Resveratrol (RSV), a natural polyphenolic substance, is one of the primary ingredients in the herb Polygonum cuspidatum Sieb.et Zucc. Currently, RSV is one of the phytochemicals that has been widely investigated and has various biological activities, such as anti-apoptotic, antioxidant, anti-inflammatory, and, anticancer properties (Miguel et al., 2021). In terms of brain-related ailments, both experimental and clinical investigations have shown that RSV has beneficial effects on neurodegenerative diseases, ischemic stroke, and depression (Gomes et al., 2018; Gu et al., 2019; Khoury et al., 2019). In rats intraperitoneally injected with DOX (2.5 mg/kg/week) for 4 weeks, RSV (10 mg/kg/day) effectively improved the short- and long-term memory impairments as well as alleviated microglial and astrocyte over-activation in the cortex, hypothalamus, and hippocampus (Moretti et al., 2021). For breast cancer, docetaxel, adriamycin, and cyclophosphamide (DAC) are commonly used in combination. Shi and colleagues showed that pretreatment with RSV (50 and 100 mg/kg/day) for 1 week significantly decreased pro-inflammatory cytokines expression, increased neuronal activities in pre-front and hippocampus, elevated the neuroplasticity biomarkers expression, and improved cognitive impairment in mice treated with DAC (Shi et al., 2018). However, it is arduous to translate RSV into clinical utilities owning to the low stability, high metabolism, and poor bioavailability (Amri et al., 2012). Furthermore, although RSV has been shown to possess the ability to translate from blood to brain in rodents and humans (Wang et al., 2002; Turner et al., 2015), the distribution of RSV in the central CNS is very poor for the existence of the blood-brain barrier and choroid plexus (Ganesan et al., 2015). Interestingly, a recent study has shown that the administration of RSV via the nose can reach cerebrospinal fluid through the olfactory region (Pandareesh et al., 2015). Furthermore, RSV has a high membrane permeability based on its high oil-water partition coefficient, therefore, RSV is suitable for designing as NBDD preparation (Hao et al., 2016). For example, Trotta et al. (2018) found that nasal administration of the chitosan-coated lipid microparticles with resveratrol could markedly increase the bioavailability of RSV in the cerebrospinal fluid and decrease the RSV distribution in the bloodstream, indicating that the NBDD can directly delivery RSV to the brain. Salem and colleagues also developed an RSV-loaded intranasal transpersonal mucoadhesive gel, which significantly enhanced RSV bioavailability and achieve direct nose-to-brain targeting (Salem et al., 2019). Collectively, the above results suggested that RSV is a promising agent for the treatment of CRCI and the administration of RSV via NBDD would promote its efficiency via the increased bioavailability and alleviated adverse effects.

Polydatin, also known as piceid (3,4′,5-trihydroxystilbene3-β-D-glucoside), is a natural stilbene that primarily existed in Polygonum cuspidatum Sieb. et Zucc. Numerous preclinical studies have reported that polydatin possesses anti-inflammatory and antioxidant abilities (Tang et al., 2022). Polydatin can scavenge free radicals and then protect cardiomyocytes through regulating lipid metabolism, and antagonizing platelet aggregation (Wu M. et al., 2020). Furthermore, due to its anti-inflammatory and anti-oxidant effects, polydatin exerted protective activities against ischemia-reperfusion injury in many organs, such as the heart, kidneys, lungs, and cerebellum (Sun and Wang, 2020). In terms of chemobrain, previous studies have pointed out that polydatin (50 mg/kg/day) can mitigate DOX-induced learning and memory deficits, and protect the hippocampal architecture from damage. Further mechanistic studies reveal that polydatin administration in DOX-treated rats restores the nuclear factor-erythroid 2-related factor 2 (Nrf2) levels and reduces the nuclear factor kappa-B (NF-κB) expression in the hippocampus. Overall, polydatin can alleviate cognitive impairment and improve neurological function via its anti-inflammatory and antioxidant activities. Although earlier studies have reported that polydatin and its metabolites can cross the BBB, the potential drawbacks of pharmacokinetic, including low selectivity, rapid metabolism, and poor bioavailability limit its clinical application (Huang et al., 2018; Fakhri et al., 2021). Recently, it has been reported that polymeric nanocapsules loaded with polydatin exhibit comparable inhibitory effects on inflammatory responses and oxidative stress in lipopolysaccharide (LPS)-treated neurons as naïve polydatin with preserving the free form of polydatin (Basta-Kaim et al., 2019). Other novel delivery systems of polydatin, for example, polydatin-loaded liposomes could enhance the release profile of polydatin, which markedly improve the polydatin bioavailability and extend drug circulation time (Wang X. et al., 2015). However, there were no studies focusing on polydatin-related NBDD in neuroprotection. Therefore, more researches are needed to explore the protective effects of polydatin on chemobrain, especially through NBDD.

Epigallocatechin-3-gallate (EGCG), a major active polyphenol in green tea, has been demonstrated to possess neuroprotective effects in neurodegenerative diseases and neural injury. These pharmacological activities are mainly ascribed to their antioxidative, anti-inflammatory, and antiapoptotic properties. As we know, EGCG is one of the most effective phenolic compounds in free radical scavenging. According to statistics, EGCG remarkably decreases the levels of nitrosative and oxidative stress in the brain cortex after cisplatin exposure, through suppressing the contents of Malondialdehyde (MDA) as well as elevating the nitric oxide (NO) and total antioxidant capacity (TAC) levels (Arafa and Atteia, 2020). On the other hand, treatment with EGCG significantly decreased pro-inflammatory cytokines (TNF-α and IL-6) levels in the brain cortex tissue. Meanwhile, EGCG also exerted anti-apoptotic effects with increasing Bcl-2 expression and suppressing Bcl-2-associated X (Bax) and caspase-3 expression in rat exposured to cisplatin (Arafa and Atteia, 2020). BDNF, as a member of neurotrophins, play a significant part in regulating synaptic plasticity, survival, differentiation, and regeneration. Interestingly, both BDNF and AChE showed positive correlations with TAC and Bcl-2 in the brain cortex. In contrast, remarkable negative correlations were observed between the expression of BDNF, and AChE and the production of NO, MDA, TNF-α, IL-6, inducible nitric oxide synthase (iNOS), Bax, and caspase-3. To sum up, EGCG may exert protective roles in cisplatin triggered-chemobrain. Despite the fact that EGCG is beneficial in CRCI, EGCG application is limited because of the poor pharmacokinetics which is reflected by low bioavailability, fast metabolism, and rapid removal (Alam et al., 2022). To improve EGCG pharmacokinetics, a series of EGCG nanoformulations are currently emerging due to the colloidal stability, advanced tissue permeability, and drug bioavailability (Mehmood et al., 2022). For instance, chitosan-based EGCG significantly promoted the uptake and retention time of intestinal epithelium and improved the effectiveness of EGCG against atherosclerosis (Hong et al., 2014). Transdermal EGCG gel also significantly increased plasma levels and prolonged its half-life (Lambert et al., 2006). In terms of neuroprotection, zheng et al. demonstrated that EGCG-loaded liposomes (phosphatidylserine-EGCG-liposomes and phosphatidylserine-EGCG-Vitamin E-liposomes) significantly alleviated LPS-induced neuroinflammation in vitro and Parkinson rat models (Cheng et al., 2021). Other drug delivery methods on NPs-based EGCG include intravenous, ocular, and intratumoral routes. However, there is no report about EGCG for the treatment of CNS disorders via NBDD. Further study on the NBDD application in enhancing EGCG credibility in treating CRCI is needed.

Curcumin (CUR), the principal polyphenol of the traditional medicine known as turmeric, is one of the widely studied phytochemicals with a wide range of health benefits. Experimental studies have reported that CUR exhibits neuroprotective effects in a series of CNS diseases, including traumatic brain injury, cerebral ischemic damage, neurodegenerative diseases, and cognitive deficits caused by toxicants (Bhat et al., 2019; Khayatan et al., 2022). Epidemiological research also confirmed that the long-term use of CUR is safe and ameliorates cognitive dysfunction in the elderly (Ng et al., 2006; Cox et al., 2015). It has been shown that CUR protected the brain from damage principally by attenuating microglia/astrocyte activation-mediated neuroinflammatory responses, inhibiting free radical production, alleviating blood-brain barrier disruption, and improving cerebral blood flow et al. (Reddy et al., 2018; Fan and Lei, 2022). Regarding the protective effects of CUR on chemobrain, recent research by Yi and colleagues showed that CUR could protect against cisplatin-triggered neurotoxicity in mice (Yi et al., 2020). In the study, administration of CUR (100 mg/kg) effectively alleviated cisplatin-induced cognitive deficits by regulating apoptosis-related proteins, promoting autophagy, and initiating neurogenesis and synaptogenesis. Oz et al. also reported that the rats exposed to cisplatin (5 mg/kg/week, 5 weeks) resulted in cognitive deficits, increased MDA contents, and inhibited superoxide dismutase (SOD) activities in the hippocampus. However, supplementation of CUR (300 mg/kg/day, 5 weeks) improved cognition, decreased oxidative stress, and restored cholinergic functions (Oz et al., 2015). Recently, several studies also demonstrated that CUR effectively antagonized the neurotoxicity induced by DOX. For example, Moretti and coworkers found that DOX exposure (2.5 mg/kg/week, 4 weeks) impaired short- and long-term memory in rats, while CUR via oral administration (100 mg/kg/day) for 28 days significantly reversed DOX-triggered astrogliosis, microgliosis, and memory loss (Moretti et al., 2021). Taken together, CUR possesses certain anti-chemobrain effects, antioxidant, and anti-inflammatory effects. Nevertheless, CUR application is restricted by the fact of its insufficient bioavailability and rapid metabolism. Therefore, it is essential to enhance the effective concentration of CUR in the brain to ensure its successful application. The nanotransformation of CUR is considered a strategy to improve its efficacy in the brain (Yallapu et al., 2012; Chen et al., 2013). It has been reported that CUR could cross the BBB to enter brain tissue, however, CUR nanoparticulation possessed more retention time in the hippocampus and cerebral cortex than CUR (Tsai et al., 2011). Besides, the CUR nanoparticulation has a 10–14 fold higher absorption rate than free CUR (Yallapu et al., 2012). The nanoparticle formulation of CUR significantly increased its absorption rate, bioavailability, and plasma concentration (Cheng et al., 2013). A previous study has reported that a nanoparticle loaded with CUR effectively inhibited cisplatin (12 mg/kg)-induced inflammatory cytokines production, lipid peroxidation, and acetylcholinesterase activity (Khadrawy et al., 2019). Meanwhile, the benefits of CUR nanoparticulation in suppressing DOX-caused neurotoxicity in rat’s brain have also been reported (Khadrawy et al., 2021). More importantly, it has been revealed that the intranasal administration of CUR can block liver metabolism, which provides more benefits than the CUR administration intraperitoneally or orally (Subhashini et al., 2013). Therefore, NBDD may be a new strategy to deliver CUR to the brain. Shinde and coworkers reported that the intranasal administration of CUR microemulsion markedly has higher Cmax and area-under-the-curve plasma/serum concentrations (AUC) in the brain (Shinde and Devarajan, 2017). Chen et al. 2013 designed a kind of CUR hydrogel, and its intravenous administration remarkably promoted brain-uptake efficiency, and elevated curcumin distribution in the cerebellum and hippocampus. Madane and Mahajan reported that there was higher CUR concentration in the brain after intranasal administration of CUR-loaded nanostructured lipid carrier (Madane and Mahajan, 2016). Sintov et al. also designed amyloLipid nanovesicles loaded with CUR, which significantly increased the concentration of CUR both in the brain and plasma, alleviated amyloid-β-protein (Aβ) accumulation, and suppressed Aβ-caused inflammatory responses (Sintov, 2020). At present, the studies provide application prospects for CUR administration via NBDD as a promising strategy for treating chemobrain.

Caffeic acid phenethyl ester (CAPE), a bioactive polyphenolic compound, which is first discovered from propolis. The high permeability of CAPE allows it to be cleaved by intracellular esterases and then to release caffeic acid. As a polyphenol, CAPE contains hydroxyls within the catechol ring, which guarantees its antioxidant activities. In addition, several studies also suggested that CAPE is a potential inhibitor of NF-κB activation (Natarajan et al., 1996). All these features provide the molecular basis for its neuroprotective activities in the central and peripheral nervous systems (Cetin and Deveci, 2019). Experiment studies have shown that CAPE can markedly improve DOX-damaged learning and memory functions in passive avoidance tests and morris water maze. Furthermore, CAPE effectively reversed DOX-caused oxidative stress, which was reflected by the upregulation of GSH levels and reduced lipid peroxidation in hippocampal and cortical tissues (Ali et al., 2020). Additionally, the inhibition of astrocytes activation, pro-inflammatory cytokines (COX-2 and TNF-α) production, and NF-kB nuclear translocation by CAPE was also reported (Ali et al., 2020). Besides, it has also been revealed that CAPE markedly hampers DOX-triggered caspase-3 activation. The above research suggests that the protection of CAPE against chemobrain is attributed to its regulation of oxidation damages and neuroinflammation, which indicates that CAPE as a promising therapeutic option for chemobrain. However, although CAPE could cross the BBB, the water insolubility, rapid clearance, and short half-life restrict its clinical application. To our understanding, few studies have reported the CAPE-loaded delivery system targeting the CNS. For instance, it has been reported that the intravenous administration of a kind of liposome loaded with CAPE significantly promotes BBB penetration and increases CAPE concentration in the ischemic brain (Lu et al., 2022). Therefore, it may be possible to improve CAPE brain targeting by investigating new NBDD.

Sulforaphane (SFN) (1-isothiocyanato-4-methylsulfonylbutane), an aliphatic lipophilic organosulfur, is obtained from the plants of cauliflower, broccoli, and cabbage. According to previous research, SFN possesses various biological activities, such as antioxidant, anti-inflammatory, and antiapoptotic properties. Given that inflammatory responses and oxidative stress are considered to be the main mechanisms of CNS diseases, SFN is a promising bioactive agent for treating PD, AD, and multiple sclerosis. Clinical studies have also shown that SFN can improve cognitive and behavioral deficits in patients with Autism Spectrum Disorder (ASD) and schizophrenia (Singh and Zimmerman, 2016; Momtazmanesh et al., 2020). Besides, another clinical trial conducted in China on the treatment of SFN in AD patients is still ongoing (NCT04213391). In terms of the neuroprotective effects of SFN on chemobrain, recent research has shown that SFN-loaded within iron oxide nanoparticles (SFN-Fe₃O₄) via intranasal administration significantly alleviated cisplatin induced neurotoxicology (Ibrahim Fouad et al., 2022). Furthermore, treatment with SFN-Fe₃O₄ significantly restored GSH and NO contents as well as inhibited the levels of lipid peroxidation (LPO) in rat brain tissues (Ibrahim Fouad et al., 2022). Besides, SFN-Fe₃O₄ also inhibited cisplatin-induced upregulation of AChE. Interestingly, Fouad et a. found that compared with free SFN, SFN-Fe₃O₄ had greater neuroprotective potential in animal models, which suggests to us that NBDD-based SFN-Fe₃O₄ may have better brain targeting, physicochemical stability, and bioavailability. Notably, long-term exposure to Fe₃O₄ might increase the generation of ROS and trigger neurotoxicity. In general, brain-targeted FPN is an effective strategy for chemobrain treatment, but more nanoparticles need to be further studied by scientists.

Luteolin (LUT) (3,4,5,7-tetrahydroxy flavone) as a naturally sourced flavonoid, is abundant in a variety of plant species, including chrysanthemum flowers, broccoli, celery, and hot pepper. It is well documented that LUT can penetrate BBB by regulating Rho GTPase and exerting neuroprotective effects. Recently, Imosemi et al. reported that LUT significantly reversed DOX-induced downregulation of catalase (CAT), SOD, glutathione peroxidase(GPX), and glutathione S-transferase(GST) activities as well as upregulation of LPO and reactive oxygen and nitrogen species (RONS) levels in cerebral, cerebellar cortex and hypothalamus (Imosemi et al., 2022). Furthermore, given that DOX has been reported to induce neuroinflammation in many studies, and LUT can alleviate DOX-induced inflammatory responses by decreasing the NO and MPO levels as well as inhibiting TNF-α and IL-1β production (Imosemi et al., 2022). Interestingly, it has been reported that apoptosis induced by LUT has been regarded as one of the primary mechanistic in the treatment of breast cancer. However, LUT can also block DOX-triggered activities of caspase-3 in brain tissues, indicating that LUT can significantly inhibit neuronal cell apoptosis caused by DOX (Imosemi et al., 2022). However, the low water solubility of LUT largely minimizes its bioavailability and effectiveness (Majumdar et al., 2014). Recently, several studies highlighted the drug brain targeting properties of nanoparticles based-LUT through BNDD. A previous study verified that intranasal administration of chitosan-coated nanoemulsion containing LUT could be detected in brain tissues, which remarkably increased brain bioavailability as well as improved the half-life time of LUT in both plasma and brain (Diedrich et al., 2022). Abbas and colleagues designed a novel LUT-loaded chitosan decorated nanoparticles that could significantly improve the short-term and long-term spatial memory, reduce Aβ aggregation and hyperphosphorylated-tau, and inhibit pro-inflammatory mediators’ levels in Alzheimer’s disease models intranasally (Abbas et al., 2022). The bile-salt-based nano-vesicles loaded with LUT via intranasal administration also effectively improved the progression of AD compared to LUT suspension (Elsheikh et al., 2022). Collectively, LUT is a promising drug for the treatment of CRCI, and the delivery of LUT-loaded nano drugs through the NBDD is a new strategy.

Quercetin (Que), a dietary flavonoid compound mainly from cherry, onions, tea, strawberry, and grape, possesses multiple pharmacological properties. Due to its lipophilicity features, Que can easily diffuse across the BBB, such that Que can reach the brain region and perform neuroprotective actions. In vivo experimental study, DOX treatment caused depression-like behavior disorders and oxidative damage by elevating MDA contents and reducing GSH and GST levels in the brain tissues of rats (Merzoug et al., 2014). Meanwhile, it has been reported that the immunosuppressive and myelosuppressive were serious adverse reactions of DOX exposure. DOX increased the plasma levels of corticosterone as well as altered hematological changes, to be precise, DOX decreased the total white blood cell numbers and the percentage of lymphocytes (Merzoug et al., 2014). Nevertheless, Que administration effectively improved behavior deficits, decreased MDA levels, up-regulated GSH and GST expression, reduced corticosterone levels in plasma, and restored leucopenia and lymphopenia in DOX-treated rats (Merzoug et al., 2014). Chemotherapy during pregnancy could lead to oxidative damage in the fetal brain, which may be the reason for congenital malformations (Cevik et al., 2013). Interestingly, Doğan et al. showed that compared with CYC- or DOX-exposed female rats, Que significantly reduced the activities of MDA and as well as up-regulated the expression of SOD, GSH, and CAT in fetal brain tissues (Dogan et al., 2015). Notably, human trials of Que have generally been well tolerated. Administration of Que at a concentration of 1000 mg/day or more for several months showed no adverse effects in serum electrolytes, renal and hepatic function, blood parameters, or hematology (Batiha et al., 2020). Ferry et al. studied the pharmacokinetic properties of Que in cancer patients intravenously, and they verified that 945 mg/m2 was a comparatively safe dose (Ferry et al., 1996). Taken together, Que may be an effectively neuroprotective agent and it is expected to act as an effective agent to treat chemobrain. However, the poor solubility and bioavailability of Que resulted in low levels in the circulatory system and organs. Consequently, it’s in great demand to develop novel dosage forms for Que to target the brain via NBDD. Ahmad and workers designed a Que-loaded mucoadhesive nanoemulsion (QMNE) and found that compared with oral and intravenous administration, intranasal administration of QMNE significantly increased its bioavailability and brain targeting in cerebral ischemic models (Ahmad et al., 2018). Dou and colleagues developed a natural phyto-antioxidant albumin nanoagent, HSA@QC nanoparticle, which encapsulated Que in human serum albumin, they found that intranasal administration of HSA@QC obviously alleviated Aβ aggregation, neuronal apoptosis, and oxidative stress, as well as synaptic damage in the brain of APP/PS1 mice (Dou et al., 2021). It is well known that cyclodextrins can be used as nasal excipients since they can solubilize lipophilic drugs and water-Insoluble drugs (Rassu et al., 2020). Papakyriakopoulou et al. prepared nasal powders which are composed of Que-cyclodextrins (methyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin), and the product significantly improved dissolution and nasal mucosa (Papakyriakopoulou et al., 2021). Besides, Que based-nanomaterials have been reported as promising nose-brain drug delivery systems including Que-loaded nanoemulsions, omega-3 nanoemulsions loaded with Que, and novel chitosan-coated-PLGA-nanoparticles (Ahmad et al., 2020; Vaz G. R. et al., 2022; Vaz G. et al., 2022). Therefore, the development of Que based on BNDD seems to be a feasible scheme for the treatment of chemobrain.

Naringin (Nar) is a prominent flavonone glycoside that is extensively present in tomatoes, grapefruits, and other citrus fruits. The pharmacological properties of Nar have been acknowledged, encompassing its anti-inflammatory, anti-oxidant, and antiradical activities, as well as its ability to suppress tumor effects. Recent research has demonstrated that Nar exhibits anxiolytic effects and neuroprotective actions against neurodegenerative disorders, traumatic brain injury, and cerebral ischemia in animal models. Furthermore, Nar has been shown to significantly ameliorate cisplatin-induced behavioral impairments and mitigate oxidative injury in the hippocampus. As we know, one of the main functions of cholinergic is responsible for modulating learning and memory (Chtourou et al., 2015). At the same time, Chtourou and colleagues have shown that Nar effectively alleviates cisplatin-induced upregulation of AChE activity in the hippocampus of rats, indicating that Nar could prevent the excitotoxicity induced by cisplatin (Chtourou et al., 2015). Furthermore, another study also suggested that Nar could alleviate oxidative injury, improve mitochondrial functions and decrease TNF-α and IL-1β levels in DOX-induced behavioral deficits mice (Kwatra et al., 2016). Interestingly, Kwatra et al. also found that Nar could alleviate DOX-induced depressive-like behavior and compared to sertraline, Nar showed comparable antidepressant effects. In addition, the combined regimen containing Nar and sertraline showed additive effects in the treatment of DOX-induced neurotoxicity (Kwatra et al., 2016). It gives us enlightenment that the combination with natural products regimen may new strategy in neuroprotection, which needs further research to confirm. Although Nar possesses the ability to cross the BBB and shows lesser adverse effects, its low bioavailability and fast elimination remarkably disturbed its clinical use. Therefore, NPs loaded-Nar may improve its delivery. For instance, compared with free Nar, the Nar phospholipid complex showed a longer half-life and stronger anti-oxidative abilities (Maiti et al., 2006). The Nar-cyclodextrin complex shows higher water dissolvability and thermal stability (Shulman et al., 2011). Furthermore, Nar-loaded liposome also exhibits improved dissolvability and bioavailability (Wang et al., 2017). However, to the best of our knowledge, little research about Nar on neuroprotection through brain drug delivery strategy was reported. More studies are needed to ascertain the insights into the safety and efficacy of NPs loaded-Nar in the treatment of chemobrain.

Ellagic acid (EA) is a naturally four-ring polyphenolic compound abundant in vegetables and fruits, including pomegranate, grapes, strawberries, and nuts. EA contains a hydrophilic part with four hydroxyls and two lactones and a lipophilic part with two hydrocarbon rings. This structure facilitates EA to scavenge both superoxide and reactive nitrogen species. Therefore, the pharmacological characteristics of EA are fundamentally related to its anti-oxidative activity. There is growing evidence revealing that MDA is regarded as one of the biomarkers of lipid peroxidation involved in oxidative damage in nervous system diseases. It has been reported that EA could remarkably decrease the MDA contents and upregulate the GSH production in the brain tissues of rats induced by DOX (Rizk et al., 2017). Beyond the well-established antioxidative effects, EA is also known to have anti-inflammatory activities (Mishra and Vinayak, 2014). The production of TNF-α and the expression of iNOS were markedly decreased after EA treatment in DOX-treated brain tissues. Besides, EA also showed anti-apoptotic effects by decreasing the expression of caspase-3 (Rizk et al., 2017). To sum up, it is possible that EA could treat chemobrain by reducing oxidative stress, inflammatory responses, and apoptosis. Nevertheless, it should be mentioned that the poor solubility in water, poor absorption, and rapid elimination remarkably limited the usage of EA. Currently, researchers have designed EA-based micro- or nano-particulate systems, including microspheres (Ogawa et al., 2002), nanoparticles (Arulmozhi et al., 2013), liposomes (Stojiljkovic et al., 2019) and pH-dependent microassemblies (Barnaby et al., 2011). For instance, EA-loaded NPs are more effective than EA alone in decreasing oxidative homeostasis and alleviating Alzheimer’s disease (Harakeh et al., 2021). The EA-loaded calcium-alginate NPs are superior to free EA in ameliorating pentylenetetrazol-related experimental epileptic seizures (El-Missiry et al., 2020). Therefore, it’s attractive to concern the clinical applications of drug delivery systems loaded with EA in treating chemobrain.

Rutin, also named vitamin P, is a flavonol glycoside that extensively existed in natural plants. Rutin has been demonstrated to possess a full range of pharmacological properties, including anti-inflammatory, anti-oxidative, antidepressant, and anticancer activities. Previously, Rutin has been proved to alleviate DOX-induced cardiotoxicity as well as improve nephrotoxicity and reproductive toxicity induced by cisplatin (Alhoshani et al., 2017; Ma et al., 2017). Recent research demonstrated that Rutin could protect against DOX-triggered neuronal injury (Ramalingayya et al., 2017). Administration of ten cycles of DOX (2.5 mg/kg for 5 days) caused cognitive dysfunction in rats. However, co-administration with Rutin (50 mg/kg) effectively improved cognitive impairment (Ramalingayya et al., 2017). Furthermore, Rutin treatment significantly improved morphological changes caused by DOX, particularly neurite length, and width. In addition, the neuronal apoptosis, intracellular ROS, and the levels of TNF-α were remarkably decreased during Rutin treatment, suggesting that Rutin might be a good anti-chemobrain drug candidate (Ramalingayya et al., 2017). Ramalingayya and colleagues also found that Rutin treatment alleviated episodic and spatial memory impairment, improved myelosuppression, and ameliorated brain oxidative stress induced by DOX (Ramalingayya et al., 2019). Besides, they also verified that pretreatment with Rutin had little influence on the anticancer activity of DOX (Ramalingayya et al., 2019). In a word, these studies indicated that Rutin has the potential to be an effective drug for chemobrain. Additionally, the neuroprotective role of Rutin against cisplatin-induced neurotoxic was also reported. Cisplatin causes peroxidation of lipid membranes by increasing free oxygen radicals and decreasing the production of antioxidants, which ultimately leads to the death of neurons (Sugihara and Gemba, 1986). It is well known that the upregulation of TBAR in intracellular indicates the increasing of free oxygen radicals and glutathione guards against free radical assault (Slater et al., 1987; Meister, 1991). Rutin treatment improved TBAR and GSH changes in rats challenged by cisplatin (Almutairi et al., 2017). Moreover, in the brain, as anti-oxidants, paraoxonases (PONs) play a key role in nerve myelination (Tang et al., 2011). Exposure to cisplatin significantly reduced PON-1 and PON-3 expression by at least four-fold. Interestingly, Almutairi et al. have shown that administration of Rutin markedly restored PON-1 and PON-3 expression to normal levels (Almutairi et al., 2017). Besides, the antioxidant and anti-apoptotic effects of Rutin against the toxic effects of cisplatin in peripheral nerve tissue have been demonstrated (Yasar et al., 2019). Taşlı et al. also demonstrated that Rutin co-administration could alleviate the cisplatin-induced detrimental effects through suppressing inflammation and lipid peroxidation, thereby reducing histopathology in the retina and optic nerves (Yasar et al., 2019). Collectively, Rutin not only plays a neuroprotective effect in CNS but also shows a certain role in the peripheral nervous system. Consistent with other natural products, hepatic first-pass metabolism, and BBB contributes to less bioavailability of Rutin in the body. Hence, novel drug carrier systems and targeting the brain might be a promising way. For example, compared with free Rutin, Rutin-loaded mucoadhesive polymeric nanoparticles administrated via nasal delivery significantly markedly increased the Rutin concentration in the brain and had better protective effects on cerebral ischemia (Ahmad et al., 2016a). Ahmad and Collenges also designed Rutin-loaded chitosan NPs, which effectively improved drug delivery into the brain after intranasal administration (Ahmad et al., 2016b). In conclusion, Rutin-loaded NPs are promising in guarding neurons against cell death and oxidative stress during chemotherapy.

Morin as a naturally resourced polyphenol extensively presents in the leaves, branches, fruits, and stems of numerous plants. Accumulating evidence have shown that Morin has a great ability to improve brain damage, including Parkinson’s disease, cerebral ischemia-reperfusion, and sepsis-triggered cognitive deficits (Xu X. E. et al., 2020; Khamchai et al., 2020; Ishola et al., 2022). Compared with DOX treated-only, Morin remarkably alleviated DOX-induced degenerative changes in neurons and hyperemia (Kuzu et al., 2018). Due to the double bond and the hydroxyl between C2 and C3 atoms, Morin has a high antioxidant potential (Solairaja et al., 2021). Notably, Morin can further inhibit MDA production and upregulated the levels of antioxidative enzyme activities, such as SOD, GSH, and GPx in brain tissues of DOX-treated animal models (Kuzu et al., 2018). It has been reported that during neuroinflammation, astrocytes are one of the main players (Ben Haim et al., 2015). Morin can also block DOX-induced activation of astrocytes in both gray matter and white matter of brain tissues, as well as decrease TNF-α and IL-1β levels. Meanwhile, Morin showed anti-apoptotic effects by upregulating the DOX-decreased anti-apoptotic gene Bcl-2 in the brain. Importantly, several studies have verified that Morin shows little toxicity and is well tolerated (Caselli et al., 2016). To sum up, Morin seems attractive in the treatment of chemobrain, but even better if it shows brain targeting further. However, to the best of our knowledge, few studies have revealed the potential therapeutic effects of Morin-loaded NPs, and the nasal brain delivery system gives us a new idea.

Epicatechin (EC) is one of the major catechins primarily exerted in cocoa, apples, and the leaves of the tea plant. A number of large-scale epidemiological studies have demonstrated positive relationships between the consumption of these EC-rich foods and cognitive function. Acute exposure to DOX significantly decreased body weight and increased the mortality rate of rats, however, pretreatment with EC remarkably reversed these changes. EC treatment markedly reduced the morphological changes induced by DOX (Mohamed et al., 2011). Moreover, administration of EC before DOX treatment significantly inhibited astrocytes activation, decreased the levels of TNF-α and NO as well as reduced TNF-α, NF-κB and iNOS mRNA levels in brain tissues. Therefore, EC can alleviate inflammatory response in the brain exposed to DOX. On the other hand, EC also reversed DOX-triggered oxidative stress with decreasing MDA production and elevating the expression level of catalase, SOD and GSH-Px. To sum up, EC has certain protective effects on chemobrain through anti-inflammatory and antioxidant properties. However, the long-term toxic and side effects of EC are still unknown. Interestingly, chitosan-coated-PLGA-nanoparticle exhibited noteworthy enhancements in nasal permeation and retention of catechin hydrate, rendering it a promising and secure brain-targeted delivery system for treating brain diseases (Ahmad et al., 2020). Therefore, the nanodrug via nose-brain delivery might improve brain-targeting and alleviate ADR.

Juglanin (JUG) is a novel natural compound sourced from the herb of Polygonum aviculare (Liu et al., 2008). Prior research has established the significant antioxidant, anti-inflammatory, and anticancer properties of JUG (Zhao et al., 2020b). It has been reported that DOX exposure significantly induces body weight loss, triggers behavioral deficits, and results in depression-like behaviors. Experiment studies showed that treatment with JUG effectively reverses these changes induced by DOX (Wei et al., 2022). Furthermore, Wei et al. observed that the levels of SOD, GSH, and CAT were decreased, and the contents of MDA was increased in brain tissues of DOX-treated group, which were subsequently reversed by JUG treatment. These findings suggest that JUG may possess a protective effect on DOX-induced chemobrain by modulating oxidative stress. Additionally, studies also indicated the potential benefits of JUG in the alleviation of neuroinflammation via decreasing the expression of TNF-α, IL-6, IL-1β, and NF-KB. In addition, administration of JUG significantly lowered the DOX-elevated AchE activities and caspase-3 activity (Wei et al., 2022). Collectively, all these results suggested that JUG might be a potential drug candidate in the treatment of chemobrain. As we know, JUG is hydrophobic with low bioavailability, which limits its clinical application. However, there is a lack of research on the pharmacokinetic of JUG as well as JUG-loaded NPs targeting the brain.

Galangin (GAL; 3,5,7-trihydroxy flavone), a natural flavonoid extensively existing in galangal and honey, has many bioactive properties, including anti-inflammatory, antimicrobial, antiviral, anti-obesogenic, and antioxidant effects. It has been shown that GAL can reduce DOX-triggered cognitive deficits and anxiety-like behavior (Abd El-Aal et al., 2022). Of course, like other flavonoids, GAL can abolish DOX-induced inflammatory and oxidative stress in the brain by reducing the production of IL-1β, IL-6, and TNF-α and modulating the activities of MDA and GSH. Furthermore, El-Aal et al. showed that GAL significantly enhanced BDNF expression and mitigated DOX-provoked necroptosis in the hippocampus (Abd El-Aal et al., 2022). All these findings suggest that GAL is a promising drug for the treatment of chemobrain with good neuroprotective effects. At present, most studies focus on the biochemical changes caused by GAL in animal models and there is no direct evidence of its effectiveness in humans. Besides, despite the benefits of GAL in neuroprotection, its efficacy has been limited by weak intestinal absorption, poor bioavailability, and high first-pass metabolism. Therefore, more studies are needed to explore the benefit of NBDD in overcoming the restriction of GAL.

Ginsenosides, a class of triterpenoid saponin, serve as the primary active constituents of ginseng. Among these, Ginsenoside Rg1 (Rg1) emerges as a crucial pharmacological compound. Experimental evidence has shown that administering DAC intraperitoneally three times with a 2-day interval leads to a significant reduction in MEMRI signal intensities in brain regions and impairs cognitive performance. However, Rg1 co-administration (5 mg/kg/day or 10 mg/kg/day) 1 week prior to the DAC regimen for 3 weeks effectively mitigates these changes in a dose-dependent manner (Shi et al., 2019). Moreover, empirical evidence demonstrated that Rg1 protected DAC-induced chemobrain by regulating the microglial polarization as well as reducing the production of TNF-α and IL-6 (Shi et al., 2019). Additionally, Rg1 has been extensively investigated for its neuroprotective properties and has been widely employed in clinical settings with minimal adverse effects. However, prior studies have suggested that Rg1 exhibits poor absorption and rapid depletion, and lacks efficacy in traversing the BBB to attain the therapeutic concentrations in brain tissues (Sun et al., 2005; Zhou et al., 2014). Hence, the utilization of a novel drug delivery system to increase the transportation of Rg1 across the BBB appear to be a promising approach. For instance, the transferrin receptor (TfR), which is highly enriched in the endothelium of brain capillaries, may facilitate transcytosis of transferrin or antibodies against the TfR across the BBB. To target the brain and achieve improved therapeutic outcomes, nanoparticles containing digoxin and loperamide based on transferrin or antibodies against the TfR (OX26 antibody) have been employed. Shen et al. have designed poly-γ-glutamic acid and OX26 antibody-based nanoparticles to load Rg1 (PHRO). They discovered that administrating PHRO injection via tail venous could effectively penetrate the BBB, resulting in the sustained release of Rg1, which ultimately decreased the volume of cerebral infarction and enhanced recovery of neurons in rats suffering diabetes and cerebral infarction (Shen et al., 2017; Shen et al., 2019). Additionally, Rg1-loaded complex nanovesicles could also across BBB and promote angiogenesis (Shang et al., 2022). Notably, Li et al. developed self-assembled Dox@Rg1 nanoparticles that not only mitigated DOX-induced cardiotoxicity but also enhanced its antitumor efficacy (Li et al., 2021). Taken together, Rg1-based NPs hold promise as potential therapeutic agents for the treatment of CRCI and may offer simultaneous benefits of anti-cancer effects.

Asiatic acid (AA) is a naturally occurring pentacyclic triterpene that serves as the primary bioactive constituent in the extract of the tropical herb Centella asiatica L. This plant has been recommended by pharmacopeia in China, Germany, and India for its potential to improve wound healing (Thong-On et al., 2014). AA has demonstrated a diverse range of pharmacological activities, including anti-inflammatory, antioxidant, and apoptosis-regulating properties, which may account for its therapeutic efficacy in various diseases. Impressively, AA exhibits a higher capacity to inhibit lipid peroxidation than several prominent antioxidants such as probucol, ascorbic acid, and alpha-tocopherol. Importantly, the lipophilicity, physicochemical properties, and bioavailability of AA suggest that AA has the potential to cross the BBB and provide neuroprotection. Previously, AA has been patented as a cognition enhancer for the treatment of dementia and amelioration of cognitive, cerebrovascular, and central nervous system conditions (EP0383171A2). with regard to mitigating chemobrain, rats exposed to 5-FU (25 mg/kg) on day 8, 11, 14, 17 and 20 exhibited cognitive impairment and accelerated cell death in the hippocampus. However, both co-treatment with AA (30 mg/kg), either before exposure to 5-FU (preventive), after exposure to 5-FU (recovery), or throughout the duration of the experiment could counteract the cognitive deficits (Chaisawang et al., 2017). JU Welbat et al. also showed that administration of AA significantly reversed the 5-FU-caused decrease of Notch1 sex determining region Y-box 2 (SOX2), nestin, doublecortin (DCX), and Nrf2 levels. Besides, AA treatment also reduced p21-positive cell number and MDA content in the hippocampus (Welbat et al., 2018). Taken together, combining the outstanding efficacy and safety properties of AA and its brain penetration ability, AA looks to be a viable drug candidate for the treatment of chemobrain.

Ganoderic acid (GA) is a prominent triterpenoid compound isolated from Ganoderma lucidum. A growing body of evidence shows that GA exhibits a diverse biological activity, such as antibacterial, antitumor, anti-oxidation and anti-apoptosis effects. Experimental findings indicate that the GA administration significantly improves cognitive dysfunctions in mice exposed to 5-FU, whereas both spatial and non-spatial memory decline in the absence of GA (Abulizi et al., 2021). Furthermore, studies have shown that GA confers protection against 5-FU-induced structural injuries of neurons by mitigating mitochondrial impairment, which involves ameliorating intracellular mitochondrial swelling and crest fractures, promoting mitochondrial biogenesis, and inhibiting mitochondrial fission (Abulizi et al., 2021). Pro-inflammatory cytokines have been found to exist remarkable toxic effects on neuronal cells, particularly in the hippocampus (Wang X. M. et al., 2015). Additionally, 5-FU has been shown to induce age-associated cognitive decline in mice by upregulating cytokine expression (Groves et al., 2017). Notably, supplementation of GA significantly downregulated the production of IL-6 and decreased the expression of COX-2. Biomedical studies have shown that GA is a promising drug candidate for treating chemobrain, whereas the low abundance, complex extraction, and purification procedures cause significant restrictions on its use on a laboratory scale. Hence, the challenge of augmenting the concentration of GA and enhancing the techniques for extracting and refining GA from Ganoderma lucidum necessitates resolution (Xia et al., 2014).

Astaxanthin (AST), a xanthophyll carotenoid present in diverse microorganisms and marine organisms, possesses distinctive chemical properties due to its molecular structure. AST can directly penetrate cells and neutralize active oxygen and free radicals, thereby acting as a naturally occurring antioxidant with antioxidative activity surpassing that of vitamin E by 500 times (Wu L. et al., 2020). Prior studies have documented the diverse biological properties of AST, including immunomodulatory, antioxidant, hypoglycaemic, and hypolipidaemic activities. With regard to neurological diseases, the lipid-soluble capacity of AST enables it to readily traverse BBB and exert direct effects on CNS. Additionally, following single and repeated dietary ingestion, AST accumulates in the hippocampus and cerebral cortexes of rat brains, underscoring its importance in the treatment of neurological conditions (Zhang et al., 2014; Manabe et al., 2018). In vivo experimental investigations have demonstrated that AST treatment (at a dose of 25 mg/kg) confers significant protection against DOX-induced memory impairment in rats. The restorative effects of AST on hippocampal histopathological architecture and decrease hippocampal apoptotic markers (cytochrome c and caspase-3 activities) have been demonstrated (El-Agamy et al., 2018). Furthermore, AST has been reported to reduce MDA levels and increase GSH and catalase contents, while inhibiting astrocytes activation and downregulating TNF-α, PGE2, and COX-2 levels. The findings suggest that AST can strengthen the antioxidant defense system and mitigate neuroinflammation induced by DOX (El-Agamy et al., 2018). Currently, AST is widely utilized as a food additive, dietary supplement, and clinical drug with no observed side effects in animals and humans. For instance, a prior study has confirmed that there are no adverse effects observed after administrating AST (6 mg/day) in adult humans (Spiller and Dewell, 2003). Hence, it appears that minimal constraints exist in the management of chemobrain. Nonetheless, the inadequate stability and solubility of AST contribute to poor absorption, which ultimately impedes its clinical utilization. In recent times, Santonocito et al. have devised AST-loaded stealth lipid nanoparticles (AST-SSLNs) which have demonstrated a substantial improvement in the stability and bioavailability of AST in the brain. Furthermore, AST-SSLN has shown a superior antioxidant capacity in comparison to free AST (Santonocito et al., 2021). Simultaneously, Fe₃O₄/AST/Transferrin NPs, the AST nanoparticles coated with transferrin and polyethylene glycol (PEG), exhibits better water dispersibility and biocompatibility than free AST, resulting in heightened neuroprotective activity (You et al., 2019). Besides, the ASX thermosreversible nasal gel (ATX-NLC in situ gel) formulated by incorporating poloxamer-127 to AST nanostructured liposomes, can augment AST accumulation in the brain, thereby serving as an adjunctive therapeutic agent for Parkinson’s disease (Gautam et al., 2021). In general, AST represents a promising approach for the treatment of chemobrain, and nanoparticle-based delivery of AST via NBDD holds significant potential.

C. indicus protein (CI protein), a 43 kD protein, is extracted and purified from the leaves of Cajanus indicus L. Historically, these leaves have been utilized for treating various hepatic disorders, such as jaundice and hepatomegaly (Manna et al., 2007). Recent research has demonstrated the protective properties of CI protein against carbon tetrachloride-related hepatic disorders, galactosamine-induced nephrotoxicity, and doxorubicin-triggered nephrotoxicity (Ghosh et al., 2006; Sinha et al., 2007; Pal and Sil, 2012). Additionally, Ghosh et al. (2006) have confirmed the capacity of CI protein in mitigating oxidant and scavenging free radicals. As we know, the overproduction of lipid peroxidation and subsequent neuronal cell death are primary indicators of neurotic injury in chemobrain. Interestingly, experimental studies have observed that CI protein administration (3 mg/kg) for 4 days markedly inhibits DOX-induced oxidative stress, reflected by decreased content of MDA, protein carbonyl and GICSSG, and upregulated-GR, GSH, and GPx activities in the brain tissue (Pal et al., 2012). The lipid-dependent ATPases that are bound to the membrane play a significant part in nerve transmission, active transport, and the maintenance of cellular homeostasis. Furthermore, CI protein treatment significantly reversed the DOX-induced decrease in the activities of Na+, K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase (Pal et al., 2012). Additionally, the present study has also suggested that CI protein inhibits mitochondria-dependent apoptotic cell death by decreasing the expression of cytochrome c, caspase-3, caspase-9, Bad/Bcl-2, and PARP in the brain tissues of mice (Pal et al., 2012). These findings suggest that CI protein has the potential to prevent chemobrain and develop drugs via further research.

C-phycocyanin (C-PC) a protein-binding pigment that existed in cyanobacteria, is extensively utilized as a dietary supplement, colorant, and fluorescent dye for the ability to aid in the process of photosynthesis. Pharmacological studies have shown that C-PC possesses numerous biological functions, including anti-inflammatory, antioxidant, anti-necroptosis, and anti-tumor properties. Recently, C-PC has garnered significant attention in the field of neuroprotection. It has been reported that C-PC can improve multiple sclerosis by inhibiting inflammatory responses and oxidative stress (Penton-Rol et al., 2016). Additionally, C-PC has been found to exert beneficial effects on streptozotocin-induced cognitive deficits by attenuating neuroinflammation and apoptosis (Agrawal et al., 2020). Interestingly, it has also been observed that C-PC possesses neuroprotective effects on DOX-induced chemobrain. Wang et al. demonstrated that C-PC (50 mg/kg) treatment improved spatial learning and rescued synaptic density induced by DOX (Wang et al., 2021). Co-administration of C-PC with DOX significantly ameliorated mitochondrial damage in the hippocampus. Moreover, C-PC inhibited DOX-induced neuroinflammatory response in the hippocampus, as evidenced by the decrease of TNF-α, IL-1β, and IL-6 levels, as well as a reduction of the number of IBA-1 and glial fibrillary acidic protein (GFAP)-positive cells. Additionally, C-PC administration also decreased the content of MDA, protein carbonyl, and 8-OHdG while increasing the activities of GSH and SOD. Mitochondrial dysfunction has been demonstrated to participate in DOX-induced brain injury and serve as a contributing factor to CRCI. Administration of C-PC significantly ameliorated DOX-induced mitochondrial damage in the hippocampus, demonstrated by restored mitochondrial enzyme complex activity, increased mitochondrial respiratory control ratio, ATP production, and reduced ROS production (Wang et al., 2021). Importantly, as a natural constituent, C-PC has been approved to use as functional food or dietary supplement due to its nontoxic and non-carcinogenic (Romay and Gonzalez, 2000; Penton-Rol et al., 2021). Taken together, these findings suggest that C-PC is a viable candidate for the treatment of CRCI. Excitingly, the therapy for neurological diseases utilizing C-PC and BNDD has been reported with promising results. Min et al. have found that C-PC-based liposomes with 20% cholesterol administrated via the nose-to-brain system showed extended neuroprotective effects in animal models of cerebral ischemia (Min et al., 2017). Additionally, Chung et al. designed chitosan-coated C-PC liposome (C-PC liposome) and verified that nasal administration of C-PC liposome resulted in smaller infarct size and improved behavioral test outcomes in rat Middle Cerebral Artery Occlusion (MCAO) models in comparison to free C-PC (Chung et al., 2018). Collectively, these findings suggest that C-PC is a valuable candidate for treating CRCI, and its efficacy might be further enhanced by NBDD.

Astragali Radix (AR), a traditional Chinses medicine (Huangqi), is the dried root of Astragalus species (Li et al., 2019). To date, there are over 100 compounds extracted and identified in AR, containing flavonoids, polysaccharides, saponins, and amino acids (Auyeung et al., 2016; Liu et al., 2017). Currently, it has been demonstrated that AR may offer protection against heart, lung, liver, kidney, and brain injury in a variety of oxidative stress-related disease models (Hong et al., 1992; Shahzad et al., 2016). AR administration significantly reversed DOX-induced weight loss in rat models. Furthermore, AR treatment remarkably recovered the elevation of MDA and the ratio of SOD/MDA in brain tissues caused by DOX (Yu et al., 2021). The homeostasis of amino acid metabolism is closely associated with the redox balance in the brain of mammals. Yu et al. found that DOX exposure significantly upregulated six amino acid expressions in brain tissues, including glycine, serine, glutamate, citrulline, ornithine, and alanine, which were closely associated with reactive oxygen species occurrence. Notably, the AR administration effectively reversed these changes (Yu et al., 2021). In a word, given the extremely low toxicity, AR has been approved as a dietary supplement in China and the USA, suggesting that AR is one of the most promising candidates for the treatment of CRCI. However, similar to many natural products, some compounds in AR exhibit low water solubility and inadequate bioavailability, thereby restricting their practical applications. Consequently, additional studies are necessary to enhance its utilization by optimizing its dosage form. For instance, Yu et al. made a commendable effort to combine Astragalus polysaccharide (APS) with gels to attain sustained APS release to regulate immunity (Yu et al., 2017). Yakubogullari et al. combined Astragaloside VII (AST VII) with APS to formulate nano-preparations, which served as an adjuvant of influenza vaccine, resulting in prominent regulatory effects in immunity and viral defense system (Yakubogullari et al., 2019). Hence, future research should concentrate on the dosage forms by utilizing and developing polysaccharides, flavonoids, and saponins in AR, extremely nano-preparations.

Tiliacora triandra (Colebr.) Diels (TT) as a plant of the Menispermaceae family is widely spread in Southeast Asia. Due to its richness in polyphenols and flavonoid compounds, TT is commonly used for anti-pyretic, anti-bacterial, and anti-malarial activities. A prior study has explored the neuroprotection of TT and pointed to the protection of TT against brain oxidative stress, neurological degeneration, and cerebral infarction in a murine model of cerebral ischemia-reperfusion (Thong-Asa and Bullangpoti, 2020). In addition, T. triandra leaf extract has been found to possess the ability to improve spatial learning and memory and maintained ChAT activity in the hippocampus (Wachiryah and Hathaipat, 2018). Recent studies have found that TT administration (250 mg/kg or 500 mg/kg) orally for 5 weeks significantly prevents weight loss, alleviates pathological damage in the brain, and improves cognitive dysfunction induced by cisplatin (Huang et al., 2021). Simultaneously, TT significantly inhibited CDDP-induced oxidative stress and neuroinflammation by decreasing MDA levels, elevating the activities of GPx, SOD, GSH, and CAT, and impeding the production of TNF-α, IL-1β, and IL-6 (Huang et al., 2021). Bcl-2 and the caspase families are key regulators of the apoptotic pathway. It has also been reported that TT reduces acetylcholinesterase activities, decreases caspase-3 levels, and increases Bcl-2 expression in brain tissues, indicating that TT can protect against cisplatin-induced neuronal death in rat models. Collectively, although the components of the extract of Tiliacora triandra require further elucidation, the crude TT exhibits excellent potential for advancement through nanotechnology as medicine and/or nutraceutical products, given the overall efficacy against CRCI.

Ergothioneine (EGT), a naturally occurring compound initially discovered from ergot fungus, is exclusively produced by certain fungi and bacteria. Despite the inability of animals to synthesize EGT, it is widely absorbed and transported into cells by the cell membrane-specific carnitine/organic cation transporter (OCTN1) (Grundemann, 2012). EGT is a potent physiological antioxidant, thereby exerting a protective role in many oxidative stress-related diseases, including diabetes, chronic kidney and liver diseases, diabetes, cardiovascular diseases, and cancer (Paul, 2022). Notably, EGT shows high blood-brain barrier permeability and possesses neuroprotective effects, which are associated with the expression of OCTN1 (Nakamichi et al., 2012). The regulation of cellular functions by EGT has been found in neurons, neural stem cells, microglia, and cerebral vascular endothelial cells (Ishimoto and Kato, 2022; Nakamichi et al., 2022). Recent experimental studies have shown that supplementation of EGT (2 or 8 mg/kg/day) for 58 days significantly restores EGT levels in brain tissues, prevents memory and learning impairment, and alleviates body weight loss induced by cisplatin (Song et al., 2010). Simultaneously, EGT has been demonstrated to inhibit cisplatin-triggered neurotoxicology by reducing MDA levels and increasing the ratio of GSH/GSSG (Song et al., 2010). Furthermore, in vitro studies have defined that EGT treatment can alleviate the cisplatin-induced damage in PC12 cell proliferation and PCN cell axonal and dendritic growth. These findings suggest that EGT prevents cisplatin-caused neuronal injury and improves cognition, which is possibly mediated by its inhibition of oxidative stress and restoration of AChE content in neuronal cells. In view of the fact that EGT can reach millimolar levels in brain tissues with little toxicity, more experimental and clinical studies on the treatment of CRCI with EGT supplements are strongly encouraged (Halliwell et al., 2018; Tang et al., 2018).

Bixin, a liposoluble di-apocarotenoid, is extracted from the seeds of Bixa orellana which is extensively utilized for the treatment of infectious and inflammatory diseases in Mexico and South America. Due to its safety, Bixin is certified by the FDA as a natural food colorant and additive due to its safety (Xue et al., 2018). Pharmacological studies have reported that Bixin exhibits a diverse range of activities, including anti-inflammatory, antioxidative, and anti-tumor properties (Rivera-Madrid et al., 2016). Previously, a vitro study has indicated that Bixin can capture ROS, while animal studies also demonstrated that Bixin protects against oxidative DNA damage and lipid peroxidation (Kumar et al., 2018). Furthermore, the prior investigation has established Bixin as a novel inducer of Nrf2, which has the potential to quench ROS and impede inflammation and fibrosis in lung tissue (Xue et al., 2018). Considering the correlation between chemotherapeutic drug-induced neurotoxicity and ROS production, Bixin may serve as a promising effective agent against CRCI. Experimental findings have shown Bixin markedly decreases DNA percentage in tail and micronuclei frequency in PC12 cells exposed to cisplatin. Although studies have demonstrated that Bixin can cross BBB, there is still a lack of in vivo studies of Bixin on CRCI (Yu et al., 2020). Therefore, more effects are still required to fully elucidate the neuroprotective effects of Bixin on CRCI and its potential mechanisms.