REVIEW article

Front. Pharmacol., 18 May 2022

Sec. Neuropharmacology

Volume 13 - 2022 | https://doi.org/10.3389/fphar.2022.854249

Neuroprotective Effects of Quercetin on Ischemic Stroke: A Literature Review

  • 1. Xi’an Hospital of Traditional Chinese Medicine, Xi’an, China

  • 2. Shaanxi University of Chinese Medicine, Xianyang, China

  • 3. Guang’anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing, China

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Abstract

Ischemic stroke (IS) is characterized by high recurrence and disability; however, its therapies are very limited. As one of the effective methods of treating acute attacks of IS, intravenous thrombolysis has a clear time window. Quercetin, a flavonoid widely found in vegetables and fruits, inhibits immune cells from secreting inflammatory cytokines, thereby reducing platelet aggregation and limiting inflammatory thrombosis. In pre-clinical studies, it has been shown to exhibit neuroprotective effects in patients with ischemic brain injury. However, its specific mechanism of action remains unknown. Therefore, this review aims to use published data to elucidate the potential value of quercetin in patients with ischemic brain injury. This article also reviews the plant sources, pharmacological effects, and metabolic processes of quercetin in vivo, thus focusing on its mechanism in inhibiting immune cell activation and inflammatory thrombosis as well as promoting neuroprotection against ischemic brain injury.

1 Introduction

Quercetin, which is present in many plants, has become a nutraceutical because of its significant antioxidant and anti-inflammatory activities (Shen et al., 2021; Zou et al., 2021), especially with its ability to scavenge free radicals (Anand David et al., 2016). Clinical studies have shown that quercetin has certain therapeutic effects on cardiovascular diseases (Dehghani et al., 2021), metabolic syndrome (Leyva-Soto et al., 2021), COVID-19 (Di Pierro et al., 2021), and central nervous system diseases.

Ischemic stroke (IS) is caused by hypoxic necrosis of brain tissue due to impaired blood supply to the brain, thereby leading to ischemia. It is the third leading cause of death worldwide (GBD, 2021). In 2017, there were 80.5 (UI78.9-82.6) deaths per 100,000 people, of which 45% were related to IS (Avan et al., 2019); IS accounted for 62.4% of stroke events in 2019 (GBD, 2021). Various risk factors, such as hypertension, diabetes, high body mass index, and smoking, determine the prevalence of IS and its complications; the antioxidant and inflammatory balance mechanisms in the body are severely damaged, thus causing an increase in neuronal reactive oxygen species (ROS), dysfunction, calcium excess, and oxidative stress (Lo et al., 2003).

Vitamins, carotenoids, and quercetin, which are natural antioxidants, are effectively used to prevent IS. Their mechanism may be related to the synergistic effects of vitamins and antioxidants (Ratnam et al., 2006). The molecular structure of quercetin is C15H10O7 (Magar and Sohng, 2020), which means that there is one -OH at each of the 3, 3′, 5, 7, and 4′ positions (Rice-Evans et al., 1997), and is present in a variety of plants and fruits (Figure 1). Quercetin is a polyphenol belonging to the flavonoid family (Brüll et al., 2015). Inflammatory thrombus formation exacerbates nerve damage in IS (De Meyer et al., 2022). Clinical studies have found that oral quercetin can reduce collagen-stimulated platelet tyrosine phosphorylation and thus inhibit platelet aggregation (Hubbard et al., 2004). Quercetin pre-treatment also reduces lipopolysaccharide-induced neutrophil IL-6 secretion (Liu J. et al., 2005). This process slows the formation of inflammatory thrombi, thus reducing the occurrence of IS.

FIGURE 1

Recent studies have demonstrated the neuroprotective properties of quercetin in in vivo and in vitro IS models (Yang et al., 2021). Therefore, this article is the first to describe the source and physicochemical properties of quercetin as well as the pathogenesis of ischemic brain injury. The therapeutic potential of quercetin in ischemic brain injury has been highlighted, including its role in limiting the secretion of inflammatory factors by various immune cells, thereby inhibiting inflammatory thrombosis, oxidative stress, apoptosis, autophagy.

2 Source and Physicochemical Properties of Quercetin

The term, “quercetin,” has been used since the mid-18th century and is derived from the Latin word, “quercetum” (Jaimand et al., 2012). Quercetin is highly lipophilic and has poor water solubility, rapid metabolism, short half-life, and low bioavailability (Mukhopadhyay and Prajapati, 2015). Meanwhile, it is a unique polyphenol found in large quantities in various leafy vegetables, fruits, and herbs, such as apples, berries, long-leaf berry cilantro, cumin, lingonberry, lingonberry, wild grapes, and onions (Yang D. et al., 2020; Sharifi-Rad et al., 2021). According to previous research, quercetin has more than seven biological features, including neuroprotection, anti-allergy, anti-oxidation, anti-inflammation, immune regulation, anti-microbial, and anti-tumor properties (Bjeldanes and Chang, 1977; Dajas, 2012; Oboh et al., 2016; Darband et al., 2018; Dhiman et al., 2019; Huang et al., 2020; Shabbir et al., 2021). However, some studies have indicated that quercetin can induce mutations and promote mutagenesis (Bjeldanes and Chang, 1977). Conversely, Sumi et al. (2013) found that quercetin glucoside promoted angiogenesis after ischemia, but did not promote tumor growth.

In addition, the effectiveness of quercetin depends mainly on the plant source, dose, and chemical properties after processing (Najda et al., 2019). It can also be combined with salivary proteins to form soluble protein-quercetin binary aggregates. It is generated in the small intestines and is directly absorbed by the sodium-dependent glucose transporter-1 in the cecum and colon (Manach et al., 2004). Quercetin is also absorbed by intestinal epithelial cells, thus entering the liver through lipophilic dispersion and undergoing metabolism (Shen et al., 2021). In humans, quercetin has very low bioavailability and is highly unstable (0–50%), with a half-life of 1–2 h in the body after ingesting quercetin-rich foods or supplements (Graefe et al., 1999). Furthermore, quercetin poorly crosses the blood-brain barrier (BBB) (Oliveira et al., 2021). After dietary absorption, quercetin is digested and metabolized extremely quickly; therefore, its pharmacological effects are concentrated on in vitro studies rather than in vivo (Williams et al., 2004; Barnes et al., 2011). Therefore, various approaches have been attempted to improve the bioavailability of quercetin in the brain, such as enzyme modification or nano-encapsulation (Pateiro et al., 2021). Simultaneously, nanotechnology and targeted vectors are solutions to overcome the shortcomings of quercetin, such as low bioavailability and poor BBB passage (Naseri et al., 2015). The bioavailability of quercetin is 50 times higher than that of standard quercetin products after being packaged into nanocapsules (Riva et al., 2019). Alternatively, it changes the basic structure of quercetin to improve its pharmacokinetic and neuroprotective abilities (Chen et al., 2005). Table 1 summarises the sources of quercetin.

TABLE 1

Scientific NameWalnutActive PortionsFamilyReferences
Davidia involucrata BaillDove treeFruits and seedsNyssaceaeGirardelo et al. (2020)
Mangifera indica L.MangoFruits and KernelsAnacardiaceaeMwaurah et al. (2020)
Arctium lappa L.Great Burdock AcheneFruits and rootsAsteraceaeMoro and T P S Clerici, (2021)
Punica granatum L.PomegranateLeaves and fruits LythraceaeRojas-Garbanzo et al. (2021)
Theobroma speciosumTheobromaShells and beansSterculiaceaeMar et al. (2021)
Allium cepa L.OnionBulbsLiliaceaeFredotović et al. (2021)
Capsicum annuum LSweet PepperfruitsSolanaceaeGuevara et al. (2021)
Syringa vulgaris L.LilacFlowers and leavesOleaceae Hanganu et al. (2021)
Sorbus aucuparia L.mountain-ashFruitsRosaceaeRutkowska et al. (2021)
GracilariaSeaweedFruitsGracilariaceaePourakbar et al. (2021)
Musa nana LourBananaSkins and fruitsMusaceaeBashmil et al. (2021)
Lactuca sativa L.LettuceLeavesAsteraceaeAssefa et al. (2021)
Abies alba MillSilver firLeavesPinaceae Vek et al. (2021)
Juglans regia L.WalnutNutsJuglandaceaeKalogiouri and Samanidou, (2021)
Malus pumila MillapplePeels and fruitsRosaceaeYousefi-Manesh et al. (2021)
Arnica montana L.A. MontanaFlowers and rootsAsteraceaeNieto-Trujillo et al. (2021)
Paronychia argentea LP. argenteaLeaves and HerbsCaryophyllaceaeAbdelkhalek et al. (2021)

Sources of quercetin.

3 Pathogenesis of Ischemic Stroke

3.1 Inflammatory Thrombus

In the pathophysiological process of IS, inflammatory thrombi lead to cerebral vascular occlusion, inflammatory response, and severe nerve damage after ischemic events (De Meyer et al., 2022). Early platelet adhesion and activation are key factors for the development of IS inflammatory thrombosis. The main receptors that mediate platelet adhesion are glycoprotein (GP) VI and integrin α2β1, both of which bind to the GPIbα subunit of collagen and the GPIB-IX-V complex, which interact with the von Willebrand factor (vWF) (Poulter et al., 2017; Constantinescu-Bercu et al., 2022; Feitsma et al., 2022). After endothelial injury, vWF interacts with GPIbα, thus causing platelets to decelerate on the fixed vWF (Constantinescu-Bercu et al., 2022; Kanaji et al., 2022) and thereby contributing to platelet aggregation. The use of GPIbα-vWF inhibitors restores vascular patency by specifically breaking down the outer layer of the occlusive thrombus (Le Behot et al., 2014). Subsequently, platelet activation induces a conformational change in the GPIIb/IIIa surface receptor and its affinity to fibrinogen and vWF, thus promoting platelet aggregation (O'Brien and Salmon, 1990).

In addition, vWF was found in different samples of thrombus extracted from IS patients; the thrombus contained 20.3% ± 10.1% vWF on average (Denorme et al., 2016). In a middle cerebral artery occlusion (MCAO) rat model, cerebral infarct size and fibrinogen deposition were significantly increased in platelet-only vWF chimeric rats (Verhenne et al., 2015). Interestingly, vWF can be cleaved by metalloprotease ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13. ADAMTS13 effectively dissolves anti-tissue-plasminogen activator (t-PA) thrombus within 5–60 min of MCAO occlusion (Denorme et al., 2016). Furthermore, caADAMTS13, a ADAMTS13 variant, significantly reduced residual vWF, fibrin, and platelet aggregation as well as neutrophil recruitment in the middle cerebral artery (MCA) (South et al., 2022).

However, thrombosis not only involves simple platelet aggregation, but also includes leukocyte-platelet complexation (Li et al., 2015; Pircher et al., 2019; Schrottmaier et al., 2020). This may be because basic diseases, such as hyperlipidemia and hyperglycemia, stimulate hematopoietic cells in the bone marrow to produce a large number of white blood cells in the circulating blood (Stumvoll et al., 2005; Zhou et al., 2016; Vekic et al., 2019). Neutrophils are closely related to thrombosis in IS patients with COVID-19 (Genchi et al., 2022). Neutrophils account for the majority of leukocytes in IS thrombi, followed by macrophages and T cells (Heo et al., 2020). This difference is partly due to their proportion in the circulating blood under physiological conditions; however, IS is also related to the level of activation of various white blood cells. Thrombus formation is a series of complex events that occur sequentially in the vascular system, including endothelial activation, neutrophil extracellular trap (NET) formation, vWF secretion, blood cell adhesion, aggregation, and activation (Yang J. et al., 2020). Genetic deletion of PKM2 in bone marrow hematopoietic cells reduces NET after cerebral ischemia/reperfusion, which further reduces fibrinogen, platelet deposition, and inflammatory cytokines in the brain (Dhanesha et al., 2022). Similarly, rats lacking CD84 on their platelets or T cells showed reduced cerebral thrombosis and milder nerve damage after MCAO (Schuhmann et al., 2020). In contrast, endothelial CD69 deficiency increases fibrinogen and vWF levels in ischemic tissue and exacerbates nerve injury (Brait et al., 2019). Thus, inhibition of inflammatory thrombi formation is one of the goals of IS prevention.

3.2 Immune Activation

Activation of immune cells, including neutrophils, T cells, and microglia, is involved in brain tissue repair after IS (Ma et al., 2017). Subsequently, neutrophils are attracted along a concentration gradient of chemokines in areas of ischemia to release pro-inflammatory factors, ROS, proteases, and matrix metalloproteinases (MMPs) (Wang et al., 2007), thus leading to the disruption of the BBB and exacerbation of neurological damage (Rosell et al., 2008). Similarly, in the acute phase of IS, Th1 and Th17 cells degrade tight junction proteins (TJ) by secreting IFN-γ, IL-17, and IL-21, thereby further disrupting the integrity of the BBB (Gelderblom et al., 2012; Clarkson et al., 2014). T cells and their isoforms have also been associated with repair and functional improvement in late brain injury (Liesz et al., 2009). During ongoing inflammation, activated M1 microglia phagocytose astrocyte ends and disrupt the integrity of the BBB by secreting various vascular proteins (Wang et al., 2018; Haruwaka et al., 2019).

3.3 Oxidative Stress

Oxidative stress and mitochondrial dysfunction are important factors for the development of cerebral ischemic injury (Lo et al., 2003). Mitochondria are central to ROS production and cell death (Lo et al., 2003). Cerebral ischemia induces a cascade of excessive ROS production. Excess ROS leads to lipid peroxidation (LPO), exacerbates oxidative damage to proteins and nucleic acids, and contributes to neuronal apoptosis and BBB destruction (Allen and Bayraktutan, 2009; Kleinschnitz et al., 2010; Casas et al., 2017; Sun et al., 2018). Immune activation and oxidative stress also contribute to programmed neuronal death in the ischemic zone.

3.4 Procedural Death

Both hypoxia and ischemia induce autophagy. Shortly thereafter, autophagic vesicles accumulate extensively in the brain tissue (Tuo et al., 2021). Mitochondrial autophagy facilitates the maintenance of cellular homeostasis under mild ischemia or hypoxia. In contrast, sustained ischemia-reperfusion (I/R) results in prolonged autophagy, thus promoting neuronal cell damage or even death (Zhang et al., 2013). Similarly, neuronal apoptosis is the main mechanism through which I/R injury induces cell death. The balance between anti-apoptotic Bcl-2 and pro-apoptotic Bax protein expression is critical for the regulation of apoptosis (Culmsee and Plesnila, 2006). ROS production and mitochondria-dependent apoptosis play an important role in neuronal death following I/R injury (Jordan et al., 2011; Wang et al., 2014). After IS, a series of molecular events induced by oxidative stress overlap with iron sagging/oxidation processes; these have common molecular targets, such as LPO and glutathione (GSH) depletion (Seiler et al., 2008; Choi et al., 2013; Yang et al., 2014). Iron death is dependent on excessive iron accumulation, with the core process being LPO (Cao and Dixon, 2016). In a rat model of MCAO, GSH inhibited iron death by driving glutathione peroxidase 4 (GPx4) expression, thereby protecting neurons and reducing core ischemic areas (Karuppagounder et al., 2016; Alim et al., 2019).

4 Pharmacological Effects of Quercetin on Ischemic Stroke

4.1 Inhibition of Immune Cell Recruitment

The activation of peripheral immune cells promotes platelet aggregation. Pre-treatment of activated T cells with quercetin blocks IL-12-induced JAK-STAT tyrosine phosphorylation, thereby reducing T cell proliferation and Th1 differentiation (Muthian and Bright, 2004). Quercetin has a similar effect on neutrophils. NETs are closely associated with inflammatory thromboses. Quercetin does not directly affect NET formation, but inhibits it in peripheral blood polykaryotic cells by downregulating TNF-α production in lipopolysaccharide (LPS) peripheral blood monocytes (Yuan et al., 2020; Jo et al., 2021). During inflammation, LPS delays the spontaneous apoptosis of neutrophils, while quercetin accelerates this process (Liu J. J. et al., 2005; Yuan et al., 2020). This is associated with a reduction in the expression of inflammatory cytokines, activation of PKCa, and enhancement of CD95-mediated apoptosis in neutrophils (Russo et al., 2003). Quercetin effectively protects LDL from neutrophil-mediated modification at physiological concentrations (1 µM) and inhibits myeloperoxidase (MPO) oxidative damage (Loke et al., 2008) (Figure 2). Subsequently, quercetin downregulates the TLR-NF-κB signaling pathway, reduces the activities of COX, 5-LOx, NOS, MPO, and CRP, inhibits ldL-induced adhesion molecule expression, and ameliorates endothelial dysfunction in atherosclerosis (Bhaskar et al., 2016). Quercetin also reduces the activity of neutrophil MPO and inhibits the production of HOCl, a powerful oxidant, to protect endothelial cells from oxidative damage (Lu et al., 2018). In contrast, Suri et al. (2008) found that quercetin did not exert excessive influence on neutrophils, but only reduced the calcium response induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP).

FIGURE 2

4.2 Inhibition of Thrombosis

The key factor for the occurrence of IS is the formation of an inflammatory thrombus; thrombolysis significantly alleviates brain injury. Quercetin, a natural flavonol compound, can significantly reduce diabetes-induced platelet aggregation (Mosawy et al., 2014), which may be related to the inhibition of compact platelet granule exocytosis (Mosawy et al., 2013b). Similarly, quercetin inhibits agonists (ADP, collagen, and thrombin) as well as induces platelet aggregation and granule secretion (Liang et al., 2015). Quercetin also binds to the GPIIb/IIIa platelet receptor, thus inhibiting the aggregation-promoting properties of calcium ion carriers and avoiding an increase in platelet-derived particles; these improve hemorheology (Zaragozá et al., 2021) and reduce thrombosis after carotid artery injury induced by FeCl3 in C57BL/6 rats (Mosawy et al., 2013a). Quercetin also effectively blocked in vivo FeCl3-induced arterial thrombosis and reduced IS infarct volume by inhibiting glycoprotein VI (GPVI)-mediated platelet signal transduction (Oh et al., 2021).

The binding of collagen to GPVI leads to receptor aggregation, which stimulates tyrosine phosphorylation and thus causes platelet aggregation (Gibbins et al., 1996; Poole et al., 1997). Quercetin inhibits platelet activation by inhibiting various components of the GPVI signaling pathway (e.g., collagenous tyrosine phosphorylation) (Hubbard et al., 2003; Hubbard et al., 2006; Wright et al., 2010), which may be a key factor for improving nerve injury in IS. In clinical trials, platelet aggregation was inhibited 30 and 120 min after oral quercetin administration, with a corresponding reduction in collagen-stimulated platelet tyrosine phosphorylation (Hubbard et al., 2004). Quercetin also inhibited platelet aggregation when collagen was stimulated at concentrations between 0.5 and 1.0 μg/ml, with IC50 values below 3 μM (Hubbard et al., 2003). Thus, these results support the clinical transformation of quercetin.

In contrast, Lee et al. (2013) found that quercetin did not reduce PT, aPTT, or platelet aggregation in experimental rats. They revealed that its downregulation of mitogen-activated protein kinase (MAPK) activation restricted tissue factor expression, thereby prolonging the time for atherothrombosis development. In endothelial cells, quercetin transcription induces the human t-PA gene by requiring a specific Sp1 (b) element within the proximal promoter region, which is mediated by the P38 MAPK-dependent signaling pathway (Pan et al., 2008).

Protein disulfide isomerase (PDI), a thiol isomerase secreted by vascular cells, is required for thrombosis. Quercetin-3-rutinoside prevents thrombosis in a PDI-dependent manner in experimental rats (Jasuja et al., 2012). Oral administration of 1,000 mg isoquercetin can reduce the plasma concentration of D-dimer by 21.9% and inhibit the activity of PDI in the plasma, thereby exerting an antithrombotic effect (Zwicker et al., 2019). This was related to the reduction of platelet-dependent thrombin content by blocking the production of platelet factor Va (Stopa et al., 2017). Intravenous administration of quercetin significantly attenuated TNF-α levels and prothrombin activity in a rabbit model of LPS-induced DIC (Yu et al., 2013) (Figure 2). Nonetheless, oral quercetin did not prevent thrombo-embolic stroke in an earlier Dutch cohort study (Knekt et al., 2000). This finding may be related to the use of dietary quercetin content as an intervening factor. Table 2 summarizes the role of quercetin and its derivatives in limiting thrombosis.

TABLE 2

IngredientDoseExperimental ModelMechanismReferences
quercetin6 mg/kgC57BL/6 mice; FeCl3-induced carotid artery injury↓GPIIb/IIIa activation; ↓platelet granule exocytosis; Inhibits platelet aggregationMosawy et al. (2013a)
quercetin-3-rutinoside0.5 mg/kgC57BL/6J mice; Laser-induced injury/FeCl3 injuryInhibit fibrin production; ↓Expression of PDI; Inhibits platelet aggregation and thrombosisJasuja et al. (2012)
isoquercetin500 mg or 1,000 mgHealthy cohort (a-e) abstaining from quercetin-rich foods 72 h before intervention, excluding those with oral anticoagulants or antiplatelet drugs↓PDI activity; ↓platelet factor Va; ↓platelet-dependent thrombinStopa et al. (2017)
quercetin2 mg or 10 mgSD rats, FeCl3-induced carotid artery injury↓blood triglyceride, ↓glucose levels; ↓tissue factor, ↓MAPK activationBrüll et al. (2015)
quercetin_Healthy non-smokers with normal coagulation function, not using immunologics, antiplatelet, NSAIDsetc.Blocks GPIIb/IIIa receptors; ↓Platelet activation and aggregationZaragozá et al. (2021)
quercetin0.5 mg/kg, 1 mg/kg, 2 mg/kgAdult male New Zealand white rabbits, DIC experimental models↑Protein C and ATIII; ↓APTT, ↓PT, ↓TNF-α; Anti-inflammatory and anticoagulantYu et al. (2013)
quercetin50 mg/kg, 100 mg/kgWild-type (WT, C57BL/6 strain, 6–8 weeks old, 18–22 g BW) male mice, FeCl3-induced in vivo thrombosis↓granule secre, ↓ROS; ↓platelet aggregation; tionInhibition of αIIbβ3 integrin and GPVI signaling;Oh et al. (2021)
quercetin1 μMQuercetin pretreated human umbilical vein endothelial cells for 0–24 h↑ t-PA gene expression; activate p38MAPKPan et al. (2008)
quercetin6 mg/kgDiabetes C57BL/6 mice; FeCl3-induced carotid artery injury↓granule exocytosis; Inhibits platelet hyperaggregation and thrombosisMosawy et al. (2014)
quercetin5 mg or 69 mgA two-treatment, randomized, double-blind, crossover study↓Syk tyrosine phosphorylation; Inhibits collagen stimulated platelet aggregationHubbard et al. (2006)
quercetin-4¢-O-b-D-glucoside150 mg or 300 mgThose who did not take aspirin and a low quercetin diet 14 days before the study↓Syk tyrosine phosphorylation; Inhibition of GPVI signal transductionHubbard et al. (2004)
Isoquercetin500 mg or 1000 mgPatients with advanced cancer; A multicenter, multidose, open-label phase II clinical trial↓D-dimer, ↓platelet dependent thrombin; Inhibition of PDI activityZwicker et al. (2019)

Anti-platelet aggregation effect of quercetin.

4.3 The Role of Histomorphology

In an in vitro ischemia model, quercetin-treated cells showed improved tolerance to oxygen-glucose deprivation (OGD) or oxygen glucose recovery (ROG) (Lee et al., 2016). Quercetin administration reduced the corrected total infarct volume and edema percentage by 43.6% and 48.5%, respectively, along with a significant behavioral recovery effect (Lee et al., 2015). Quercetin and Kolaviron pre-treatment significantly improved the I/R-induced changes in brain water content. Significant remission of cerebral infarction was observed in the Kolaviron and quercetin treatment groups (Akinmoladun et al., 2015), which might be linked to the role of quercetin in the Sirt1/nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling cascade (Yang et al., 2021). Compared to free quercetin or quercetin-carrying exosome (quercetin-EXO) therapy, treatment with quercetin/mAb gAP43-EXO dramatically reduced infarct size and improved neurological recovery in MCAO reperfusion-induced rats (Guo et al., 2021) (Figure 3). Simultaneously, quercetin improved the IS-associated motor and sensory deficits in the dorsal striatum, which may be related to the upregulation of MC4R-mRNA expression (Ulya et al., 2021). More intuitively, quercetin showed 6.79 2 ± 0.41 right turn in rats in the permanent MCAO model and 9.31 ± 0.33 right turn in the control group. Most rats in the treatment group showed mild to moderate neuromotor deficits (p < 0.0001) (Ahn and Jeon, 2015). In addition, the infarct volume of rats in the control and treatment groups was 26.35 ± 2.25% and 14.87 ± 1.75%, respectively (Park et al., 2020). Quercetin can improve cognitive function in rats with ischemic injury. In the Morris water maze (MWM) test, quercetin therapy restored spatial learning deficits by increasing the time and amount of access to the central region (Le et al., 2020). By boosting the number of new Olig2+ oligodendrocyte progenitors in the subventricular zone, quercetin alleviated hypoxia/ischemia (HI)-induced cognitive impairment (Qu et al., 2014). Compared with the control group, I/R rats pre-treated with quercetin (20 mg/kg) for 7 days showed a significant reduction in cognitive impairment as well as improvement in motor capacity, cerebral edema, and infarct volume (p < 0.001) (Viswanatha et al., 2018; Viswanatha et al., 2019). Table 3 summarizes the neuroprotective effects of quercetin on IS.

FIGURE 3

TABLE 3

Ischemic strokeIn vitro/In vivoDoseEffective Molecular MechanismReferences
MCAOin vitro/in vivo10 mg/kg↓ PP2A subunit B; inhibition of glutamate toxicityPark et al. (2019)
MCAO/Rin vitro/in vivo3.4 mg/ml↑NQO-1, ↑HO-1, ↑SOD1, ↑GPx1; ↓ROS activation of Nrf2/HO-1 pathway; reduce I/R damage;Guo et al. (2021)
OGDin vitro10 µM↑synaptophysin; promote the growth of neuritesOrbán-Gyapai et al. (2014)
MCAO/Rin vivo30 mg/kg↑GPx, ↑SOD, ↑CAT; ↓PARP, ↓caspase-3, ↓p53, ↓LPO; protection of Na+K+-ATPase ActivityAhmad et al. (2011)
MCAOin vivo30 mg/kg↓caspase-3, ↓PARP; inhibit the apoptosis pathway; reduce neuronal defects and neuronal degenerationPark et al. (2018)
Focal cortical ischemiain vivo25 μmol/kg↓MMP-9; reduce the damage of BBBLee et al. (2011)
pMCAO/Glutamatein vitro/in vivo10 mg/kg↑Bcl2; ↓caspase-3, ↓Bax; reduce calcium overload of intracellular and hippocampal neuronsPark et al. (2020)
HIBI/OGDin vitro/in vivo50 mg/kg↓IL-1β, ↓IL-6, ↓TNF-α; ↑SOD1,↑ SOD2, ↑GPX-1, ↑CAT; increase cell viability; Inhibit TLR4/NF-κB signaling pathway; improve dyskinesia and cognitive impairmentLe et al. (2020)
pMCAOin vivo30 mg/kg↑ GSH; protect neurons and glial cellsRivera et al. (2008)
MCAOin vivo10 mg/kg↑[NAD+], ↑adenosine homocysteinase, ↑pyruvate kinase, ↑carboxy terminal hydrolase L1; ↓HSP60, ↓HSP2Shah et al. (2018)
MCAO/HUMSCsin vivo25 mol/kg↓caspase-3, ↓IL-6, ↓IL-1b; ↑IL-4, ↑IL-10, ↑transforming growth factor-b1; promote nerve function recoveryZhang et al. (2016)
MCAOin vivo10 mg/kgreduce infarct size and edema; antioxidant and neuroprotective activityLee et al. (2015)
MCAO/OGDRin vitro/in vivo25 mg/kganti-oxidative, anti-inflammatory, and antiapoptotic effects; reduces changes in ERK/Akt phosphorylation and protein phosphatase activityWang et al. (2020)
common carotid artery occlusion and reperfusionin vivo2.7 mg/kg↓iNOS,↓ caspase-3, ↓ROS; ↑ HO-1, ↑SOD1, ↑GSH; protect the mitochondrial membrane; protect mitochondrial membranes and neuronal cellsGhosh et al. (2013)

Neuroprotective effects of quercetin in different IS models.

4.4 Prevention of Oxidative Stress

4.4.1 Quercetin

The mitochondria are the main source of oxidative stress. Quercetin can activate mitochondrial large-conductance Ca2+ to regulate potassium (mitoBKCa) channels, participate in mitochondrial depolarization, and protect brain tissue from HI damage (Kampa et al., 2021). Quercetin synergistically enhances mitochondrial spare respiration, maintains neuronal mitochondrial function, and increases the expression of CREB target genes (PGC-1a), which promote neuronal survival and mitochondrial biogenesis in an OGD model (Nichols et al., 2015). Furthermore, quercetin can control the Sirt1/Nrf2/HO-1 pathway, thus drastically reducing ROS formation following IS (Yang et al., 2021). In several IS models, quercetin revealed a dose-dependent reversal of OGD-induced declines in superoxide dismutase-1 (SOD1), SOD2, glutathione peroxidase-1 (GPX-1), and catalase (CAT) levels (Le et al., 2020), which may be achieved by its LPO-reducing capability (Shalavadi et al., 2020). Another study pointed out that quercetin also regulates the expression of oxidase and other antioxidant enzyme genes, thereby preventing IS-associated oxidative stress (Yamagata, 2019). Further studies showed that quercetin induced the expression of Nrf2 in erythrocytes, thus strongly inhibiting the production of adhesion molecules; this action may be related to the antioxidant effect of HO-1 (Li C. et al., 2016). Lee et al. (2016) discovered that quercetin increased the expression of Nrf2, HO-1, and nitric oxide synthase 1 (NOS1) in SHSY5Y cells, thus indicating its antioxidative stress impact.

4.4.2 Quercetin and Other Herbs

Quercetin and other herbal pre-treatments inhibit I/R-induced decreases in catalase and SOD enzyme activity, prevent LPO production, and increase GSH levels (Viswanatha et al., 2018; Viswanatha et al., 2019). Additionally, reduced NO and hippocampal lactate dehydrogenase (LDH) levels were observed in the cortex, striatum, and hippocampus of I/R rats (Ojo et al., 2019). Furthermore, intragastric injection of quercetin and rutin 10 min before reperfusion significantly reduced malondialdehyde (MDA) and myeloperoxidase (MPO) levels, increased endogenous antioxidant enzyme SOD and CAT levels, and improved I/R-induced inflammatory response (Annapurna et al., 2013).

4.4.3 Optimization of Quercetin

Optimization of quercetin can significantly improve its efficiency and pharmacological effects across the BBB. Quercetin liposome preparations slow down the decline of GSH levels in the ipsilateral striatum and cortex after ischemia; it also maintains GSH levels in the ischemic areas and increases GSH concentration in neuronal and glial cells (Rivera et al., 2008). During cerebral I/R, intracellular GSH levels significantly increased in young and old rats receiving nano-quercetin (27 mg/kg) (Ghosh et al., 2013). Quercetin/mAb GAP43-Exo targets neurons by mediating mAb GAP43, thus enhancing the accumulation of quercetin in the ischemic areas as well as inhibiting ROS production by activating the Nrf2/HO-1 pathway to increase LDH levels (Guo et al., 2021). Quercetin/mAb GAP43-Exo decreased oxidative stress-induced I/R damage by boosting the nuclear translocation of Nrf2 and upregulating the transcription of NAD(P)H dehydrogenase quinone-1 (NQO-1), HO-1, SOD1 and GPx1 (Guo et al., 2021) (Figure 3).

4.5 Protection of Hippocampal Neurons

IS significantly induced endogenous neurogenesis in the dentate gyrus of the hippocampus. However, newborn neurons are difficult to differentiate into mature neurons (Arvidsson et al., 2002; Doeppner et al., 2011). Quercetin maintains isocitrate dehydrogenase levels in MCAO animal models and helps to preserve neuronal cell energy production, thereby reducing IS-induced neuronal cell damage (Shah et al., 2018). Moreover, quercetin attenuates the decrease in PP2A subunit B expression caused by glutamate treatment, thus further reducing neuronal cell death (Park et al., 2019). Through the Sirt1/Nrf2/HO-1 signaling pathway, quercetin restores the normal structure of hippocampal neurons in I/R mice with severe neuronal injury (Yang et al., 2021). Quercetin also reduces the activity and pathophysiology of the following processes: protein tyrosine and serine/threonine phosphatase in rat cortical tissue, oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal slices and neuronal/glial cell lines, phosphorylation of ERK and Akt, and I/R-induced hindbrain damage (Wang et al., 2020). Quercetin treatment can also significantly increase the activity of SHSY5Y cells and E18 mouse cortical neurons (Lee et al., 2016), enhance the expression of synaptophysin in PC12 cells in the OGD model, and promote neurite growth in PC12 cells (Orbán-Gyapai et al., 2014). Three days after reperfusion, oral administration of nano-encapsulated quercetin reduced the activity of iNOS and caspase-3, expanded the number of neurons in the hippocampus, and prevented neuronal cell damage (Ghosh et al., 2013) (Figure 3).

4.6 Promotion of Autophagy

The mechanism of quercetin-induced autophagy in cell survival is complex because of the large number of biomolecules involved in this process. Based on the scope of the damage caused by HI, autophagy is used as a pro-apoptotic signal, wherein quercetin can be used as its inducer (Costa et al., 2016). In models of oxidative damage and ischemia, studies have revealed that the protective impact of quercetin is directly linked to the induction of autophagy (Wu et al., 2017). As a result, autophagy is linked to the pro-survival mechanism of quercetin in IS-induced brain injury and other related events (Wang et al., 2011; Zhi et al., 2016; Granato et al., 2017; Liu et al., 2017) (Figure 3). Quercetin has a protective effect against MCAO-induced neuronal cell apoptosis and likewise induces autophagy-mediated neuronal PC12 cell survival (Ahn and Jeon, 2015; Park et al., 2018). In IS, if myeloid cells lack an autophagy response, inflammatory glial cells would thus play a significant role in neuronal cell apoptosis by increasing ischemia; this happens in compensation for the reduced activity of myeloid cells (Kotoda et al., 2018). In this case, autophagy protected the neurons from ischemia-induced cell death. Surprisingly, quercetin, like many other polyphenols, induces autophagy (Pallauf and Rimbach, 2013). Quercetin plays a role in cellular survival by activating autophagy in brain myeloid cells (Chang et al., 2017). Furthermore, in MCAO-induced ischemia, quercetin altered the apoptosis/autophagy interaction and its linkage with the nuclear factor kappa B (NF-κB) signaling pathway by upregulating ubiquitin carboxy-terminal hydrolase L1, which is a related gene enzyme, at almost double the rate (Chirumbolo et al., 2019).

4.7 Inhibition of Apoptosis

Quercetin upregulates the intracellular Ca2+ concentration in the cerebral cortical and hippocampal neurons of MCAO rats. It also regulates the gene expression of Bcl-2, Bax, and caspase-3, thereby preventing apoptosis (Park et al., 2020). Another study found that quercetin reduced HI-induced cortical cell death by blocking the neuro-inflammatory response mediated by the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway (Wu et al., 2019). The anti-apoptotic activity of quercetin may be due to its ability to suppress inflammatory genes in BV2 microglia (Mrvová et al., 2015). In addition, quercetin has also been reported to improve I/R-induced cognitive deficits as well as inhibit neuronal apoptosis by increasing p-Akt and decreasing p-ASK1, P-JNK3, cleaved caspase-3, and FADD protein expressions (Pei et al., 2016). Furthermore, quercetin not only inhibits acid toxicity mediated by acid-sensing ion channels, but also improves neuronal apoptosis in focal cerebral ischemia by reducing caspase-3 and PARP expression through the PI3K/Akt pathway (Park et al., 2018). After local cerebral ischemia, human umbilical cord mesenchymal stem cells (HUMSCs) transplanted with quercetin can reduce pro-inflammatory cytokines IL-1B and IL-6, increase anti-inflammatory cytokines IL-4 and IL-10, inhibit the expression of apoptosis factor caspase-3, and promote the recovery of nerve function (Zhang et al., 2016). Furthermore, isorhamnetin (30-methoxy-3,40,5, 7-tetrahydroxy flavanone), a quercetin metabolite, has been demonstrated to lower blood pressure and endothelial dysfunction in spontaneously hypertensive rats (Sánchez et al., 2006; Sanchez et al., 2007). In the methylglyoxal-binding OGD model, isorhamnetin inhibited caspase 8 activation and decreased Fas and FasL expression, thereby lowering the activation and ability of NF-κB to perform an anti-mitochondrial-dependent apoptotic role (Li W. et al., 2016) (Figure 3).

5 Conclusion and Perspectives

Quercetin has a unique chemical structure and is widely found in our daily diet (e.g., vegetables and fruits), thus making it easy to obtain. Quercetin has showed respectable therapeutic effects on IS-induced models. It inhibits inflammatory thrombosis, reduces cerebral edema, infarct size, and oxidative stress, promotes autophagy and anti-apoptosis, and can be used as an adjuvant agent in the treatment of IS. Importantly, quercetin has been found to inhibit platelet activation and limit inflammatory thrombosis in both animal and clinical studies. The anti-inflammatory properties of quercetin are mediated by the regulation of the expression of various inflammatory factors. It also prevents neuronal death by stimulating the NF-κB signaling pathway, which suppresses caspase-3 and Bax, and promotes Bcl-2 expression.

To date, a number of studies have suggested that quercetin can be used as a neuroprotective drug in the treatment of IS. However, owing to its poor bioavailability and ability to cross the BBB, its application in the clinical setting is limited. Therefore, future research should focus on optimizing the conformation of quercetin or developing a quercetin nano-drug delivery system to improve its bioavailability and BBB passing rate. Meanwhile, we should pay attention to the effects of quercetin on neurogenesis and synaptic plasticity after IS. More clinical trials should also be designed to clarify the effective dose of quercetin in the treatment of IS. Quercetin also has a variety of metabolic components in the body; only a few studies have focused on the pharmacological effects of its metabolites, thus warranting further research on its biochemical and metabolic properties.

Statements

Author contributions

LZ, LY, JM, and FY were involved in literature search, manuscript writing, draft preparation, graphic production, and content production. XC, WM, and SL were involved in conception, drafting, and editing of the manuscript.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

  • 1

    AbdelkhalekA.Al-AskarA. A.AlsubaieM. M.BehiryS. I. (2021). First Report of Protective Activity of Paronychia Argentea Extract against Tobacco Mosaic Virus Infection. Plants10 (11), 2435. 10.3390/plants10112435

  • 2

    AhmadA.KhanM. M.HodaM. N.RazaS. S.KhanM. B.JavedH.et al (2011). Quercetin Protects against Oxidative Stress Associated Damages in a Rat Model of Transient Focal Cerebral Ischemia and Reperfusion. Neurochem. Res.36 (8), 1360–1371. 10.1007/s11064-011-0458-6

  • 3

    AhnT. B.JeonB. S. (2015). The Role of Quercetin on the Survival of Neuron-like PC12 Cells and the Expression of α-synuclein. Neural Regen. Res.10 (7), 1113–1119. 10.4103/1673-5374.160106

  • 4

    AkinmoladunA. C.AkinrinolaB. L.OlaleyeM. T.FarombiE. O. (2015). Kolaviron, a Garcinia Kola Biflavonoid Complex, Protects against Ischemia/reperfusion Injury: Pertinent Mechanistic Insights from Biochemical and Physical Evaluations in Rat Brain. Neurochem. Res.40 (4), 777–787. 10.1007/s11064-015-1527-z

  • 5

    AlimI.CaulfieldJ. T.ChenY.SwarupV.GeschwindD. H.IvanovaE.et al (2019). Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell177 (5), 1262–e25. e1225. 10.1016/j.cell.2019.03.032

  • 6

    AllenC. L.BayraktutanU. (2009). Oxidative Stress and its Role in the Pathogenesis of Ischaemic Stroke. Int. J. Stroke4 (6), 461–470. 10.1111/j.1747-4949.2009.00387.x

  • 7

    Anand DavidA. V.ArulmoliR.ParasuramanS. (2016). Overviews of Biological Importance of Quercetin: A Bioactive Flavonoid. Pharmacogn. Rev.10 (20), 84–89. 10.4103/0973-7847.194044

  • 8

    AnnapurnaA.AnsariM. A.ManjunathP. M. (2013). Partial Role of Multiple Pathways in Infarct Size Limiting Effect of Quercetin and Rutin against Cerebral Ischemia-Reperfusion Injury in Rats. Eur. Rev. Med. Pharmacol. Sci.17 (4), 491–500.

  • 9

    ArvidssonA.CollinT.KirikD.KokaiaZ.LindvallO. (2002). Neuronal Replacement from Endogenous Precursors in the Adult Brain after Stroke. Nat. Med.8 (9), 963–970. 10.1038/nm747

  • 10

    AssefaA. D.HurO.-S.HahnB.-S.KimB.RoN.-Y.RheeJ.-H. (2021). Nutritional Metabolites of Red Pigmented Lettuce (Lactuca sativa) Germplasm and Correlations with Selected Phenotypic Characters. Foods10 (10), 2504. 10.3390/foods10102504

  • 11

    AvanA.DigalehH.Di NapoliM.StrangesS.BehrouzR.ShojaeianbabaeiG. (2019). Socioeconomic Status and Stroke Incidence, Prevalence, Mortality, and Worldwide Burden: An Ecological Analysis From the Global Burden of Disease Study 2017. BMC Medicine17 (1), 191. 10.1186/s12916-019-1397-3

  • 12

    BarnesS.PrasainJ.D'AlessandroT.ArabshahiA.BottingN.LilaM. A.et al (2011). The Metabolism and Analysis of Isoflavones and Other Dietary Polyphenols in Foods and Biological Systems. Food Funct.2 (5), 235–244. 10.1039/c1fo10025d

  • 13

    BashmilY. M.AliA.BkA.DunsheaF. R.SuleriaH. A. R. (2021). Screening and Characterization of Phenolic Compounds from Australian Grown Bananas and Their Antioxidant Capacity. Antioxidants10 (10), 1521. 10.3390/antiox10101521

  • 14

    BhaskarS.SudhakaranP. R.HelenA. (2016). Quercetin Attenuates Atherosclerotic Inflammation and Adhesion Molecule Expression by Modulating TLR-NF-Κb Signaling Pathway. Cell Immunol.310, 131–140. 10.1016/j.cellimm.2016.08.011

  • 15

    BjeldanesL. F.ChangG. W. (1977). Mutagenic Activity of Quercetin and Related Compounds. Science197 (4303), 577–578. 10.1126/science.327550

  • 16

    BraitV. H.Miró-MurF.Pérez-de-PuigI.NotarioL.HurtadoB.PedragosaJ.et al (2019). CD69 Plays a Beneficial Role in Ischemic Stroke by Dampening Endothelial Activation. Circ. Res.124 (2), 279–291. 10.1161/circresaha.118.313818

  • 17

    BrüllV.BurakC.Stoffel-WagnerB.WolfframS.NickenigG.MüllerC.et al (2015). Effects of a Quercetin-Rich Onion Skin Extract on 24 H Ambulatory Blood Pressure and Endothelial Function in Overweight-To-Obese Patients with (Pre-)hypertension: a Randomised Double-Blinded Placebo-Controlled Cross-Over Trial. Br. J. Nutr.114 (8), 1263–1277. 10.1017/s0007114515002950

  • 18

    CaoJ. Y.DixonS. J. (2016). Mechanisms of Ferroptosis. Cell Mol. Life Sci.73, 2195–2209. 10.1007/s00018-016-2194-1

  • 19

    CasasA. I.GeussE.KleikersP. W. M.MenclS.HerrmannA. M.BuendiaI.et al (2017). NOX4-dependent Neuronal Autotoxicity and BBB Breakdown Explain the Superior Sensitivity of the Brain to Ischemic Damage. Proc. Natl. Acad. Sci. U. S. A.114 (46), 12315–12320. 10.1073/pnas.1705034114

  • 20

    ChangJ. L.ChowJ. M.ChangJ. H.WenY. C.LinY. W.YangS. F.et al (2017). Quercetin Simultaneously Induces G0/G1 -phase Arrest and Caspase-Mediated Crosstalk between Apoptosis and Autophagy in Human Leukemia HL-60 Cells. Environ. Toxicol.32 (7), 1857–1868. 10.1002/tox.22408

  • 21

    ChenX.YinO. Q.ZuoZ.ChowM. S. (2005). Pharmacokinetics and Modeling of Quercetin and Metabolites. Pharm. Res.22 (6), 892–901. 10.1007/s11095-005-4584-1

  • 22

    ChirumboloS.VellaA.BjørklundG. (2019). Quercetin Might Promote Autophagy in a Middle Cerebral Artery Occlusion-Mediated Ischemia Model: Comments on Fawad-Ali Shah et al. Neurochem. Res.44 (2), 297–300. 10.1007/s11064-018-2692-7

  • 23

    ChoiI. Y.LimJ. H.KimC.SongH. Y.JuC.KimW. K. (2013). 4-hydroxy-2(E)-Nonenal Facilitates NMDA-Induced Neurotoxicity via Triggering Mitochondrial Permeability Transition Pore Opening and Mitochondrial Calcium Overload. Exp. Neurobiol.22 (3), 200–207. 10.5607/en.2013.22.3.200

  • 24

    ClarksonB. D.LingC.ShiY.HarrisM. G.RayasamA.SunD.et al (2014). T Cell-Derived Interleukin (IL)-21 Promotes Brain Injury Following Stroke in Mice. J. Exp. Med.211 (4), 595–604. 10.1084/jem.20131377

  • 25

    Constantinescu-BercuA.WangY. A.WoollardK. J.ManginP.VanhoorelbekeK.CrawleyJ. T. B.et al (2022). The GPIbα Intracellular Tail - Role in Transducing VWF- and collagen/GPVI-Mediated Signaling. Haematologica107 (4), 933–946. 10.3324/haematol.2020.278242

  • 26

    CostaL. G.GarrickJ. M.RoquèP. J.PellacaniC. (2016). Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More. Oxid. Med. Cell Longev.2016, 2986796. 10.1155/2016/2986796

  • 27

    CulmseeC.PlesnilaN. (2006). Targeting Bid to Prevent Programmed Cell Death in Neurons. Biochem. Soc. Trans.34, 1334–1340. 10.1042/bst0341334

  • 28

    DajasF. (2012). Life or Death: Neuroprotective and Anticancer Effects of Quercetin. J. Ethnopharmacol.143 (2), 383–396. 10.1016/j.jep.2012.07.005

  • 29

    DarbandS. G.KavianiM.YousefiB.SadighparvarS.PakdelF. G.AttariJ. A.et al (2018). Quercetin: A Functional Dietary Flavonoid with Potential Chemo-Preventive Properties in Colorectal Cancer. J. Cell Physiol.233 (9), 6544–6560. 10.1002/jcp.26595

  • 30

    De MeyerS. F.LanghauserF.HaupeltshoferS.KleinschnitzC.CasasA. I. (2022). Thromboinflammation in Brain Ischemia: Recent Updates and Future Perspectives. Stroke. 53(5), 101161strokeaha122038733. 10.1161/strokeaha.122.038733

  • 31

    DehghaniF.Sezavar Seyedi JandaghiS. H.JananiL.SarebanhassanabadiM.EmamatH.VafaM. (2021). Effects of Quercetin Supplementation on Inflammatory Factors and Quality of Life in Post-myocardial Infarction Patients: A Double Blind, Placebo-Controlled, Randomized Clinical Trial. Phytother. Res.35 (4), 2085–2098. 10.1002/ptr.6955

  • 32

    DenormeF.LanghauserF.DesenderL.VandenbulckeA.RottensteinerH.PlaimauerB.et al (2016). ADAMTS13-mediated Thrombolysis of t-PA-resistant Occlusions in Ischemic Stroke in Mice. Blood127 (19), 2337–2345. 10.1182/blood-2015-08-662650

  • 33

    DhaneshaN.PatelR. B.DoddapattarP.GhatgeM.FloraG. D.JainM.et al (2022). PKM2 Promotes Neutrophil Activation and Cerebral Thromboinflammation: Therapeutic Implications for Ischemic Stroke. Blood139 (8), 1234–1245. 10.1182/blood.2021012322

  • 34

    DhimanP.MalikN.Sobarzo-SánchezE.UriarteE.KhatkarA. (2019). Quercetin and Related Chromenone Derivatives as Monoamine Oxidase Inhibitors: Targeting Neurological and Mental Disorders. Molecules24 (3). 10.3390/molecules24030418

  • 35

    Di PierroF.IqtadarS.KhanA.Ullah MumtazS.Masud ChaudhryM.BertuccioliA.et al (2021). Potential Clinical Benefits of Quercetin in the Early Stage of COVID-19: Results of a Second, Pilot, Randomized, Controlled and Open-Label Clinical Trial. Int. J. Gen. Med.14, 2807–2816. 10.2147/ijgm.S318949

  • 36

    DoeppnerT. R.KaltwasserB.ElAliA.ZechariahA.HermannD. M.BährM. (2011). Acute Hepatocyte Growth Factor Treatment Induces Long-Term Neuroprotection and Stroke Recovery via Mechanisms Involving Neural Precursor Cell Proliferation and Differentiation. J. Cereb. Blood Flow. Metab.31 (5), 1251–1262. 10.1038/jcbfm.2010.211

  • 37

    FeitsmaL. J.BrondijkH. C.JarvisG. E.HagemansD.BihanD. G.JerahN. E.et al (2022). Structural Insights into Collagen-Binding by Platelet Receptor Glycoprotein VI. Blood. 10.1182/blood.2021013614

  • 38

    FredotovićŽ.PuizinaJ.NazlićM.MaravićA.LjubenkovI.SoldoB.et al (2021). Phytochemical Characterization and Screening of Antioxidant, Antimicrobial and Antiproliferative Properties of Allium × Cornutum Clementi and Two Varieties of Allium cepa L. Peel Extracts. Plants10 (5), 832. 10.3390/plants10050832

  • 39

    GBD (2021). Global, Regional, and National Burden of Stroke and its Risk Factors, 1990-2019: a Systematic Analysis for the Global Burden of Disease Study 2019. LancetNeurology. 20(10). 10.1016/s1474-4422(21)00252-0

  • 40

    GelderblomM.WeymarA.BernreutherC.VeldenJ.ArunachalamP.SteinbachK.et al (2012). Neutralization of the IL-17 axis Diminishes Neutrophil Invasion and Protects from Ischemic Stroke. Blood120 (18), 3793–3802. 10.1182/blood-2012-02-412726

  • 41

    GenchiA.SemeranoA.SchwarzG.Dell'AcquaB.GullottaG. S.SampaoloM.et al (2022). Neutrophils Predominate the Immune Signature of Cerebral Thrombi in COVID-19 Stroke Patients. Acta Neuropathol. Commun.10 (1), 14. 10.1186/s40478-022-01313-y

  • 42

    GhoshA.SarkarS.MandalA. K.DasN. (2013). Neuroprotective Role of Nanoencapsulated Quercetin in Combating Ischemia-Reperfusion Induced Neuronal Damage in Young and Aged Rats. PloS one8 (4), e57735. 10.1371/journal.pone.0057735

  • 43

    GibbinsJ.AsselinJ.FarndaleR.BarnesM.LawC. L.WatsonS. P. (1996). Tyrosine Phosphorylation of the Fc Receptor Gamma-Chain in Collagen-Stimulated Platelets. J. Biol. Chem.271 (30), 18095–18099. 10.1074/jbc.271.30.18095

  • 44

    GirardeloJ. R.MunariE. L.DallorsoletaJ. C. S.CechinelG.GoettenA. L. F.SalesL. R.et al (202010961). Bioactive Compounds, Antioxidant Capacity and Antitumoral Activity of Ethanolic Extracts from Fruits and Seeds of Eugenia Involucrata DC. Food Res. Int.137, 109615. 10.1016/j.foodres.2020.109615

  • 45

    GraefeE. U.DerendorfH.VeitM. (1999). Pharmacokinetics and Bioavailability of the Flavonol Quercetin in Humans. Int. J. Clin. Pharmacol. Ther.37 (5), 219–233.

  • 46

    GranatoM.RizzelloC.Gilardini MontaniM. S.CuomoL.VitilloM.SantarelliR.et al (2017). Quercetin Induces Apoptosis and Autophagy in Primary Effusion Lymphoma Cells by Inhibiting PI3K/AKT/mTOR and STAT3 Signaling Pathways. J. Nutr. Biochem.41, 124–136. 10.1016/j.jnutbio.2016.12.011

  • 47

    GuevaraL.Domínguez-AnayaM. Á.OrtigosaA.González-GordoS.DíazC.VicenteF.et al (2021). Identification of Compounds with Potential Therapeutic Uses from Sweet Pepper (Capsicum Annuum L.) Fruits and Their Modulation by Nitric Oxide (NO). Int. J. Mol. Sci.22 (9). 10.3390/ijms22094476

  • 48

    GuoL.HuangZ.HuangL.LiangJ.WangP.ZhaoL.et al (2021). Surface-modified Engineered Exosomes Attenuated Cerebral Ischemia/reperfusion Injury by Targeting the Delivery of Quercetin towards Impaired Neurons. J. Nanobiotechnol19 (1), 141. 10.1186/s12951-021-00879-4

  • 49

    HanganuD.NiculaeM.IelciuI.OlahN.-K.MunteanM.BurtescuR.et al (2021). Chemical Profile, Cytotoxic Activity and Oxidative Stress Reduction of Different Syringa Vulgaris L. Extracts. Molecules26 (11), 3104. 10.3390/molecules26113104

  • 50

    HaruwakaK.IkegamiA.TachibanaY.OhnoN.KonishiH.HashimotoA.et al (2019). Dual Microglia Effects on Blood Brain Barrier Permeability Induced by Systemic Inflammation. Nat. Commun.10 (1), 5816. 10.1038/s41467-019-13812-z

  • 51

    HeoJ. H.NamH. S.KimY. D.ChoiJ. K.KimB. M.KimD. J.et al (2020). Pathophysiologic and Therapeutic Perspectives Based on Thrombus Histology in Stroke. J. Stroke22 (1), 64–75. 10.5853/jos.2019.03440

  • 52

    HuangY. Y.WangZ. H.DengL. H.WangH.ZhengQ. (2020). Oral Administration of Quercetin or its Derivatives Inhibit Bone Loss in Animal Model of Osteoporosis. Oxid. Med. Cell Longev.2020, 6080597. 10.1155/2020/6080597

  • 53

    HubbardG. P.StevensJ. M.CicmilM.SageT.JordanP. A.WilliamsC. M.et al (2003). Quercetin Inhibits Collagen-Stimulated Platelet Activation through Inhibition of Multiple Components of the Glycoprotein VI Signaling Pathway. J. Thromb. Haemost.1 (5), 1079–1088. 10.1046/j.1538-7836.2003.00212.x

  • 54

    HubbardG. P.WolfframS.de VosR.BovyA.GibbinsJ. M.LovegroveJ. A. (2006). Ingestion of Onion Soup High in Quercetin Inhibits Platelet Aggregation and Essential Components of the Collagen-Stimulated Platelet Activation Pathway in Man: a Pilot Study. Br. J. Nutr.96 (3), 482–488.

  • 55

    HubbardG. P.WolfframS.LovegroveJ. A.GibbinsJ. M. (2004). Ingestion of Quercetin Inhibits Platelet Aggregation and Essential Components of the Collagen-Stimulated Platelet Activation Pathway in Humans. J. Thromb. Haemost.2 (12), 2138–2145. 10.1111/j.1538-7836.2004.01067.x

  • 56

    JaimandK.RezaeeM. B.BehradZ.Najafy-AshtianyA. (2012). Comparison of Extraction and Measurement of Quercetin from Stigma, Style, Sepals, Petals and Stamen of Crocus Sativus by HPLC in Combination with Heat and Ultrasonic. J. Med. Plants Prod.2, 167–170.

  • 57

    JasujaR.PassamF. H.KennedyD. R.KimS. H.van HessemL.LinL.et al (2012). Protein Disulfide Isomerase Inhibitors Constitute a New Class of Antithrombotic Agents. J. Clin. Invest.122 (6), 2104–2113. 10.1172/jci61228

  • 58

    JoH. M.AhnC.KimH.KangB. T.JeungE. B.YangM. P. (2021). Effect of Quercetin on Formation of Porcine Neutrophil Extracellular Trap. Vet. Immunol. Immunopathol.241, 110335. 10.1016/j.vetimm.2021.110335

  • 59

    JordanJ.de GrootP. W.GalindoM. F. (2011). Mitochondria: the Headquarters in Ischemia-Induced Neuronal Death. Cent. Nerv. Syst. Agents Med. Chem.11 (2), 98–106. 10.2174/187152411796011358

  • 60

    KalogiouriN. P.SamanidouV. F. (2021). A Validated Ultrasound-Assisted Extraction Coupled with SPE-HPLC-DAD for the Determination of Flavonoids in By-Products of Plant Origin: An Application Study for the Valorization of the Walnut Septum Membrane. Molecules26 (21), 6418. 10.3390/molecules26216418

  • 61

    KampaR. P.SękA.SzewczykA.BednarczykP. (2021). Cytoprotective Effects of the Flavonoid Quercetin by Activating Mitochondrial BKCa Channels in Endothelial Cells. Biomed. Pharmacother.142, 112039. 10.1016/j.biopha.2021.112039

  • 62

    KanajiS.MorodomiY.WeilerH.ZarpellonA.MontgomeryR. R.RuggeriZ. M.et al (2022). The impact of aberrant von Willebrand Factor-GPIbα Interaction on Megakaryopoiesis and Platelets in Humanized Type 2B von Willebrand Disease Model Mouse. Haematologica. 10.3324/haematol.2021.280561

  • 63

    KaruppagounderS. S.AlimI.KhimS. J.BourassaM. W.SleimanS. F.JohnR.et al (2016). Therapeutic Targeting of Oxygen-Sensing Prolyl Hydroxylases Abrogates ATF4-dependent Neuronal Death and Improves Outcomes after Brain Hemorrhage in Several Rodent Models. Sci. Transl. Med.8 (328), 328ra29. 328ra329. 10.1126/scitranslmed.aac6008

  • 64

    KleinschnitzC.GrundH.WinglerK.ArmitageM. E.JonesE.MittalM.et al (2010). Post-stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration. PLoS Biol.8 (9). 10.1371/journal.pbio.1000479

  • 65

    KnektP.IsotupaS.RissanenH.HeliövaaraM.JärvinenR.HäkkinenS.et al (2000). Quercetin Intake and the Incidence of Cerebrovascular Disease. Eur. J. Clin. Nutr.54 (5), 415–417. 10.1038/sj.ejcn.1600974

  • 66

    KotodaM.FurukawaH.MiyamotoT.KoraiM.ShikataF.KuwabaraA.et al (2018). Role of Myeloid Lineage Cell Autophagy in Ischemic Brain Injury. Stroke49 (6), 1488–1495. 10.1161/strokeaha.117.018637

  • 67

    Le BehotA.GaubertiM.Martinez De LizarrondoS.MontagneA.LemarchandE.RepesseY.et al (2014). GpIbα-VWF Blockade Restores Vessel Patency by Dissolving Platelet Aggregates Formed under Very High Shear Rate in Mice. Blood123 (21), 3354–3363. 10.1182/blood-2013-12-543074

  • 68

    LeK.SongZ.DengJ.PengX.ZhangJ.WangL.et al (2020). Quercetin Alleviates Neonatal Hypoxic-Ischemic Brain Injury by Inhibiting Microglia-Derived Oxidative Stress and TLR4-Mediated Inflammation. Inflamm. Res.69 (12), 1201–1213. 10.1007/s00011-020-01402-5

  • 69

    LeeJ. K.KwakH. J.PiaoM. S.JangJ. W.KimS. H.KimH. S. (2011). Quercetin Reduces the Elevated Matrix Metalloproteinases-9 Level and Improves Functional Outcome after Cerebral Focal Ischemia in Rats. Acta Neurochir. (Wien)153 (6), 1321–1329. discussion 1329. 10.1007/s00701-010-0889-x

  • 70

    LeeS. M.MoonJ.ChungJ. H.ChaY. J.ShinM. J. (2013). Effect of Quercetin-Rich Onion Peel Extracts on Arterial Thrombosis in Rats. Food Chem. Toxicol.57, 99–105. 10.1016/j.fct.2013.03.008

  • 71

    LeeY. H.KimH. J.YooH.JungS. Y.KwonB. J.KimN. J.et al (2015). Synthesis of (2-amino)ethyl Derivatives of Quercetin 3-O-Methyl Ether and Their Antioxidant and Neuroprotective Effects. Bioorg Med. Chem.23 (15), 4970–4979. 10.1016/j.bmc.2015.05.023

  • 72

    LeeY. J.BernstockJ. D.NagarajaN.KoB.HallenbeckJ. M. (2016). Global SUMOylation Facilitates the Multimodal Neuroprotection Afforded by Quercetin against the Deleterious Effects of Oxygen/glucose Deprivation and the Restoration of Oxygen/glucose. J. Neurochem.138 (1), 101–116. 10.1111/jnc.13643

  • 73

    Leyva-SotoA.Alejandra Chavez-SantoscoyR.PorrasO.Hidalgo-LedesmaM.Serrano-MedinaA.Alejandra Ramírez-RodríguezA.et al (2021). Epicatechin and Quercetin Exhibit In Vitro Antioxidant Effect, Improve Biochemical Parameters Related to Metabolic Syndrome, and Decrease Cellular Genotoxicity in Humans. Food Res. Int.142, 110101. 10.1016/j.foodres.2020.110101

  • 74

    LiC.ZhangW. J.FreiB. (2016a). Quercetin Inhibits LPS-Induced Adhesion Molecule Expression and Oxidant Production in Human Aortic Endothelial Cells by P38-Mediated Nrf2 Activation and Antioxidant Enzyme Induction. Redox Biol.9, 104–113. 10.1016/j.redox.2016.06.006

  • 75

    LiJ.KimK.BaraziaA.TsengA.ChoJ. (2015). Platelet-neutrophil Interactions under Thromboinflammatory Conditions. Cell Mol. Life Sci.72 (14), 2627–2643. 10.1007/s00018-015-1845-y

  • 76

    LiW.ChenZ.YanM.HeP.ChenZ.DaiH. (2016b). The Protective Role of Isorhamnetin on Human Brain Microvascular Endothelial Cells from Cytotoxicity Induced by Methylglyoxal and Oxygen-Glucose Deprivation. J. Neurochem.136 (3), 651–659. 10.1111/jnc.13436

  • 77

    LiangM. L.DaX. W.HeA. D.YaoG. Q.XieW.LiuG.et al (2015). Pentamethylquercetin (PMQ) Reduces Thrombus Formation by Inhibiting Platelet Function. Sci. Rep.5, 11142. 10.1038/srep11142

  • 78

    LieszA.Suri-PayerE.VeltkampC.DoerrH.SommerC.RivestS.et al (2009). Regulatory T Cells Are Key Cerebroprotective Immunomodulators in Acute Experimental Stroke. Nat. Med.15 (2), 192–199. 10.1038/nm.1927

  • 79

    LiuJ. J.SongC. W.YueY.DuanC. G.YangJ.HeT.et al (2005b). Quercetin Inhibits LPS-Induced Delay in Spontaneous Apoptosis and Activation of Neutrophils. Inflamm. Res.54 (12), 500–507. 10.1007/s00011-005-1385-2

  • 80

    LiuJ.LiX.YueY.LiJ.HeT.HeY. (2005a). The Inhibitory Effect of Quercetin on IL-6 Production by LPS-Stimulated Neutrophils. Cell Mol. Immunol.2 (6), 455–460.

  • 81

    LiuY.GongW.YangZ. Y.ZhouX. S.GongC.ZhangT. R.et al (2017). Quercetin Induces Protective Autophagy and Apoptosis through ER Stress via the P-STAT3/Bcl-2 axis in Ovarian Cancer. Apoptosis22 (4), 544–557. 10.1007/s10495-016-1334-2

  • 82

    LoE. H.DalkaraT.MoskowitzM. A. (2003). Mechanisms, Challenges and Opportunities in Stroke. Nat. Rev. Neurosci.4 (5), 399–415. 10.1038/nrn1106

  • 83

    LokeW. M.ProudfootJ. M.McKinleyA. J.NeedsP. W.KroonP. A.HodgsonJ. M.et al (2008). Quercetin and its In Vivo Metabolites Inhibit Neutrophil-Mediated Low-Density Lipoprotein Oxidation. J. Agric. Food Chem.56 (10), 3609–3615. 10.1021/jf8003042

  • 84

    LuN.SuiY.TianR.PengY. Y. (2018). Inhibitive Effects of Quercetin on Myeloperoxidase-dependent Hypochlorous Acid Formation and Vascular Endothelial Injury. J. Agric. Food Chem.66 (19), 4933–4940. 10.1021/acs.jafc.8b01537

  • 85

    MaY.WangJ.WangY.YangG. Y. (2017). The Biphasic Function of Microglia in Ischemic Stroke. Prog. Neurobiol.157, 247–272. 10.1016/j.pneurobio.2016.01.005

  • 86

    MagarR. T.SohngJ. K. (2020). A Review on Structure, Modifications and Structure-Activity Relation of Quercetin and its Derivatives. J. Microbiol. Biotechnol.30 (1), 11–20. 10.4014/jmb.1907.07003

  • 87

    ManachC.ScalbertA.MorandC.RémésyC.JiménezL. (2004). Polyphenols: Food Sources and Bioavailability. Am. J. Clin. Nutr.79 (5), 727–747. 10.1093/ajcn/79.5.727

  • 88

    MarJ. M.da SilvaL. S.MoreiraW. P.BiondoM. M.PontesF. L. D.CamposF. R.et al (2021). Edible Flowers from Theobroma Speciosum: Aqueous Extract Rich in Antioxidant Compounds. Food Chem.356, 129723. 10.1016/j.foodchem.2021.129723

  • 89

    MoroT. M. A.ClericiM. T. P. S. (2021). Burdock (Arctium Lappa L) Roots as a Source of Inulin-type Fructans and Other Bioactive Compounds: Current Knowledge and Future Perspectives for Food and Non-food Applications. Food Res. Int.141, 109889. 10.1016/j.foodres.2020.109889

  • 90

    MosawyS.JacksonD. E.WoodmanO. L.LindenM. D. (2013a). Inhibition of Platelet-Mediated Arterial Thrombosis and Platelet Granule Exocytosis by 3',4'-dihydroxyflavonol and Quercetin. Platelets24 (8), 594–604. 10.3109/09537104.2012.749396

  • 91

    MosawyS.JacksonD. E.WoodmanO. L.LindenM. D. (2014). The Flavonols Quercetin and 3',4'-dihydroxyflavonol Reduce Platelet Function and Delay Thrombus Formation in a Model of Type 1 Diabetes. Diab Vasc. Dis. Res.11 (3), 174–181. 10.1177/1479164114524234

  • 92

    MosawyS.JacksonD. E.WoodmanO. L.LindenM. D. (2013b). Treatment with Quercetin and 3',4'-dihydroxyflavonol Inhibits Platelet Function and Reduces Thrombus Formation In Vivo. J. Thromb. Thrombolysis36 (1), 50–57. 10.1007/s11239-012-0827-2

  • 93

    MrvováN.ŠkandíkM.KuniakováM.RačkováL. (2015). Modulation of BV-2 Microglia Functions by Novel Quercetin Pivaloyl Ester. Neurochem. Int.90, 246–254. 10.1016/j.neuint.2015.09.005

  • 94

    MukhopadhyayP.PrajapatiA. K. (2015). Quercetin in Anti-diabetic Research and Strategies for Improved Quercetin Bioavailability Using Polymer-Based Carriers - a Review. RSC Adv.5 (118), 97547–97562. 10.1039/c5ra18896b

  • 95

    MuthianG.BrightJ. J. (2004). Quercetin, a Flavonoid Phytoestrogen, Ameliorates Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling through JAK-STAT Pathway in T Lymphocyte. J. Clin. Immunol.24 (5), 542–552. 10.1023/B:JOCI.0000040925.55682.a5

  • 96

    MwaurahP. W.KumarS.KumarN.PanghalA.AttkanA. K.SinghV. K.et al (2020). Physicochemical Characteristics, Bioactive Compounds and Industrial Applications of Mango Kernel and its Products: A Review. Compr. Rev. food Sci. food Saf.19 (5), 2421–2446. 10.1111/1541-4337.12598

  • 97

    NajdaA.KlimekK.BalantS.Wrzesinska-JedrusiakE.PiekarskiW. (2019). Optimization of the Process of Polyphenol Extraction from Mentha Spicata with Various Solvents. Przemysl Chem.98 (8), 1286–1289.

  • 98

    NaseriN.ValizadehH.Zakeri-MilaniP. (2015). Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Structure, Preparation and Application. Adv. Pharm. Bull.5 (3), 305–313. 10.15171/apb.2015.043

  • 99

    NicholsM.ZhangJ.PolsterB. M.ElustondoP. A.ThirumaranA.PavlovE. V.et al (2015). Synergistic Neuroprotection by Epicatechin and Quercetin: Activation of Convergent Mitochondrial Signaling Pathways. Neuroscience308, 75–94. 10.1016/j.neuroscience.2015.09.012

  • 100

    Nieto-TrujilloA.Cruz-SosaF.Luria-PérezR.Gutiérrez-RebolledoG. A.Román-GuerreroA.Burrola-AguilarC.et al (2021). Arnica montana Cell Culture Establishment, and Assessment of its Cytotoxic, Antibacterial, α-Amylase Inhibitor, and Antioxidant In Vitro Bioactivities. Plants10 (11), 2300. 10.3390/plants10112300

  • 101

    O'BrienJ. R.SalmonG. P. (1990). An Independent Haemostatic Mechanism: Shear Induced Platelet Aggregation. Adv. Exp. Med. Biol.281, 287–296. 10.1007/978-1-4615-3806-6_30

  • 102

    ObohG.AdemosunA. O.OgunsuyiO. B. (2016). Quercetin and its Role in Chronic Diseases. Adv. Exp. Med. Biol.929, 377–387. 10.1007/978-3-319-41342-6_17

  • 103

    OhT. W.DoH. J.JeonJ. H.KimK. (2021). Quercitrin Inhibits Platelet Activation in Arterial Thrombosis. Phytomedicine80, 153363. 10.1016/j.phymed.2020.153363

  • 104

    OjoO. B.AmooZ. A.SaliuI. O.OlaleyeM. T.FarombiE. O.AkinmoladunA. C. (2019). Neurotherapeutic Potential of Kolaviron on Neurotransmitter Dysregulation, Excitotoxicity, Mitochondrial Electron Transport Chain Dysfunction and Redox Imbalance in 2-VO Brain Ischemia/reperfusion Injury. Biomed. Pharmacother.111, 859–872. 10.1016/j.biopha.2018.12.144

  • 105

    OliveiraA. I.PinhoC.SarmentoB.DiasA. C. P. (2021). Quercetin-biapigenin Nanoparticles Are Effective to Penetrate the Blood-Brain Barrier. Drug Deliv. Transl. Res.12, 267–281. 10.1007/s13346-021-00917-6

  • 106

    Orbán-GyapaiO.RaghavanA.VasasA.ForgoP.HohmannJ.ShahZ. A. (2014). Flavonoids Isolated from Rumex Aquaticus Exhibit Neuroprotective and Neurorestorative Properties by Enhancing Neurite Outgrowth and Synaptophysin. CNS Neurol. Disord. Drug Targets13 (8), 1458–1464. 10.2174/1871527313666141023154446

  • 107

    PallaufK.RimbachG. (2013). Autophagy, Polyphenols and Healthy Ageing. Ageing Res. Rev.12 (1), 237–252. 10.1016/j.arr.2012.03.008

  • 108

    PanW.ChangM. J.BooyseF. M.GrenettH. E.BradleyK. M.WolkowiczP. E.et al (2008). Quercetin Induced Tissue-type Plasminogen Activator Expression Is Mediated through Sp1 and P38 Mitogen-Activated Protein Kinase in Human Endothelial Cells. J. Thromb. Haemost.6 (6), 976–985. 10.1111/j.1538-7836.2008.02977.x

  • 109

    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

  • 110

    ParkD. J.KangJ. B.ShahM. A.KohP. O. (2019). Quercetin Alleviates the Injury-Induced Decrease of Protein Phosphatase 2A Subunit B in Cerebral Ischemic Animal Model and Glutamate-Exposed HT22 Cells. J. Vet. Med. Sci.81 (7), 1047–1054. 10.1292/jvms.19-0094

  • 111

    ParkD. J.ShahF. A.KohP. O. (2018). Quercetin Attenuates Neuronal Cells Damage in a Middle Cerebral Artery Occlusion Animal Model. J. Vet. Med. Sci.80 (4), 676–683. 10.1292/jvms.17-0693

  • 112

    PateiroM.GómezB.MunekataP. E. S.BarbaF. J.PutnikP.KovačevićD. B.et al (2021). Nanoencapsulation of Promising Bioactive Compounds to Improve Their Absorption, Stability, Functionality and the Appearance of the Final Food Products. Molecules26 (6), 1547. 10.3390/molecules26061547

  • 113

    PeiB.YangM.QiX.ShenX.ChenX.ZhangF. (2016). Quercetin Ameliorates Ischemia/reperfusion-Induced Cognitive Deficits by Inhibiting ASK1/JNK3/caspase-3 by Enhancing the Akt Signaling Pathway. Biochem. Biophys. Res. Commun.478 (1), 199–205. 10.1016/j.bbrc.2016.07.068

  • 114

    PircherJ.EngelmannB.MassbergS.SchulzC. (2019). Platelet-Neutrophil Crosstalk in Atherothrombosis. Thromb. Haemost.119 (8), 1274–1282. 10.1055/s-0039-1692983

  • 115

    PooleA.GibbinsJ. M.TurnerM.van VugtM. J.van de WinkelJ. G.SaitoT.et al (1997). The Fc Receptor Gamma-Chain and the Tyrosine Kinase Syk Are Essential for Activation of Mouse Platelets by Collagen. Embo J.16 (9), 2333–2341. 10.1093/emboj/16.9.2333

  • 116

    PoulterN. S.PollittA. Y.OwenD. M.GardinerE. E.AndrewsR. K.ShimizuH.et al (2017). Clustering of Glycoprotein VI (GPVI) Dimers upon Adhesion to Collagen as a Mechanism to Regulate GPVI Signaling in Platelets. J. Thromb. Haemost.15 (3), 549–564. 10.1111/jth.13613

  • 117

    PourakbarL.MoghaddamS. S.EnshasyH. A. E.SayyedR. Z. (2021). Antifungal Activity of the Extract of a Macroalgae, Gracilariopsis Persica, against Four Plant Pathogenic Fungi. Plants10 (9), 1781. 10.3390/plants10091781

  • 118

    QuX.QiD.DongF.WangB.GuoR.LuoM.et al (2014). Quercetin Improves Hypoxia-Ischemia Induced Cognitive Deficits via Promoting Remyelination in Neonatal Rat. Brain Res.1553, 31–40. 10.1016/j.brainres.2014.01.035

  • 119

    RatnamD. V.AnkolaD. D.BhardwajV.SahanaD. K.KumarM. N. (2006). Role of Antioxidants in Prophylaxis and Therapy: A Pharmaceutical Perspective. J. Control Release113 (3), 189–207. 10.1016/j.jconrel.2006.04.015

  • 120

    Rice-EvansC.MillerN.PagangaG. (1997). Antioxidant Properties of Phenolic Compounds. Trends plant Sci.2 (4), 152–159. 10.1016/s1360-1385(97)01018-2

  • 121

    RivaA.RonchiM.PetrangoliniG.BosisioS.AllegriniP. (2019). Improved Oral Absorption of Quercetin from Quercetin Phytosome®, a New Delivery System Based on Food Grade Lecithin. Eur. J. Drug Metab. Pharmacokinet.44 (2), 169–177. 10.1007/s13318-018-0517-3

  • 122

    RiveraF.CostaG.AbinA.UrbanaviciusJ.ArrutiC.CasanovaG.et al (2008). Reduction of Ischemic Brain Damage and Increase of Glutathione by a Liposomal Preparation of Quercetin in Permanent Focal Ischemia in Rats. Neurotox. Res.13 (2), 105–114. 10.1007/bf03033562

  • 123

    Rojas-GarbanzoC.RodríguezL.PérezA. M.Mayorga-GrossA. L.Vásquez-ChavesV.FuentesE.et al (2021). Anti-platelet Activity and Chemical Characterization by UPLC-DAD-ESI-QTOF-MS of the Main Polyphenols in Extracts from Psidium Leaves and Fruits. Food Res. Int.141, 110070. 10.1016/j.foodres.2020.110070

  • 124

    RosellA.CuadradoE.Ortega-AznarA.Hernández-GuillamonM.LoE. H.MontanerJ. (2008). MMP-9-positive Neutrophil Infiltration Is Associated to Blood-Brain Barrier Breakdown and Basal Lamina Type IV Collagen Degradation during Hemorrhagic Transformation after Human Ischemic Stroke. Stroke39 (4), 1121–1126. 10.1161/strokeaha.107.500868

  • 125

    RussoM.PalumboR.MupoA.TostoM.IacominoG.ScognamiglioA.et al (2003). Flavonoid Quercetin Sensitizes a CD95-Resistant Cell Line to Apoptosis by Activating Protein Kinase Calpha. Oncogene22 (21), 3330–3342. 10.1038/sj.onc.1206493

  • 126

    RutkowskaM.Kolodziejczyk-CzepasJ.OwczarekA.ZakrzewskaA.MagieraA.OlszewskaM. A. (2021). Novel Insight into Biological Activity and Phytochemical Composition of Sorbus Aucuparia L. Fruits: Fractionated Extracts as Inhibitors of Protein Glycation and Oxidative/nitrative Damage of Human Plasma Components. Food Res. Int.147, 110526. 10.1016/j.foodres.2021.110526

  • 127

    SánchezM.GalisteoM.VeraR.VillarI. C.ZarzueloA.TamargoJ.et al (2006). Quercetin Downregulates NADPH Oxidase, Increases eNOS Activity and Prevents Endothelial Dysfunction in Spontaneously Hypertensive Rats. J. Hypertens.24 (1), 75–84. 10.1097/01.hjh.0000198029.22472.d9

  • 128

    SanchezM.LodiF.VeraR.VillarI. C.CogolludoA.JimenezR.et al (2007). Quercetin and Isorhamnetin Prevent Endothelial Dysfunction, Superoxide Production, and Overexpression of P47phox Induced by Angiotensin II in Rat Aorta. J. Nutr.137 (4), 910–915. 10.1093/jn/137.4.910

  • 129

    SchrottmaierW. C.MussbacherM.SalzmannM.AssingerA. (2020). Platelet-leukocyte Interplay during Vascular Disease. Atherosclerosis307, 109–120. 10.1016/j.atherosclerosis.2020.04.018

  • 130

    SchuhmannM. K.StollG.BieberM.VögtleT.HofmannS.KlausV.et al (2020). CD84 Links T Cell and Platelet Activity in Cerebral Thrombo-Inflammation in Acute Stroke. Circ. Res.127 (8), 1023–1035. 10.1161/circresaha.120.316655

  • 131

    SeilerA.SchneiderM.FörsterH.RothS.WirthE. K.CulmseeC.et al (2008). Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15-lipoxygenase Dependent- and AIF-Mediated Cell Death. Cell Metab.8 (3), 237–248. 10.1016/j.cmet.2008.07.005

  • 132

    ShabbirU.RubabM.DaliriE. B.-M.ChelliahR.JavedA.OhD.-H. (2021). Curcumin, Quercetin, Catechins and Metabolic Diseases: The Role of Gut Microbiota. Nutrients13 (1), 206. 10.3390/nu13010206

  • 133

    ShahF. A.ParkD. J.KohP. O. (2018). Identification of Proteins Differentially Expressed by Quercetin Treatment in a Middle Cerebral Artery Occlusion Model: A Proteomics Approach. Neurochem. Res.43 (8), 1608–1623. 10.1007/s11064-018-2576-x

  • 134

    ShalavadiM. H.ChandrashekharV. M.MuchchandiI. S. (2020). Neuroprotective Effect of Convolvulus Pluricaulis Choisy in Oxidative Stress Model of Cerebral Ischemia Reperfusion Injury and Assessment of MAP2 in Rats. J. Ethnopharmacol.249, 112393. 10.1016/j.jep.2019.112393

  • 135

    Sharifi-RadJ.QuispeC.ShaheenS.El HaouariM.AzziniE.ButnariuM.et al (2021). Flavonoids as Potential Anti-Platelet Aggregation Agents: From Biochemistry to Health Promoting Abilities. Crit. Rev. Food Sci. Nutr. [Epub ahead of print], 1–14. 10.1080/10408398.2021.1924612

  • 136

    ShenP.LinW.DengX.BaX.HanL.ChenZ.et al (2021). Potential Implications of Quercetin in Autoimmune Diseases. Front. Immunol.12, 689044. 10.3389/fimmu.2021.689044

  • 137

    SouthK.SalehO.LemarchandE.CouttsG.SmithC. J.SchiesslI.et al (2022). Robust Thrombolytic and Anti-inflammatory Action of a Constitutively Active ADAMTS13 Variant in Murine Stroke Models. Blood139 (10), 1575–1587. 10.1182/blood.2021012787

  • 138

    StopaJ. D.NeubergD.PuligandlaM.FurieB.FlaumenhaftR.ZwickerJ. I. (2017). Protein Disulfide Isomerase Inhibition Blocks Thrombin Generation in Humans by Interfering with Platelet Factor V Activation. JCI Insight2 (1), e89373. 10.1172/jci.insight.89373

  • 139

    StumvollM.GoldsteinB. J.van HaeftenT. W. (2005). Type 2 Diabetes: Principles of Pathogenesis and Therapy. Lancet365 (9467), 1333–1346. 10.1016/s0140-6736(05)61032-x

  • 140

    SumiM.TateishiN.ShibataH.OhkiT.SataM. (2013). Quercetin Glucosides Promote Ischemia-Induced Angiogenesis, but Do Not Promote Tumor Growth. Life Sci.93 (22), 814–819. 10.1016/j.lfs.2013.09.005

  • 141

    SunM. S.JinH.SunX.HuangS.ZhangF. L.GuoZ. N.et al (2018). Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy. Oxid. Med. Cell Longev.2018, 3804979. 10.1155/2018/3804979

  • 142

    SuriS.TaylorM. A.VerityA.TriboloS.NeedsP. W.KroonP. A.et al (2008). A Comparative Study of the Effects of Quercetin and its Glucuronide and Sulfate Metabolites on Human Neutrophil Function In Vitro. Biochem. Pharmacol.76 (5), 645–653. 10.1016/j.bcp.2008.06.010

  • 143

    TuoQ. z.ZhangS. t.LeiP. (2021). Mechanisms of Neuronal Cell Death in Ischemic Stroke and Their Therapeutic Implications. Med. Res. Rev.42, 259–305. 10.1002/med.21817

  • 144

    UlyaT.ArdiantoC.AnggreiniP.BudiatinA. S.SetyawanD.KhotibJ. (2021). Quercetin Promotes Behavioral Recovery and Biomolecular Changes of Melanocortin-4 Receptor in Mice with Ischemic Stroke. J. Basic Clin. Physiol. Pharmacol.32 (4), 349–355. 10.1515/jbcpp-2020-0490

  • 145

    VekV.KeržičE.PoljanšekI.EklundP.HumarM.OvenP. (2021). Wood Extractives of Silver Fir and Their Antioxidant and Antifungal Properties. Molecules26 (21), 6412. 10.3390/molecules26216412

  • 146

    VekicJ.ZeljkovicA.StefanovicA.Jelic-IvanovicZ.Spasojevic-KalimanovskaV. (2019). Obesity and Dyslipidemia. Metabolism92, 71–81. 10.1016/j.metabol.2018.11.005

  • 147

    VerhenneS.DenormeF.LibbrechtS.VandenbulckeA.PareynI.DeckmynH.et al (2015). Platelet-derived VWF Is Not Essential for Normal Thrombosis and Hemostasis but Fosters Ischemic Stroke Injury in Mice. Blood126 (14), 1715–1722. 10.1182/blood-2015-03-632901

  • 148

    ViswanathaG. L.VenkatarangannaM. V.PrasadN. B. L.HanumanthappaS. (2018). Chemical Characterization and Cerebroprotective Effect of Methanolic Root Extract of Colebrookea Oppositifolia in Rats. J. Ethnopharmacol.223, 63–75. 10.1016/j.jep.2018.05.009

  • 149

    ViswanathaG. L.VenkatarangannaM. V.PrasadN. B. L.ShylajaH. (2019). Achyranthes aspera Linn. Alleviates Cerebral Ischemia-Reperfusion-Induced Neurocognitive, Biochemical, Morphological and Histological Alterations in Wistar Rats. J. Ethnopharmacol.228, 58–69. 10.1016/j.jep.2018.09.018

  • 150

    WangJ.WangP.LiS.WangS.LiY.LiangN.et al (2014). Mdivi-1 Prevents Apoptosis Induced by Ischemia-Reperfusion Injury in Primary Hippocampal Cells via Inhibition of Reactive Oxygen Species-Activated Mitochondrial Pathway. J. Stroke Cerebrovasc. Dis.23 (6), 1491–1499. 10.1016/j.jstrokecerebrovasdis.2013.12.021

  • 151

    WangJ.XingH.WanL.JiangX.WangC.WuY. (2018). Treatment Targets for M2 Microglia Polarization in Ischemic Stroke. Biomed. Pharmacother.105, 518–525. 10.1016/j.biopha.2018.05.143

  • 152

    WangK.LiuR.LiJ.MaoJ.LeiY.WuJ.et al (2011). Quercetin Induces Protective Autophagy in Gastric Cancer Cells: Involvement of Akt-mTOR- and Hypoxia-Induced Factor 1α-Mediated Signaling. Autophagy7 (9), 966–978. 10.4161/auto.7.9.15863

  • 153

    WangQ.TangX. N.YenariM. A. (2007). The Inflammatory Response in Stroke. J. Neuroimmunol.184, 53–68. 10.1016/j.jneuroim.2006.11.014

  • 154

    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

  • 155

    WilliamsR. J.SpencerJ. P.Rice-EvansC. (2004). Flavonoids: Antioxidants or Signalling Molecules?Free Radic. Biol. Med.36 (7), 838–849. 10.1016/j.freeradbiomed.2004.01.001

  • 156

    WrightB.MoraesL. A.KempC. F.MullenW.CrozierA.LovegroveJ. A.et al (2010). A Structural Basis for the Inhibition of Collagen-Stimulated Platelet Function by Quercetin and Structurally Related Flavonoids. Br. J. Pharmacol.159 (6), 1312–1325. 10.1111/j.1476-5381.2009.00632.x

  • 157

    WuL.ZhangQ.DaiW.LiS.FengJ.LiJ.et al (20172017). Quercetin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy by Inhibiting ERK/NF-κB Pathway. Gastroenterol. Res. Pract.2017, 9724217. 10.1155/2017/9724217

  • 158

    WuM.LiuF.GuoQ. (2019). Quercetin Attenuates Hypoxia-Ischemia Induced Brain Injury in Neonatal Rats by Inhibiting TLR4/NF-Κb Signaling Pathway. Int. Immunopharmacol.74, 105704. 10.1016/j.intimp.2019.105704

  • 159

    YamagataK. (2019). Polyphenols Regulate Endothelial Functions and Reduce the Risk of Cardiovascular Disease. Curr. Pharm. Des.25 (22), 2443–2458. 10.2174/1381612825666190722100504

  • 160

    YangD.WangT.LongM.LiP. (2020a). Quercetin: Its Main Pharmacological Activity and Potential Application in Clinical Medicine. Oxid. Med. Cell Longev.2020, 8825387. 10.1155/2020/8825387

  • 161

    YangJ.WuZ.LongQ.HuangJ.HongT.LiuW.et al (2020b). Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13. Front. Immunol.11, 610696. 10.3389/fimmu.2020.610696

  • 162

    YangR.ShenY.-J.ChenM.ZhaoJ.-Y.ChenS.-H.ZhangW.et al (2021). Quercetin Attenuates Ischemia Reperfusion Injury by Protecting the Blood-Brain Barrier through Sirt1 in MCAO Rats. J. Asian Nat. Prod. Res.24, 278–289. 10.1080/10286020.2021.1949302

  • 163

    YangW. S.SriRamaratnamR.WelschM. E.ShimadaK.SkoutaR.ViswanathanV. S.et al (2014). Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell156, 317–331. 10.1016/j.cell.2013.12.010

  • 164

    Yousefi-ManeshH.DehpourA. R.NabaviS. M.KhayatkashaniM.AsgardoonM. H.DerakhshanM. H.et al (2021). Therapeutic Effects of Hydroalcoholic Extracts from the Ancient Apple Mela Rosa dei Monti Sibillini in Transient Global Ischemia in Rats. Pharmaceuticals14 (11), 1106. 10.3390/ph14111106

  • 165

    YuP. X.ZhouQ. J.ZhuW. W.WuY. H.WuL. C.LinX.et al (2013). Effects of Quercetin on LPS-Induced Disseminated Intravascular Coagulation (DIC) in Rabbits. Thromb. Res.131 (6), e270–3. 10.1016/j.thromres.2013.03.002

  • 166

    YuanK.ZhuQ.LuQ.JiangH.ZhuM.LiX.et al (2020). Quercetin Alleviates Rheumatoid Arthritis by Inhibiting Neutrophil Inflammatory Activities. J. Nutr. Biochem.84, 108454. 10.1016/j.jnutbio.2020.108454

  • 167

    ZaragozáC.MonserratJ.MantecónC.VillaescusaL.Álvarez-MonM. Á.ZaragozáF.et al (2021). Binding and Antiplatelet Activity of Quercetin, Rutin, Diosmetin, and Diosmin Flavonoids. Biomed. Pharmacother.141, 111867. 10.1016/j.biopha.2021.111867

  • 168

    ZhangL. L.ZhangH. T.CaiY. Q.HanY. J.YaoF.YuanZ. H.et al (2016). Anti-inflammatory Effect of Mesenchymal Stromal Cell Transplantation and Quercetin Treatment in a Rat Model of Experimental Cerebral Ischemia. Cell Mol. Neurobiol.36 (7), 1023–1034. 10.1007/s10571-015-0291-6

  • 169

    ZhangX.YanH.YuanY.GaoJ.ShenZ.ChengY.et al (2013). Cerebral Ischemia-Reperfusion-Induced Autophagy Protects against Neuronal Injury by Mitochondrial Clearance. Autophagy9 (9), 1321–1333. 10.4161/auto.25132

  • 170

    ZhiK.LiM.BaiJ.WuY.ZhouS.ZhangX.et al (2016). Quercitrin Treatment Protects Endothelial Progenitor Cells from Oxidative Damage via Inducing Autophagy through Extracellular Signal-Regulated Kinase. Angiogenesis19 (3), 311–324. 10.1007/s10456-016-9504-y

  • 171

    ZhouM.ZhuL.CuiX.FengL.ZhaoX.HeS.et al (2016). Influence of Diet on Leukocyte Telomere Length, Markers of Inflammation and Oxidative Stress in Individuals with Varied Glucose Tolerance: a Chinese Population Study. Nutr. J.15, 39. 10.1186/s12937-016-0157-x

  • 172

    ZouH.YeH.KamarajR.ZhangT.ZhangJ.PavekP. (2021). A Review on Pharmacological Activities and Synergistic Effect of Quercetin with Small Molecule Agents. Phytomedicine92, 153736. 10.1016/j.phymed.2021.153736

  • 173

    ZwickerJ. I.SchlechterB. L.StopaJ. D.LiebmanH. A.AggarwalA.PuligandlaM.et al (2019). Targeting Protein Disulfide Isomerase with the Flavonoid Isoquercetin to Improve Hypercoagulability in Advanced Cancer. JCI Insight4 (4). 10.1172/jci.insight.125851

Summary

Keywords

quercetin, ischemic stroke, inflammatory thrombus, neuroprotection, immune cell activation, mechanism

Citation

Zhang L, Ma J, Yang F, Li S, Ma W, Chang X and Yang L (2022) Neuroprotective Effects of Quercetin on Ischemic Stroke: A Literature Review. Front. Pharmacol. 13:854249. doi: 10.3389/fphar.2022.854249

Received

13 January 2022

Accepted

28 April 2022

Published

18 May 2022

Volume

13 - 2022

Edited by

Yongjun Sun, Hebei University of Science and Technology, China

Reviewed by

Pallavi Shrivastava, Louisiana State University, United States

Peng Sun, Shandong University of Traditional Chinese Medicine, China

Gollapalle L. Viswanatha, Independent Consultant, Bengaluru, India

Updates

Copyright

© 2022 Zhang, Ma, Yang, Li, Ma, Chang and Yang.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Xiang Chang, ; Lin Yang,

†These authors have contributed equally to this work

This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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