/strokeaha.117.018562

  • CrossRef
  • Google Scholar

• 114

  KwokS. S.BuY.LoA. C.ChanT. C.SoK. F.LaiJ. S.et al (2019). A systematic review of potential therapeutic use of lycium barbarum polysaccharides in disease. Biomed. Res. Int.2019, 4615745. 10.1155/2019/4615745

  • CrossRef
  • Google Scholar

• 115

  LanN.LianjunG. (2020). Neuroprotective effect of daurinoline on focal cerebral ischemia in rats. China Pharmacist23, 1029–1031. 10.1016/j.lfs.2003.06.042

  • CrossRef
  • Google Scholar

• 116

  LeeC.HuangK.ShawJ.ChenJ.KuoW.ShenG.et al (2020). Cordyceps militarisTrends in the immunomodulatory effects of : total extracts, polysaccharides and cordycepin. Front. Pharmacol.11, 575704. 10.3389/fphar.2020.575704

  • CrossRef
  • Google Scholar

• 117

  LeeE.KimS.Chul ChungK.ChooM.-K.KimD.-H.NamG.et al (2006). 20(S)-ginsenoside Rh2, a newly identified active ingredient of ginseng, inhibits NMDA receptors in cultured rat hippocampal neurons. Eur. J. Pharmacol.536, 69–77. 10.1016/j.ejphar.2006.02.038

  • CrossRef
  • Google Scholar

• 118

  LeeJ.-C.KimJ.ParkJ.-K.ChungG.-H.JangY.-S. (2003). The antioxidant, rather than prooxidant, activities of quercetin on normal cells:quercetin protects mouse thymocytes from glucose oxidase-mediated apoptosis. Exp. Cel Res.291, 386–397. 10.1016/s0014-4827(03)00410-5

  • CrossRef
  • Google Scholar

• 119

  LeiW.HuojunH.JinyangM.YuanxunD.SongH.ChangtaoF.et al (2020). Role of cell autophagy in protection of resveratrol against cerebral ischemia-reperfusion injury in rats. Chin. J. Clin. Neurosurg.25, 303–307. 10.1016/j.jneuroim.2017.11.015

  • CrossRef
  • Google Scholar

• 120

  LeungS. W.LaiJ. H.WuJ. C.TsaiY. R.ChenY. H.KangS. J.et al (2020). Neuroprotective effects of emodin against ischemia/reperfusion injury through activating ERK-1/2 signaling pathway. Int. J. Mol. Sci.21, 114. 10.3390/ijms21082899

  • CrossRef
  • Google Scholar

• 121

  LiD.-Q.BaoY.-M.LiY.WangC.-F.LiuY.AnL.-J. (2006). Catalpol modulates the expressions of Bcl-2 and Bax and attenuates apoptosis in gerbils after ischemic injury. Brain Res.1115, 179–185. 10.1016/j.brainres.2006.07.063

  • CrossRef
  • Google Scholar

• 122

  LiF.GongQ.-H.WuQ.LuY.-F.ShiJ.-S. (2010). Icariin isolated from Epimedium brevicornum Maxim attenuates learning and memory deficits induced by d-galactose in rats. Pharmacol. Biochem. Behav.96, 301–305. 10.1016/j.pbb.2010.05.021

  • CrossRef
  • Google Scholar

• 123

  LiF.LangF.ZhangH.XuL.WangY.ZhaiC.et al (2017). Apigenin alleviates endotoxin-induced myocardial toxicity by modulating inflammation, oxidative stress, and autophagy. Oxidative Med. Cell Longevity2017, 1–10. 10.1155/2017/2302896

  • CrossRef
  • Google Scholar

• 124

  LiF.LiW.LiX.LiF.ZhangL.WangB.et al (2016). Geniposide attenuates inflammatory response by suppressing P2Y14 receptor and downstream ERK1/2 signaling pathway in oxygen and glucose deprivation-induced brain microvascular endothelial cells. J. Ethnopharmacology185, 77–86. 10.1016/j.jep.2016.03.025

  • CrossRef
  • Google Scholar

• 125

  LiH.HuJ.MaL.YuanZ.WangY.WangX.et al (2010). Comprehensive study of baicalin down-regulating NOD2 receptor expression of neurons with oxygen-glucose deprivation in vitro and cerebral ischemia-reperfusion in vivo. Eur. J. Pharmacol.649, 92–99. 10.1016/j.ejphar.2010.09.023

  • CrossRef
  • Google Scholar

• 126

  LiH.HungA.LiM.YangA. W. H. (2019). Fritillariae thunbergii bulbus: traditional uses, phytochemistry, pharmacodynamics, pharmacokinetics and toxicity. Int. J. Mol. Sci.20, 121. 10.3390/ijms20071667

  • CrossRef
  • Google Scholar

• 127

  LiH.YanZ.ZhuJ.YangJ.HeJ. (2011). Neuroprotective effects of resveratrol on ischemic injury mediated by improving brain energy metabolism and alleviating oxidative stress in rats. Neuropharmacology60, 252–258. 10.1016/j.neuropharm.2010.09.005

  • CrossRef
  • Google Scholar

• 128

  LiL.LiH.LiM. (2015). Curcumin protects against cerebral ischemia-reperfusion injury by activating JAK2/STAT3 signaling pathway in rats. Int. J. Clin. Exp. Med.8, 14985–14991. 10.1002/brb3.1911/v2/review1

  • CrossRef
  • Google Scholar

• 129

  LiL.ZhouQ. X.ShiJ. S. (2005). Protective effects of icariin on neurons injured by cerebral ischemia/reperfusion. Chin. Med. J.118, 1637–1643. 10.5353/th_b4414290

  • CrossRef
  • Google Scholar

• 130

  LiL.ZhangH. (2020). Clinical study on Ligustrazine Hydrochloride Injection combined with ticagrelor in treatment of angina pectoris of coronary heart disease. Drugs Clinic35, 1968–1972. 10.31525/ct1-nct04022031

  • CrossRef
  • Google Scholar

• 131

  LiM.LiuX.WangY.JuX. (2020). In vitro effects of peimine on the activity of cytochrome P450 enzymes. Xenobiotica50, 1202–1207. 10.1080/00498254.2020.1761572

  • CrossRef
  • Google Scholar

• 132

  LiM.QuY. Z.ZhaoZ. W.WuS. X.LiuY. Y.WeiX. Y.et al (2012). Astragaloside IV protects against focal cerebral ischemia/reperfusion injury correlating to suppression of neutrophils adhesion-related molecules. Neurochem. Int.60, 458–465. 10.1016/j.neuint.2012.01.026

  • CrossRef
  • Google Scholar

• 133

  LiQ.WangJ.LiY.XuX. (2018). Neuroprotective effects of salidroside administration in a mouse model of Alzheimer's disease. Mol. Med. Rep.7, 139. 10.3892/mmr.2018.8757

  • CrossRef
  • Google Scholar

• 134

  LiS.JiaoY.WangH.ShangQ.LuF.HuangL.et al (2017). Sodium tanshinone IIA sulfate adjunct therapy reduces high-sensitivity C-reactive protein level in coronary artery disease patients: a randomized controlled trial. Sci. Rep.7, 17451. 10.1038/s41598-017-16980-4

  • CrossRef
  • Google Scholar

• 135

  LiS.LiuX.ChenX.BiL. (2020a). Research progress on anti-inflammatory effects and mechanisms of alkaloids from Chinese medical herbs. Evid. Based Complement. Alternat Med.2020, 1303524. 10.1155/2020/1303524

  • CrossRef
  • Google Scholar

• 136

  LiS.LuY.DingD.MaZ.XingX.HuaX.et al (2020b). Fibroblast growth factor 2 contributes to the effect of salidroside on dendritic and synaptic plasticity after cerebral ischemia/reperfusion injury. Aging12, 10951–10968. 10.18632/aging.103308

  • CrossRef
  • Google Scholar

• 137

  LiS.WangT.ZhaiL.GeK.ZhaoJ.CongW.et al (2018). Picroside II exerts a neuroprotective effect by inhibiting mPTP permeability and EndoG release after cerebral ischemia/reperfusion injury in rats. J. Mol. Neurosci.64, 144–155. 10.1007/s12031-017-1012-z

  • CrossRef
  • Google Scholar

• 138

  LiT.LiuJ.-W.ZhangX.-D.GuoM.-C.JiG. (2007). The neuroprotective effect of picroside II from hu-huang-lian against oxidative stress. Am. J. Chin. Med.35, 681–691. 10.1142/s0192415x0700517x

  • CrossRef
  • Google Scholar

• 139

  LiW.SuwanwelaN. C.PatumrajS. (2016). Curcumin by down-regulating NF-kB and elevating Nrf2, reduces brain edema and neurological dysfunction after cerebral I/R. Microvasc. Res.106, 117–127. 10.1016/j.mvr.2015.12.008

  • CrossRef
  • Google Scholar

• 140

  LiX.YeJ.ZhaoL.XiaP.PengX.YuX. (2014). Effect of Gentiana officinalis from total secoiridoid glucoside on interleukin-1β (IL-1β)-induced rat chondrocytes. Chin. Pharm. J.49, 1121–1125. 10.1016/j.biopha.2018.06.154

  • CrossRef
  • Google Scholar

• 141

  LiY.GuanY.WangY.YuC. L.ZhaiF. G.GuanL. X. (2017). Neuroprotective effect of the ginsenoside Rg1 on cerebral ischemic injury in vivo and in vitro is mediated by pparγ-regulated antioxidative and anti-inflammatory pathways. Evid. Based Complement. Alternat Med.2017, 7842082. 10.1155/2017/7842082

  • CrossRef
  • Google Scholar

• 142

  LiY.BaoY.JiangB.WangZ.LiuY.ZhangC.et al (2008). Catalpol protects primary cultured astrocytes from in vitro ischemia-induced damage. Int. J. Dev. Neurosci.26, 309–317. 10.1016/j.ijdevneu.2008.01.006

  • CrossRef
  • Google Scholar

• 143

  LiY. H.GongP. L. (2004). The protective effect of dauricine on cerebral ischemia in mice. Chin. Pharmacol. Bull.20, 564–566. 10.4268/cjcmm20140626

  • CrossRef
  • Google Scholar

• 144

  LiY.YangY.ZhaoY.ZhangJ.LiuB.JiaoS.et al (2019). Astragaloside IV reduces neuronal apoptosis and parthanatos in ischemic injury by preserving mitochondrial hexokinase-II. Free Radic. Biol. Med.131, 251–263. 10.1016/j.freeradbiomed.2018.11.033

  • CrossRef
  • Google Scholar

• 145

  LiY.YaoJ.HanC.YangJ.ChaudhryM.WangS.et al (2016). Quercetin, inflammation and immunity. Nutrients8, 167. 10.3390/nu8030167

  • CrossRef
  • Google Scholar

• 146

  LiangW.HuangX.ChenW. (2017). The effects of baicalin and baicalein on cerebral ischemia: a review. A&D8, 850–867. 10.14336/ad.2017.0829

  • CrossRef
  • Google Scholar

• 147

  LiebnerS.DijkhuizenR. M.ReissY.PlateK. H.AgalliuD.ConstantinG. (2018). Plate karl H., agalliu dritan., constantin Gabriela.Functional morphology of the blood-brain barrier in health and disease. Acta Neuropathol.135 (3), 311–336. 10.1007/s00401-018-1815-1

  • CrossRef
  • Google Scholar

• 148

  LiJ.LeiT.LinJ.LiaoW. (2019). Protective effects of Angelica polysaccharides on cerebral ischemia reperfusion injury in rats. Chin. Arch. Trad. Chin. Med.37, 2272–2276+2317. 10.3724/sp.j.1008.2010.00238

  • CrossRef
  • Google Scholar

• 149

  LiM.LiJ.LiuS.LiW. (2018). Codonopsis pilosula polysaccharide on cerebral ischemia-reperfusion injury model mice brain protection and its effect on GFAP expression. Acta Neuropharmacologica8, 42–43. 10.1016/j.carbpol.2012.07.062

  • CrossRef
  • Google Scholar

• 150

  LinB. (2011). Polyphenols and neuroprotection against ischemia and neurodegeneration. Mini Rev. Med. Chem.11, 1222–1238. 10.2174/138955711804586784

  • CrossRef
  • Google Scholar

• 151

  LinX.ZhangN. (2018). Berberine: pathways to protect neurons. Phytotherapy Res.32, 1501–1510. 10.1002/ptr.6107

  • CrossRef
  • Google Scholar

• 152

  LiuF.WangY.YaoW.XueY.ZhouJ.LiuZ. (2019). Geniposide attenuates neonatal mouse brain injury after hypoxic-ischemia involving the activation of PI3K/Akt signaling pathway. J. Chem. Neuroanat.102, 101687. 10.1016/j.jchemneu.2019.101687

  • CrossRef
  • Google Scholar

• 153

  LiuG.SongJ.GuoY.WangT.ZhouZ. (2013). Astragalus injection protects cerebral ischemic injury by inhibiting neuronal apoptosis and the expression of JNK3 after cerebral ischemia reperfusion in rats. Behav. Brain Functions9, 36. 10.1186/1744-9081-9-36

  • CrossRef
  • Google Scholar

• 154

  LiuG.WuX.TangW. (2015). Study on the chemical constituents and physiological activity of Poria cocos. J. Qiqihar University(Natural Sci. Edition)31, 50–54. 10.4268/cjcmm20140615

  • CrossRef
  • Google Scholar

• 155

  LiuH.BaiJ.TanJ.WengX. (2014). Cerebral protective effect of astragalus polysaccharide pretreatment on focal cerebral ischemia-reperfusion injury in rats. J. Pract. Diabetology10, 31–32. 10.3724/sp.j.1008.2010.00238

  • CrossRef
  • Google Scholar

• 156

  LiuJ.-h.YinF.GuoL.-x.DengX.-h.HuY.-h. (2009). Neuroprotection of geniposide against hydrogen peroxide induced PC12 cells injury: involvement of PI3 kinase signal pathway. Acta Pharmacol. Sin30, 159–165. 10.1038/aps.2008.25

  • CrossRef
  • Google Scholar

• 157

  LiuQ.JinZ.XuZ.YangH.LiL.LiG.et al (2019). Antioxidant effects of ginkgolides and bilobalide against cerebral ischemia injury by activating the Akt/Nrf2 pathway in vitro and in vivo. Cell Stress and Chaperones24, 441–452. 10.1007/s12192-019-00977-1

  • CrossRef
  • Google Scholar

• 158

  LiuR.ZhangL.LanX.LiL.ZhangT.-T.SunJ.-H.et al (2011). Protection by borneol on cortical neurons against oxygen-glucose deprivation/reperfusion: involvement of anti-oxidation and anti-inflammation through nuclear transcription factor κappaB signaling pathway. Neuroscience176, 408–419. 10.1016/j.neuroscience.2010.11.029

  • CrossRef
  • Google Scholar

• 159

  LiuX.WenS.YanF.LiuK.LiuL.WangL.et al (2018). Salidroside provides neuroprotection by modulating microglial polarization after cerebral ischemia. J. Neuroinflammation15, 39. 10.1186/s12974-018-1081-0

  • CrossRef
  • Google Scholar

• 160

  LiuY.-l.LiangJ.-h.YanL.-d.SuR.-b.WuC.-f.GongZ.-h. (2005). Effects of l-tetrahydropalmatine on locomotor sensitization to oxycodone in mice. Acta Pharmacol. Sin26, 533–538. 10.1111/j.1745-7254.2005.00101.x

  • CrossRef
  • Google Scholar

• 161

  LiuY.-r.LiP.-w.SuoJ.-j.SunY.ZhangB.-a.LuH.et al (2014). Catalpol provides protective effects against cerebral ischaemia/reperfusion injury in gerbils. J. Pharm. Pharmacol.66, 1265–1270. 10.1111/jphp.12261

  • CrossRef
  • Google Scholar

• 162

  LiuY.CuiY.LuL.GongY.HanW.PiaoG. (2020). Natural indole-containing alkaloids and their antibacterial activities. Arch. Pharm. (Weinheim)23, e2000120. 10.1002/ardp.202000120

  • CrossRef
  • Google Scholar

• 163

  LiuY.WangJ.WangW.ZhangH.ZhangX.HanC. (2015). The chemical constituents and pharmacological actions ofCordyceps sinensis. Evidence-Based Complement. Altern. Med.2015, 1–12. 10.1155/2015/575063

  • CrossRef
  • Google Scholar

• 164

  LiuQ. S.LiS. R.LiK.LiX.YinX.PangZ. (2017). Ellagic acid improves endogenous neural stem cells proliferation and neurorestoration through Wnt/beta-catenin signaling in vivo and in vitro. Mol. Nutr. Food Res.61, 113. 10.1002/mnfr.201600587

  • CrossRef
  • Google Scholar

• 165

  LiuZ.-B.LiuC.ZengB.HuangL.-P.YaoL.-H. (2017). Modulation effects of cordycepin on voltage-gated sodium channels in rat hippocampal CA1 pyramidal neurons in the presence/absence of oxygen. Neural Plasticity2017, 1–9. 10.1155/2017/2459053

  • CrossRef
  • Google Scholar

• 166

  LongY.YangQ.XiangY.ZhangY.WanJ.LiuS.et al (2020). Nose to brain drug delivery - a promising strategy for active components from herbal medicine for treating cerebral ischemia reperfusion. Pharmacol. Res.159, 104795. 10.1016/j.phrs.2020.104795

  • CrossRef
  • Google Scholar

• 167

  LuS.SunL.ShenJ.SuF.WangH.YeZ.et al (2010). Protective effects of auricularia auricular polysaccharide on chronic cerebral ischemia injury in rats. Chin. J. Pathophysiology26, 721–724. 10.3892/mmr.2018.9579

  • CrossRef
  • Google Scholar

• 168

  LuZ.-Q.DengY.-J.LuJ.-X. (2012). Effect of aloe polysaccharide on caspase-3 expression following cerebral ischemia and reperfusion injury in rats. Mol. Med. Rep.6, 371–374. 10.3892/mmr.2012.927

  • CrossRef
  • Google Scholar

• 169

  LuZ.LiuY.ShiY.ShiX.WangX.XuC.et al (2018). Curcumin protects cortical neurons against oxygen and glucose deprivation/reoxygenation injury through flotillin-1 and extracellular signal-regulated kinase1/2 pathway. Biochem. Biophysical Res. Commun.496, 515–522. 10.1016/j.bbrc.2018.01.089

  • CrossRef
  • Google Scholar

• 170

  LuoY.NieJ.GongQ.-H.LuY.-F.WuQ.ShiJ.-S. (2007). Protective effects of icariin against learning and memory deficits induced by aluminium in rats. Clin. Exp. Pharmacol. Physiol.34, 792–795. 10.1111/j.1440-1681.2007.04647.x

  • CrossRef
  • Google Scholar

• 171

  MaJ.HeW.GaoC.YuD.XueP.NiuY. (2019). Antioxidant and neuroprotective effects of Codonopsis pilosula polysaccharides on hypoxic-ischemic brain injury induced by Nrf2 pathway. Chin. J. Clin. Anat.37, 403–408. 10.4077/cjp.2011.amm059

  • CrossRef
  • Google Scholar

• 172

  MaR.XieQ.LiY.ChenZ.RenM.ChenH.et al (2020). Animal models of cerebral ischemia: a review. Biomed. Pharmacother., 131, 110686. 10.1016/j.biopha.2020.110686

  • CrossRef
  • Google Scholar

• 173

  MantschJ. R.LiS.-J.RisingerR.AwadS.KatzE.BakerD. A.et al (2007). Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement in rats. Psychopharmacology192, 581–591. 10.1007/s00213-007-0754-7

  • CrossRef
  • Google Scholar

• 174

  ManzaneroS.SantroT.ArumugamT. V. (2013). Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Neurochem. Int.62 (5), 712–718. 10.1016/j.neuint.2012.11.009

  • CrossRef
  • Google Scholar

• 175

  MaoG.ZhangL.QianF.ChenK.XuJ.XuJ.et al (2019). Research progress on anti-inflammatory activity of three kinds of iridoid glycosides in Chinese materia medica. Chin. Trad. Herbal Drugs50, 225–233. 10.21203/rs.3.rs-58802/v1

  • CrossRef
  • Google Scholar

• 176

  MaoX. W.PanC. S.HuangP.LiuY. Y.WangC. S.YanL.et al (2015). Levo-tetrahydropalmatine attenuates mouse blood-brain barrier injury induced by focal cerebral ischemia and reperfusion: involvement of Src kinase. Sci. Rep.5, 11155. 10.1038/srep11155

  • CrossRef
  • Google Scholar

• 177

  MoZ.-t.LiaoY.-l.ZhengJ.LiW.-n. (2020). Icariin protects neurons from endoplasmic reticulum stress-induced apoptosis after OGD/R injury via suppressing IRE1α-XBP1 signaling pathway. Life Sci.255, 117847. 10.1016/j.lfs.2020.117847

  • CrossRef
  • Google Scholar

• 178

  Mook-JungI.ShinJ.-E.YunS. H.HuhK.KohJ. Y.ParkH. K.et al (1999). Protective effects of asiaticoside derivatives against beta-amyloid neurotoxicity. J. Neurosci. Res.58, 417–425. 10.1002/(sici)1097-4547(19991101)58:3<417::aid-jnr7>3.0.co;2-g

  • CrossRef
  • Google Scholar

• 179

  MukherjeeA.SarkarS.JanaS.SwarnakarS.DasN. (2019). Neuro-protective role of nanocapsulated curcumin against cerebral ischemia-reperfusion induced oxidative injury. Brain Res.1704, 164–173. 10.1016/j.brainres.2018.10.016

  • CrossRef
  • Google Scholar

• 180

  NegiA. S.KumarJ. K.LuqmanS.ShankerK.GuptaM. M.KhanujaS. P. S. (2008). Recent advances in plant hepatoprotectives: a chemical and biological profile of some important leads. Med. Res. Rev.28, 746–772. 10.1002/med.20115

  • CrossRef
  • Google Scholar

• 181

  NejadK. H.DianatM.SarkakiA.NaseriM. K.BadaviM.FarboodY. (2015). Ellagic acid improves electrocardiogram waves and blood pressure against global cerebral ischemia rat experimental models. Electron. Physician7, 1153–1162. 10.14661/2015.1153-1162

  • CrossRef
  • Google Scholar

• 182

  OliveiraC.NevesN. M.ReisR. L.MartinsA.SilvaT. H. (2020). A review on fucoidan antitumor strategies: from a biological active agent to a structural component of fucoidan-based systems. Carbohydr. Polym.239, 116131. 10.1016/j.carbpol.2020.116131

  • CrossRef
  • Google Scholar

• 183

  OrhanI. E. (2012). Centella asiatica (L.) urban: from traditional medicine to modern medicine with neuroprotective potential. Evid. Based Complement. Alternat Med.2012, 946259. 10.1155/2012/946259

  • CrossRef
  • Google Scholar

• 184

  PangQ.ZhaoY.ChenX.ZhaoK.ZhaiQ.TuF. (2018). Apigenin protects the brain against ischemia/reperfusion injury via caveolin-1/VEGF in vitro and in vivo. Oxid Med. Cel Longev2018, 7017204. 10.1155/2018/7017204

  • CrossRef
  • Google Scholar

• 185

  ParkD.-J.JeonS.-J.KangJ.-B.KohP.-O. (2020). Quercetin reduces ischemic brain injury by preventing ischemia-induced decreases in the neuronal calcium sensor protein hippocalcin. Neuroscience430, 47–62. 10.1016/j.neuroscience.2020.01.015

  • CrossRef
  • Google Scholar

• 186

  PengX.ShiZ.LiangC.RenY.TanR. (2019). Protective effect of Chinese Yam polysaccharides on cerebral ischemia-reperfusion injury in mice. Pharmacol. Clin. Chin. Materia Med.35, 60–63. 10.4268/cjcmm20140327

  • CrossRef
  • Google Scholar

• 187

  PervizS.KhanH.PervaizA. (2016). Plant alkaloids as an emerging therapeutic alternative for the treatment of depression. Front. Pharmacol.7, 28. 10.3389/fphar.2016.00028

  • CrossRef
  • Google Scholar

• 188

  PutteerajM.LimW.TeohS. L.YahayaM. (2018). Flavonoids and its neuroprotective effects on brain ischemia and neurodegenerative diseases. Curr. Drug Targets19, 115. 10.2174/1389450119666180326125252

  • CrossRef
  • Google Scholar

• 189

  QianG.MinL. (2010). Protective effect of black fungus polysaccharide on hypoxic-ischemic brain damage in neonatal rats. Chin. J. Trad. Med. Sci. Technol.17, 129–130. 10.1109/hhbe.2011.6027979

  • CrossRef
  • Google Scholar

• 190

  QinP.LiX.YangH.WangZ. Y.LuD. (2019). Therapeutic potential and biological applications of cordycepin and metabolic mechanisms in cordycepin-producing fungi. Molecules24, 2231. 10.3390/molecules24122231

  • CrossRef
  • Google Scholar

• 191

  QiuS.SunH.ZhangA.-H.XuH.-Y.YanG.-L.HanY.et al (2014). Natural alkaloids: basic aspects, biological roles, and future perspectives. Chin. J. Nat. Medicines12, 401–406. 10.1016/s1875-5364(14)60063-7

  • CrossRef
  • Google Scholar

• 192

  RanK.YangD.-L.ChangY.-T.DuanK.-M.OuY.-W.WangH.-P.et al (2014). Ginkgo biloba extract postconditioning reduces myocardial ischemia reperfusion injury. Genet. Mol. Res.13, 2703–2708. 10.4238/2014.april.8.14

  • CrossRef
  • Google Scholar

• 193

  RenJ.FanC.ChenN.HuangJ.YangQ. (2011). Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats. Neurochem. Res.36, 2352–2362. 10.1007/s11064-011-0561-8

  • CrossRef
  • Google Scholar

• 194

  RenS.ZhangH.MuY.SunM.LiuP. (2013). Pharmacological effects of Astragaloside IV: a literature review. J. Trad. Chin. Med.33, 413–416. 10.1016/s0254-6272(13)60189-2

  • CrossRef
  • Google Scholar

• 195

  RosalesP. F.BordinG. S.GowerA. E.MouraS. (2020). Indole alkaloids: 2012 until now, highlighting the new chemical structures and biological activities. Fitoterapia143, 104558. 10.1016/j.fitote.2020.104558

  • CrossRef
  • Google Scholar

• 196

  RyooN.RahmanM. A.HwangH.KoS. K.NahS.-Y.KimH.-C.et al (2020). Ginsenoside Rk1 is a novel inhibitor of NMDA receptors in cultured rat hippocampal neurons. J. Ginseng Res.44, 490–495. 10.1016/j.jgr.2019.04.002

  • CrossRef
  • Google Scholar

• 197

  RyuE.SonM.LeeM.LeeK.ChoJ. Y.ChoS.et al (2014). Cordycepin is a novel chemical suppressor of Epstein-Barr virus replication. Oncoscience1, 866–881. 10.18632/oncoscience.110

  • CrossRef
  • Google Scholar

• 198

  SainiA.TaliyanR.SharmaP. (2014). Protective effect and mechanism of Ginkgo biloba extract-EGb 761 on STZ-induced diabetic cardiomyopathy in rats. Phcog Mag.10, 172–178. 10.4103/0973-1296.131031

  • CrossRef
  • Google Scholar

• 199

  SantosA. C.PereiraI.Pereira-SilvaM.FerreiraL.CaldasM.Collado-GonzálezM.et al (2019). Nanotechnology-based formulations for resveratrol delivery: effects on resveratrol in vivo bioavailability and bioactivity. Colloids Surf. B: Biointerfaces180, 127–140. 10.1016/j.colsurfb.2019.04.030

  • CrossRef
  • Google Scholar

• 200

  SavopoulosC.NtaiosG.HatzitoliosA. (2009). Is there a geographic variation in the seasonal distribution of acute myocardial infarction and sudden cardiac death?. Int. J. Cardiol.135, 253–254. 10.1016/j.ijcard.2008.03.019

  • CrossRef
  • Google Scholar

• 201

  ShafabakhshR.AsemiZ. (2019). Quercetin: a natural compound for ovarian cancer treatment. J. Ovarian Res.12, 55. 10.1186/s13048-019-0530-4

  • CrossRef
  • Google Scholar

• 202

  ShaoJ.JinH.ZhuH.LiuJ. (2013). Optimization of the technological parameters for the alcohol extraction of ginkgo flavonoid glycosides and the in vitro antioxidant study. J. China Univ. Mining Technol.42, 663–669. 10.1016/j.phytochem.2016.05.005

  • CrossRef
  • Google Scholar

• 203

  SheD. T.JoD. G.ArumugamT. V. (2017). Emerging roles of sirtuins in ischemic stroke. Transl Stroke Res.12, 147. 10.1007/s12975-017-0544-4

  • CrossRef
  • Google Scholar

• 204

  SimãoF.MattéA.PagnussatA. S.NettoC. A.SalbegoC. G. (2012b). Resveratrol preconditioning modulates inflammatory response in the rat hippocampus following global cerebral ischemia. Neurochem. Int.61, 659–665. 10.1016/j.neuint.2012.06.009

  • CrossRef
  • Google Scholar

• 205

  SimãoF.MattéA.PagnussatA. S.NettoC. A.SalbegoC. G. (2012a). Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK-3β and CREB through PI3-K/Akt pathways. Eur. J. Neurosci.36, 2899–2905. 10.1111/j.1460-9568.2012.08229.x

  • CrossRef
  • Google Scholar

• 206

  SongB.TangX.WangX.HuangX.YeY.LuX.et al (2012). Bererine induces peripheral lymphocytes immune regulations to realize its neuroprotective effects in the cerebral ischemia/reperfusion mice. Cell Immunol.276, 91–100. 10.1016/j.cellimm.2012.04.006

  • CrossRef
  • Google Scholar

• 207

  SongD.HaoJ.FanD. (2020). Biological properties and clinical applications of berberine. Front. Med.4, 144. 10.5194/hess-2020-1-rc1

  • CrossRef
  • Google Scholar

• 208

  SongM.-t.RuanJ.ZhangR.-y.DengJ.MaZ.-q.MaS.-p. (2018). Astragaloside IV ameliorates neuroinflammation-induced depressive-like behaviors in mice via the PPARγ/NF-κB/NLRP3 inflammasome axis. Acta Pharmacol. Sin39, 1559–1570. 10.1038/aps.2017.208

  • CrossRef
  • Google Scholar

• 209

  SowndhararajanK.DeepaP.KimM.ParkS. J.KimS. (2018). Neuroprotective and cognitive enhancement potentials of baicalin: a review. Brain Sci.8, 137. 10.3390/brainsci8060104

  • CrossRef
  • Google Scholar

• 210

  StanimirovicD.SatohK. (2000). Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol.10 (1), 113–126. 10.1111/j.1750-3639.2000.tb00248.x

  • CrossRef
  • Google Scholar

• 211

  SteligaA.KowiańskiP.CzubaE.WaśkowM.MoryśJ.LietzauG. (2020). Neurovascular unit as a source of ischemic stroke biomarkers-limitations of experimental studies and perspectives for clinical application. Transl. Stroke Res.11 (4), 553–579. 10.1007/s12975-019-00744-5

  • CrossRef
  • Google Scholar

• 212

  StuppnerH.WagnerH. (1989). New cucurbitacin glycosides fromPicrorhiza kurrooa. Planta Med.55, 559–563. 10.1055/s-2006-962095

  • CrossRef
  • Google Scholar

• 213

  SunJ. B.LiY.CaiY. F.HuangY.LiuS.YeungP. K.et al (2018). Scutellarin protects oxygen/glucose-deprived astrocytes and reduces focal cerebral ischemic injury. Neural Regen. Res.13, 1396–1407. 10.4103/1673-5374.235293

  • CrossRef
  • Google Scholar

• 214

  SunR.SongY.LiS.MaZ.DengX.FuQ.et al (2018). Levo-tetrahydropalmatine attenuates neuron apoptosis induced by cerebral ischemia-reperfusion injury: involvement of c-abl activation. J. Mol. Neurosci.65, 391–399. 10.1007/s12031-018-1063-9

  • CrossRef
  • Google Scholar

• 215

  SyL.XieY.YuZ. (2015). Notoginseng polysaccharide on rat ischemia-reperfusion injury of protection. J. Apoplexy Nervous Dis.32, 996–998. 10.1007/978-3-0348-8988-9_25

  • CrossRef
  • Google Scholar

• 216

  TangB.WangD.LiM.WuQ.YangQ.ShiW.et al (2017). An in vivo study of hypoxia-inducible factor-1α signaling in ginsenoside Rg1-mediated brain repair after hypoxia/ischemia brain injury. Pediatr. Res.81, 120–126. 10.1038/pr.2016.178

  • CrossRef
  • Google Scholar

• 217

  TangH.TangY.LiN.ShiQ.GuoJ.ShangE.et al (2014). Neuroprotective effects of scutellarin and scutellarein on repeatedly cerebral ischemia-reperfusion in rats. Pharmacol. Biochem. Behav.118, 51–59. 10.1016/j.pbb.2014.01.003

  • CrossRef
  • Google Scholar

• 218

  ThapaS. B.PandeyR. P.ParkY. I.Kyung SohngJ. (2019). Biotechnological advances in resveratrol production and its chemical diversity. Molecules24, 2571. 10.3390/molecules24142571

  • CrossRef
  • Google Scholar

• 219

  ThiyagarajanM.SharmaS. S. (2004). Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci.74, 969–985. 10.1016/j.lfs.2003.06.042

  • CrossRef
  • Google Scholar

• 220

  TianY.LiuA.SuJ.XuS.DaiG.XueH. (2015). Theoretical study on the structure-activity relationship of andrographolide derivatives. J. Zhengzhou University(Natural Sci. Edition)47, 103–106. 10.3109/14756361003724760

  • CrossRef
  • Google Scholar

• 221

  TsaiS.-K.HungL.-M.FuY.-T.ChengH.NienM.-W.LiuH.-Y.et al (2007). Resveratrol neuroprotective effects during focal cerebral ischemia injury via nitric oxide mechanism in rats. J. Vasc. Surg.46, 346–353. 10.1016/j.jvs.2007.04.044

  • CrossRef
  • Google Scholar

• 222

  TuF.PangQ.HuangT.ZhaoY.LiuM.ChenX. (2017). Apigenin ameliorates post-stroke cognitive deficits in rats through histone acetylation-mediated neurochemical alterations. Med. Sci. Monit.23, 4004–4013. 10.12659/msm.902770

  • CrossRef
  • Google Scholar

• 223

  TuX. K.YangW. Z.ShiS. S.ChenY.WangC. H.ChenC. M.et al (2011). Baicalin inhibits TLR2/4 signaling pathway in rat brain following permanent cerebral ischemia. Inflammation34, 463–470. 10.1007/s10753-010-9254-8

  • CrossRef
  • Google Scholar

• 224

  TuliH. S.SandhuS.SharmaA. (2013). Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin. Biotech4, 1-12. 10.1007/s13205-013-0121-9

  • CrossRef
  • Google Scholar

• 225

  Ułamek-KoziołM.CzuczwarS. J.JanuszewskiS.PlutaR. (2020). Substantiation for the use of curcumin during the development of neurodegeneration after brain ischemia. Int. J. Mol. Sci.21, 517. 10.3390/ijms21020517

  • CrossRef
  • Google Scholar

• 226

  WanW.ZhangC.DanielsenM.LiQ.ChenW.ChanY.et al (2016). EGb761 improves cognitive function and regulates inflammatory responses in the APP/PS1 mouse. Exp. Gerontol.81, 92–100. 10.1016/j.exger.2016.05.007

  • CrossRef
  • Google Scholar

• 227

  WangC.LiY.GaoS.ChengD.ZhaoS.LiuE. (2015). Breviscapine injection improves the therapeutic effect of western medicine on angina pectoris patients. PLoS One10, e0129969. 10.1371/journal.pone.0129969

  • CrossRef
  • Google Scholar

• 228

  WangD. Q.HeZ. D.FengB. S.YangC. R. (1993). Chemical constituents from Picrorhiza scrophulariiflora. Acta Botanica Yunnanica15, 83–88.

  • Google Scholar

• 229

  WangF.ZhangY.ZhengX.DaiZ.LiuB.MaS. (2019). Research progress of the structure and biological activities of iridoids compounds. Chin. Pharm. Aff.33, 323–330. 10.1159/000391383

  • CrossRef
  • Google Scholar

• 230

  WangJ.WangL.LouG.-H.ZengH.-R.HuJ.HuangQ.-W.et al (2019a). Coptidis Rhizoma: a comprehensive review of its traditional uses, botany, phytochemistry, pharmacology and toxicology. Pharm. Biol.57, 193–225. 10.1080/13880209.2019.1577466

  • CrossRef
  • Google Scholar

• 231

  WangJ.XuJ.GongX.YangM.ZhangC.LiM. (2019b). Biosynthesis, chemistry, and pharmacology of polyphenols from Chinese salvia species: a review. Molecules24, 59. 10.3390/molecules24010155

  • CrossRef
  • Google Scholar

• 232

  WangL.-Y.LiuJ.LiY.LiB.ZhangY.-Y.JingZ.-W.et al (2015). Time-dependent variation of pathways and networks in a 24-hour window after cerebral ischemia-reperfusion injury. BMC Syst. Biol.9 (1), 11. 10.1186/s12918-015-0152-4

  • CrossRef
  • Google Scholar

• 233

  WangL.MaQ. (2018). Clinical benefits and pharmacology of scutellarin: a comprehensive review. Pharmacol. Ther.190, 105–127. 10.1016/j.pharmthera.2018.05.006

  • CrossRef
  • Google Scholar

• 234

  WangL.WangP.XuK.ChenY.LiQ.LeiH. (2013). Research progress on structure-activity relationship of ligustrazine derivatives. Chin. Trad. Herbal Drugs44, 2766–2771. 10.21873/anticanres.11635

  • CrossRef
  • Google Scholar

• 235

  WangL.ZhaoH.ZhaiZ.-z.QuL.-x. (2018). Protective effect and mechanism of ginsenoside Rg1 in cerebral ischaemia-reperfusion injury in mice. Biomed. Pharmacother.99, 876–882. 10.1016/j.biopha.2018.01.136

  • CrossRef
  • Google Scholar

• 236

  WangQ.SunA. Y.SimonyiA.JensenM. D.ShelatP. B.RottinghausG. E.et al (2005). Neuroprotective mechanisms of curcumin against cerebral ischemia-induced neuronal apoptosis and behavioral deficits. J. Neurosci. Res.82, 138–148. 10.1002/jnr.20610

  • CrossRef
  • Google Scholar

• 237

  WangS.-W.LaiC.-Y.WangC.-J. (1992). Inhibitory effect of geniposide on aflatoxin B1-induced DNA repair synthesis in primary cultured rat hepatocytes. Cancer Lett.65, 133–137. 10.1016/0304-3835(92)90157-q

  • CrossRef
  • Google Scholar

• 238

  WangT.ZhaiL.ZhangH.ZhaoL.GuoY. (2015a). Picroside II inhibits the MEK-ERK1/2-COX2 signal pathway to prevent cerebral ischemic injury in rats. J. Mol. Neurosci.57, 335–351. 10.1007/s12031-015-0623-5

  • CrossRef
  • Google Scholar

• 239

  WangT.ZhaoL.GuoY.ZhangM.PeiH. (2015b). Picroside II inhibits neuronal apoptosis and improves the morphology and structure of brain tissue following cerebral ischemic injury in rats. PLoS One10, e0124099. 10.1371/journal.pone.0124099

  • CrossRef
  • Google Scholar

• 240

  WangW.MaX.HanJ.ZhouM.RenH.PanQ.et al (2016). Neuroprotective effect of scutellarin on ischemic cerebral injury by down-regulating the expression of angiotensin-converting enzyme and AT1 receptor. PLoS One11, e0146197. 10.1371/journal.pone.0146197

  • CrossRef
  • Google Scholar

• 241

  WangX. (2006). Research on the design, synthesis, biological activity and quantitative structure-activity relationship of emodin derivatives targeting matrix metalloproteinases. Jinan, China: Shandong University.

  • Google Scholar

• 242

  WangX.ChenL.TanC.XieD. (2014). Protective effect of lycium barbarum polysaccharides on cerebral ischemia-reperfusion injury model rats. China Pharm.25, 1365–1367. 10.5353/th_b5328058

  • CrossRef
  • Google Scholar

• 243

  WangX.ZhaoL. (2016). Calycosin ameliorates diabetes-induced cognitive impairments in rats by reducing oxidative stress via the PI3K/Akt/GSK-3β signaling pathway. Biochem. Biophys. Res. Commun.473, 428–434. 10.1016/j.bbrc.2016.03.024

  • CrossRef
  • Google Scholar

• 244

  WangY.DongX.LiZ.WangW.TianJ.ChenJ. (2014). Downregulated RASD1 and upregulated miR-375 are involved in protective effects of calycosin on cerebral ischemia/reperfusion rats. J. Neurol. Sci.339, 144–148. 10.1016/j.jns.2014.02.002

  • CrossRef
  • Google Scholar

• 245

  WangY.RenQ.ZhangX.LuH.ChenJ. (2018). Neuroprotective mechanisms of calycosin against focal cerebral ischemia and reperfusion injury in rats. Cel Physiol. Biochem.45, 537–546. 10.1159/000487031

  • CrossRef
  • Google Scholar

• 246

  WangY.SuY.LaiW.HuangX.ChuK.BrownJ.et al (2020). Salidroside restores an anti-inflammatory endothelial phenotype by selectively inhibiting endothelial complement after oxidative stress. Inflammation43, 310–325. 10.1007/s10753-019-01121-y

  • CrossRef
  • Google Scholar

• 247

  WangY.WuY.LiangC.TanR.TanL.TanR. (2019). Pharmacodynamic effect of ellagic acid on ameliorating cerebral ischemia/reperfusion injury. Pharmacology104, 320–331. 10.1159/000502401

  • CrossRef
  • Google Scholar

• 248

  WangY.ZhenY.WuX.JiangQ.LiX.ChenZ.et al (2015). Vitexin protects brain against ischemia/reperfusion injury via modulating mitogen-activated protein kinase and apoptosis signaling in mice. Phytomedicine22, 379–384. 10.1016/j.phymed.2015.01.009

  • CrossRef
  • Google Scholar

• 249

  WangF.YinP.LuY.ZhouZ.JiangC.LiuY.et al (2015). Cordycepin prevents oxidative stress-induced inhibition of osteogenesis. Oncotarget6, 117. 10.18632/oncotarget.6072

  • CrossRef
  • Google Scholar

• 250

  WangY.-Y.ChangC.-Y.LinS.-Y.WangJ.-D.WuC.-C.ChenW.-Y.et al (2020). Quercetin protects against cerebral ischemia/reperfusion and oxygen glucose deprivation/reoxygenation neurotoxicity. J. Nutr. Biochem.83, 108436. 10.1016/j.jnutbio.2020.108436

  • CrossRef
  • Google Scholar

• 251

  WeiH.WangS.ZhenL.YangQ.WuZ.LeiX.et al (2015). Resveratrol attenuates the blood-brain barrier dysfunction by regulation of the MMP-9/TIMP-1 balance after cerebral ischemia reperfusion in rats. J. Mol. Neurosci.55, 872–879. 10.1007/s12031-014-0441-1

  • CrossRef
  • Google Scholar

• 252

  WeiY.HongH.ZhangX.LaiW.WangY.ChuK.et al (2017). Salidroside inhibits inflammation through PI3K/Akt/HIF signaling after focal cerebral ischemia in rats. Inflammation40, 1297–1309. 10.1007/s10753-017-0573-x

  • CrossRef
  • Google Scholar

• 253

  WilliamsE. I.BettertonR. D.DavisT. P.RonaldsonP. T. (2020). Transporter-mediated delivery of small molecule drugs to the brain: a critical mechanism that can advance therapeutic development for ischemic stroke. Pharmaceutics12, 63. 10.3390/pharmaceutics12020154

  • CrossRef
  • Google Scholar

• 254

  WuL.FangF. (2020). Advances in structural modification and structure-activity relationship of berberine. Chin. J. New Drugs29, 1257–1264. 10.1001/archneur.1968.00470320053006

  • CrossRef
  • Google Scholar

• 255

  WuS.-y.WangG.-f.LiuZ.-q.RaoJ.-j.LüL.XuW.et al (2009). Effect of geniposide, a hypoglycemic glucoside, on hepatic regulating enzymes in diabetic mice induced by a high-fat diet and streptozotocin. Acta Pharmacol. Sin30, 202–208. 10.1038/aps.2008.17

  • CrossRef
  • Google Scholar

• 256

  XiaZ.ZhangR.WuP.XiaZ.HuY. (2012). Memory defect induced by beta-amyloid plus glutamate receptor agonist is alleviated by catalpol and donepezil through different mechanisms. Brain Res.1441, 27–37. 10.1016/j.brainres.2012.01.008

  • CrossRef
  • Google Scholar

• 257

  XieC.-L.LiJ.-H.WangW.-W.ZhengG.-Q.WangL.-X. (2015). Neuroprotective effect of ginsenoside-Rg1 on cerebral ischemia/reperfusion injury in rats by downregulating protease-activated receptor-1 expression. Life Sci.121, 145–151. 10.1016/j.lfs.2014.12.002

  • CrossRef
  • Google Scholar

• 258

  XieC. J.GuA. P.CaiJ.WuY.ChenR. C. (2018). Curcumin protects neural cells against ischemic injury in N2a cells and mouse brain with ischemic stroke. Brain Behav.8, e00921. 10.1002/brb3.921

  • CrossRef
  • Google Scholar

• 259

  XieW.ZhouP.SunY.MengX.DaiZ.SunG.et al (2018). Protective effects and target network analysis of ginsenoside Rg1 in cerebral ischemia and reperfusion injury: a comprehensive overview of experimental studies. Cells7, 114. 10.3390/cells7120270

  • CrossRef
  • Google Scholar

• 260

  XiongD.DengY.HuangB.YinC.LiuB.ShiJ.et al (2016). Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-κB, PPARα and PPARγ in rats. Int. Immunopharmacology30, 157–162. 10.1016/j.intimp.2015.11.035

  • CrossRef
  • Google Scholar

• 261

  XuD.HuM. J.WangY. Q.CuiY. L. (2019). Antioxidant activities of quercetin and its complexes for medicinal application. Molecules24, 119. 10.3390/molecules24061123

  • CrossRef
  • Google Scholar

• 262

  XuH.HuaY.ZhongJ.LiX.XuW.CaiY.et al (2018). Resveratrol delivery by albumin nanoparticles improved neurological function and neuronal damage in transient middle cerebral artery occlusion rats. Front. Pharmacol.9, 1403. 10.3389/fphar.2018.01403

  • CrossRef
  • Google Scholar

• 263

  XuL.DingL.SuY.ShaoR.LiuJ.HuangY. (2019). Neuroprotective effects of curcumin against rats with focal cerebral ischemia-reperfusion injury. Int. J. Mol. Med.43, 1879–1887. 10.3892/ijmm.2019.4094

  • CrossRef
  • Google Scholar

• 264

  XuN.HuangF.JianC.QinL.LuF.WangY.et al (2019). Neuroprotective effect of salidroside against central nervous system inflammation-induced cognitive deficits: a pivotal role of sirtuin 1-dependent N rf-2/HO -1/NF -κ B pathway. Phytotherapy Res.33, 1438–1447. 10.1002/ptr.6335

  • CrossRef
  • Google Scholar

• 265

  XuS.-H.YinM.-S.LiuB.ChenM.-L.HeG.-w.ZhouP.-P.et al (2017). Tetramethylpyrazine-2'-O-sodium ferulate attenuates blood-brain barrier disruption and brain oedema after cerebral ischemia/reperfusion. Hum. Exp. Toxicol.36, 670–680. 10.1177/0960327116657401

  • CrossRef
  • Google Scholar

• 266

  XueD.JiangH.XiaoK.XuanL. (2001). Isolation, identification and antioxidant effect of soy isoflavones. J. Nanjing Agric. Univ., 89–92. 10.1186/isrctn98074661

  • CrossRef
  • Google Scholar

• 267

  XueX.QuX.-J.YangY.ShengX.-H.ChengF.JiangE.-N.et al (2010). Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor κB p65 activation. Biochem. Biophysical Res. Commun.403, 398–404. 10.1016/j.bbrc.2010.11.042

  • CrossRef
  • Google Scholar

• 268

  XueX.QuanY.GongL.GongX.LiY. (2020). A review of the processed Polygonum multiflorum (Thunb.) for hepatoprotection: clinical use, pharmacology and toxicology. J. Ethnopharmacol.261, 113121. 10.1016/j.jep.2020.113121

  • CrossRef
  • Google Scholar

• 269

  XuJ.KongX.XiuH.DouY.WuZ.SunP. (2018). Combination of curcumin and vagus nerve stimulation attenuates cerebral ischemia/reperfusion injury-induced behavioral deficits. Biomed. Pharmacother.103, 614–620. 10.1016/j.biopha.2018.04.069

  • CrossRef
  • Google Scholar

• 270

  XuLJiaL.WangQ.HouJ.LiS.TengJ. (2018). Salidroside attenuates hypoxia/reoxygenation-induced human brain vascular smooth muscle cell injury by activating the SIRT1/FOXO3α pathway. Exp. Ther. Med.15, 822–830. 10.3892/etm.2017.5446

  • CrossRef
  • Google Scholar

• 271

  YanA.XieY. (2018). Effect of angelicae sinensis radix polysaccharide on oxidative stress level and inflammatory cytokine expression of brain tissues in rats with cerebral ischemia reperfusion injury. Chin. J. Exp. Trad. Med. Formulae24, 123–127. 10.1159/000418069

  • CrossRef
  • Google Scholar

• 272

  YanL.ZhouQ. H. (2012). Study on neuroprotective effects of astragalan in rats with ischemic brain injury and its mechanisms. Zhongguo Ying Yong Sheng Li Xue Za Zhi28, 373–377. 10.1016/j.jalz.2010.05.551

  • CrossRef
  • Google Scholar

• 273

  YanS.ChenL.WeiX.ChengL.KongL.LiuX.et al (2015). Tetramethylpyrazine analogue CXC195 ameliorates cerebral ischemia-reperfusion injury by regulating endothelial nitric oxide synthase phosphorylation via PI3K/Akt signaling. Neurochem. Res.40, 446–454. 10.1007/s11064-014-1485-x

  • CrossRef
  • Google Scholar

• 274

  YangJ.HuangJ.ShenC.ChengW.YuP.WangL.et al (2018a). Resveratrol treatment in different time-attenuated neuronal apoptosis after oxygen and glucose deprivation/reoxygenation via enhancing the activation of nrf-2 signaling pathway in vitro. Cel Transpl.27, 1789–1797. 10.1177/0963689718780930

  • CrossRef
  • Google Scholar

• 275

  YangJ.YanH.LiS.ZhangM. (2018b). Berberine ameliorates MCAO induced cerebral ischemia/reperfusion injury via activation of the BDNF-TrkB-PI3K/Akt signaling pathway. Neurochem. Res.43, 702–710. 10.1007/s11064-018-2472-4

  • CrossRef
  • Google Scholar

• 276

  YangX.ZhangL.JiangS.GongP.ZengF. (2009). Effect of dauricine on apoptosis and expression of apoptogenic protein after transient focal cerebral ischemia-reperfusion injury in rats. Zhongguo Zhong Yao Za Zhi34, 78–83. 10.31083/jin-170047

  • CrossRef
  • Google Scholar

• 277

  YangY.LiuP.ChenL.LiuZ.ZhangH.WangJ.et al (2013). Therapeutic effect of Ginkgo biloba polysaccharide in rats with focal cerebral ischemia/reperfusion (I/R) injury. Carbohydr. Polym.98, 1383–1388. 10.1016/j.carbpol.2013.07.045

  • CrossRef
  • Google Scholar

• 278

  YangY.LiuY.LiuM.HuW.YangX.DengY.et al (2020). The neuroprotective effects of icariin on focal cerebral ischemia reperfusion injured rats during early recovery period. Trad. Chin. Drug Res. Clin. Pharmacol.31, 662–667. 10.3892/ijmm.2019.4094

  • CrossRef
  • Google Scholar

• 279

  YeT. M.SunL. N.SuF.ShenJ.WangH. P.YeZ. G.et al (2010). Study of the effects of Auricularia auricular polysaccharide on local ischemia/reperfusion injury in rat. Zhongguo Ying Yong Sheng Li Xue Za Zhi26, 423–426. 10.14711/thesis-b878059

  • CrossRef
  • Google Scholar

• 280

  YenT.-L.ChenR.-J.JayakumarT.LuW.-J.HsiehC.-Y.HsuM.-J.et al (2016). Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats. Translational Res.170, 57–72. 10.1016/j.trsl.2015.12.002

  • CrossRef
  • Google Scholar

• 281

  YenT.-L.HsuW.-H.HuangS. K.-H.LuW.-J.ChangC.-C.LienL.-M.et al (2013). A novel bioactivity of andrographolide fromAndrographis paniculataon cerebral ischemia/reperfusion-induced brain injury through induction of cerebral endothelial cell apoptosis. Pharm. Biol.51, 1150–1157. 10.3109/13880209.2013.782051

  • CrossRef
  • Google Scholar

• 282

  YinF.LiuJ.ZhengX.GuoL.XiaoH. (2010). Geniposide induces the expression of heme oxygenase-1 via PI3K/Nrf2-signaling to enhance the antioxidant capacity in primary hippocampal neurons. Biol. Pharm. Bull.33, 1841–1846. 10.1248/bpb.33.1841

  • CrossRef
  • Google Scholar

• 283

  YinF.ZhouH.FangY.LiC.HeY.YuL.et al (2020). Astragaloside IV alleviates ischemia reperfusion-induced apoptosis by inhibiting the activation of key factors in death receptor pathway and mitochondrial pathway. J. Ethnopharmacology248, 112319. 10.1016/j.jep.2019.112319

  • CrossRef
  • Google Scholar

• 284

  YinQ.WangR.YangS.WuZ.GuoS.DaiX.et al (2017). Influence of temperature on transdermal penetration enhancing mechanism of borneol: a multi-scale study. Int. J. Mol. Sci.18, 195. 10.3390/ijms18010195

  • CrossRef
  • Google Scholar

• 285

  YingL.ChiY. (2007). Research progress on the separation and structure-activity relationship of flavonoid glycosides from botanicals. Chin. J. Inf. Trad. Chin. Med., 100–102. 10.4268/cjcmm20131120

  • CrossRef
  • Google Scholar

• 286

  YouX.YangM.MingX.LiQ.QianL.LiuY.et al (2020). Efficacy of ligustrazine hydrochloride injection combined with butylphthalide capsule in the treatment of acute cerebral infarction and the effect of hemorheology. Shaanxi J. Trad. Chin. Med.41, 743–745+757. 10.4314/tjpr.v17i9.28

  • CrossRef
  • Google Scholar

• 287

  YuB.RuanM.ZhangZ. N.ChengH. B.ShenX. C. (2016). Synergic effect of borneol and ligustrazine on the neuroprotection in global cerebral ischemia/reperfusion injury: a region-specificity study. Evid. Based Complement. Alternat Med.2016, 4072809. 10.1155/2016/4072809

  • CrossRef
  • Google Scholar

• 288

  YuB.ZhongF. M.YaoY.DengS. Q.XuH. Q.LuJ. F.et al (2019). Synergistic protection of tetramethylpyrazine phosphate and borneol on brain microvascular endothelium cells injured by hypoxia. Am. J. Transl Res.11, 2168–2180. 10.1093/chromsci/46.5.395

  • CrossRef
  • Google Scholar

• 289

  YuB.RuanM.LiangT.HuangS. W.LiuS. J.ChengH. B.et al (2017). Tetramethylpyrazine phosphate and borneol combination therapy synergistically attenuated ischemia-reperfusion injury of the hypothalamus and striatum via regulation of apoptosis and autophagy in a rat model. Am. J. Transl Res.9, 4807–4820. 10.1007/978-3-7091-6837-0_3

  • CrossRef
  • Google Scholar

• 290

  YuP.WangL.TangF.ZengL.ZhouL.SongX.et al (2017). Resveratrol pretreatment decreases ischemic injury and improves neurological function via sonic hedgehog signaling after stroke in rats. Mol. Neurobiol.54, 212–226. 10.1007/s12035-015-9639-7

  • CrossRef
  • Google Scholar

• 291

  ZhaiL.LiuM.WangT.ZhangH.LiS.GuoY. (2017). Picroside II protects the blood-brain barrier by inhibiting the oxidative signaling pathway in cerebral ischemia-reperfusion injury. PLoS One12, e0174414. 10.1371/journal.pone.0174414

  • CrossRef
  • Google Scholar

• 292

  ZhangC.ChenS.ZhangZ.XuH.ZhangW.XuD.et al (2020). Asiaticoside alleviates cerebral ischemia-reperfusion injury via NOD2/mitogen-activated protein kinase (MAPK)/Nuclear factor kappa B (NF-kappaB) signaling pathway. Med. Sci. Monit.26, e920325. 10.12659/msm.920325

  • CrossRef
  • Google Scholar

• 293

  ZhangH.-F.HuX.-M.WangL.-X.XuS.-Q.ZengF.-D. (2009). Protective effects of scutellarin against cerebral ischemia in rats: evidence for inhibition of the apoptosis-inducing factor pathway. Planta Med.75, 121–126. 10.1055/s-0028-1088368

  • CrossRef
  • Google Scholar

• 294

  ZhangH.ZhaiL.WangT.LiS.GuoY. (2017). Picroside II exerts a neuroprotective effect by inhibiting the mitochondria cytochrome C signal pathway following ischemia reperfusion injury in rats. J. Mol. Neurosci.61, 267–278. 10.1007/s12031-016-0870-0

  • CrossRef
  • Google Scholar

• 295

  ZhangJ.WuC.DuG.QinX. (2019). Astragaloside IV derived from Astragalus membranaceus: a research review on the pharmacological effects. Adv. Pharmacol.87, 89–112. 10.1016/bs.apha.2019.08.002

  • CrossRef
  • Google Scholar

• 296

  ZhangJ.YangL.GuoL. J. (2011). Effects od daurinoline on microcirculation of cerebral pia mater in mice. Med. J. Wuhan Univ.32, 187. 10.1080/10739680601139153

  • CrossRef
  • Google Scholar

• 297

  ZhangL.CuiM.ChenS. (2020a). Identification of the molecular mechanisms of peimine in the treatment of cough using computational target fishing. Molecules25, 1105. 10.3390/molecules25051105

  • CrossRef
  • Google Scholar

• 298

  ZhangL.LiF.HouC.ZhuS.ZhongL.ZhaoJ.et al (2020b). Design, synthesis, and biological evaluation of novel stachydrine derivatives as potent neuroprotective agents for cerebral ischemic stroke. Naunyn Schmiedebergs Arch. Pharmacol.393, 2529–2542. 10.1007/s00210-020-01868-4

  • CrossRef
  • Google Scholar

• 299

  ZhangQ.BianH.GuoL.ZhuH. (2016b). Pharmacologic preconditioning with berberine attenuating ischemia-induced apoptosis and promoting autophagy in neuron. Am. J. Transl Res.8, 1197–1207. 10.4016/14162.01

  • CrossRef
  • Google Scholar

• 300

  ZhangQ.BianH.GuoL.ZhuH. (2016a). Berberine preconditioning protects neurons against ischemia via sphingosine-1-phosphate and hypoxia-inducible factor-1α. Am. J. Chin. Med.44, 927–941. 10.1142/s0192415x16500518

  • CrossRef
  • Google Scholar

• 301

  ZhangQ.ZhaoY.-H. (2014). Therapeutic angiogenesis after ischemic stroke: Chinese medicines, bone marrow stromal cells (BMSCs) and their combinational treatment. Am. J. Chin. Med.42, 61–77. 10.1142/s0192415x14500049

  • CrossRef
  • Google Scholar

• 302

  ZhangR.-X.LiM.-X.JiaZ.-P. (2008). Rehmannia glutinosa: review of botany, chemistry and pharmacology. J. Ethnopharmacology117, 199–214. 10.1016/j.jep.2008.02.018

  • CrossRef
  • Google Scholar

• 303

  ZhangX.DuQ.YangY.WangJ.LiuY.ZhaoZ.et al (2018). Salidroside alleviates ischemic brain injury in mice with ischemic stroke through regulating BDNK mediated PI3K/Akt pathway. Biochem. Pharmacol.156, 99–108. 10.1016/j.bcp.2018.08.015

  • CrossRef
  • Google Scholar

• 304

  ZhangX.ZhangX.WangC.LiY.DongL.CuiL.et al (2012). Neuroprotection of early and short-time applying berberine in the acute phase of cerebral ischemia: up-regulated pAkt, pGSK and pCREB, down-regulated NF-κB expression, ameliorated BBB permeability. Brain Res.1459, 61–70. 10.1016/j.brainres.2012.03.065

  • CrossRef
  • Google Scholar

• 305

  ZhangY.FangM.SunY.ZhangT.ShiN.LiJ.et al (2018). Curcumin attenuates cerebral ischemia injury in Sprague-Dawley rats and PC12 cells by suppressing overactivated autophagy. J. Photochem. Photobiol. B: Biol.184, 1–6. 10.1016/j.jphotobiol.2018.05.010

  • CrossRef
  • Google Scholar

• 306

  ZhangX.LaiW.YingX.XuL.ChuK.BrownJ.et al (2019). Salidroside reduces inflammation and brain injury after permanent middle cerebral artery occlusion in rats by regulating PI3K/PKB/Nrf2/NFκB signaling rather than complement C3 activity. Inflammation42, 1830–1842. 10.1007/s10753-019-01045-7

  • CrossRef
  • Google Scholar

• 307

  ZhaoB.ShenC.ZhengZ.WangX.ZhaoW.ChenX.et al (2018). Peiminine inhibits glioblastoma in Vitro and in Vivo through cell cycle arrest and autophagic flux blocking. Cel Physiol. Biochem.51, 1566–1583. 10.1159/000495646

  • CrossRef
  • Google Scholar

• 308

  ZhaoT.TangH.XieL.ZhengY.MaZ.SunQ.et al (2019). Scutellaria baicalensis Georgi. (Lamiaceae): a review of its traditional uses, botany, phytochemistry, pharmacology and toxicology. J. Pharm. Pharmacol.71, 1353–1369. 10.1111/jphp.13129

  • CrossRef
  • Google Scholar

• 309

  ZhaoX.LiX.RenQ.TianJ.ChenJ. (2016). Calycosin induces apoptosis in colorectal cancer cells, through modulating the ERβ/MiR-95 and IGF-1R, PI3K/Akt signaling pathways. Gene591, 123–128. 10.1016/j.gene.2016.07.012

  • CrossRef
  • Google Scholar

• 310

  ZhaoY.LiuY.ChenK. (2016). Mechanisms and clinical application of tetramethylpyrazine (an interesting natural compound isolated from Ligusticum wallichii): current status and perspective. Oxid Med. Cel Longev2016, 2124638. 10.1155/2016/2124638

  • CrossRef
  • Google Scholar

• 311

  ZhengC.QinL.-P. (2007). Chemical components of Centella asiatica and their bioactivities. Zhong Xi Yi Jie He Xue Bao5, 348–351. 10.3736/jcim20070324

  • CrossRef
  • Google Scholar

• 312

  ZhengJ.-S.ZhengP.-D.MungurR.ZhouH.-J.HassanM.JiangS.-N. (2018). Ginkgolide B promotes the proliferation and differentiation of neural stem cells following cerebral ischemia/reperfusion injury, both in vivo and in vitro. Neural Regen. Res.13, 1204–1211. 10.4103/1673-5374.232476

  • CrossRef
  • Google Scholar

• 313

  ZhengQ.ChenZ.-X.XuM.-B.ZhouX.-L.HuangY.-Y.ZhengG.-Q.et al (2018a). Borneol, a messenger agent, improves central nervous system drug delivery through enhancing blood-brain barrier permeability: a preclinical systematic review and meta-analysis. Drug Deliv.25, 1617–1633. 10.1080/10717544.2018.1486471

  • CrossRef
  • Google Scholar

• 314

  ZhengQ.HuangY. Y.ZhuP. C.TongQ.BaoX. Y.ZhangQ. H.et al (2018b). Ligustrazine exerts cardioprotection in animal models of myocardial ischemia/reperfusion injury: preclinical evidence and possible mechanisms. Front. Pharmacol.9, 729. 10.3389/fphar.2018.00729

  • CrossRef
  • Google Scholar

• 315

  ZhengT.JiangH.JinR.ZhaoY.BaiY.XuH.et al (2019). Ginsenoside Rg1 attenuates protein aggregation and inflammatory response following cerebral ischemia and reperfusion injury. Eur. J. Pharmacol.853, 65–73. 10.1016/j.ejphar.2019.02.018

  • CrossRef
  • Google Scholar

• 316

  ZhengW.-x.CaoX.-l.WangF.WangJ.YingT.-z.XiaoW.et al (2015). Baicalin inhibiting cerebral ischemia/hypoxia-induced neuronal apoptosis via MRTF-A-mediated transactivity. Eur. J. Pharmacol.767, 201–210. 10.1016/j.ejphar.2015.10.027

  • CrossRef
  • Google Scholar

• 317

  ZhongY.GaoY.XuY.QiC.WuB. (2020). Synthesis of novel aryloxyethylamine derivatives and evaluation of their in Vitro and in Vivo neuroprotective activities. Chem. Biodivers.7, 33. 10.1080/10739680600777599

  • CrossRef
  • Google Scholar

• 318

  ZhongZ. F.HanJ.ZhangJ. Z.XiaoQ.ChenJ. Y.ZhangK.et al (2019). Neuroprotective effects of salidroside on cerebral ischemia/reperfusion-induced behavioral impairment involves the dopaminergic system. Front. Pharmacol.10, 1433. 10.3389/fphar.2019.01433

  • CrossRef
  • Google Scholar

• 319

  ZhouJ.WenB.XieH.ZhangC.BaiY.CaoH.et al (2021). Advances in the preparation and assessment of the biological activities of chitosan oligosaccharides with different structural characteristics. Food Funct.12, 926–951. 10.1039/d0fo02768e

  • CrossRef
  • Google Scholar

• 320

  ZhouJ.WuJ.ChenX.FortenberyN.EksiogluE.KodumudiK. N.et al (2011). Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions. Int. Immunopharmacology11, 890–898. 10.1016/j.intimp.2011.01.007

  • CrossRef
  • Google Scholar

• 321

  ZhouP.DuS.ZhouL.SunZ.ZhuoL. H.HeG.et al (2019). Tetramethylpyrazine2′Osodium ferulate provides neuroprotection against neuroinflammation and brain injury in MCAO/R rats by suppressing TLR-4/NF-κB signaling pathway. Pharmacol. Biochem. Behav.176, 33–42. 10.1016/j.pbb.2018.08.010

  • CrossRef
  • Google Scholar

• 322

  ZhouY.LiH.-q.LuL.FuD.-l.LiuA.-j.LiJ.-h.et al (2014). Ginsenoside Rg1 provides neuroprotection against blood brain barrier disruption and neurological injury in a rat model of cerebral ischemia/reperfusion through downregulation of aquaporin 4 expression. Phytomedicine21, 998–1003. 10.1016/j.phymed.2013.12.005

  • CrossRef
  • Google Scholar

• 323

  ZhouZ.LuJ.LiuW.-W.ManaenkoA.HouX.MeiQ.et al (2018). Advances in stroke pharmacology. Pharmacol. Ther.191, 23–42. 10.1016/j.pharmthera.2018.05.012

  • CrossRef
  • Google Scholar

• 324

  ZhuH.-F.WanD.LuoY.ZhouJ.-L.ChenL.XuX.-Y. (2010). Catalpol increases brain angiogenesis and up-regulates VEGF and EPO in the rat after permanent middle cerebral artery occlusion. Int. J. Biol. Sci.6, 443–453. 10.7150/ijbs.6.443

  • CrossRef
  • Google Scholar

• 325

  ZouJ.GaoP.HaoX.XuH.ZhanP.LiuX. (2018). Recent progress in the structural modification and pharmacological activities of ligustrazine derivatives. Eur. J. Med. Chem.147, 150–162. 10.1016/j.ejmech.2018.01.097

  • CrossRef
  • Google Scholar

• 326

  ZuoW.YanF.ZhangB.HuX.MeiD. (2018). Salidroside improves brain ischemic injury by activating PI3K/Akt pathway and reduces complications induced by delayed tPA treatment. Eur. J. Pharmacol.830, 128–138. 10.1016/j.ejphar.2018.04.001

  • CrossRef
  • Google Scholar