Green tea (Camellia sinensis), the first tea to be discovered in the world, originated in China and has since spread globally. Aside from water, green tea is recognized as the most popular beverage consumed worldwide (Zhao et al., 2022). Moreover, green tea is a type of unfermented tea, which prevents the oxidation of polyphenolic components and largely preserves the natural components of fresh tea leaves, especially catechins. Catechins are colorless, astringent, water-soluble compounds; the main essential components of green tea (Graham, 1992). EGCG is the most active of the six major catechin compounds contained in green tea (catechin, gallocatechin, epicatechin, epigallocatechin, epigallocatechin gallate, and EGCG), accounting for 10%–15% of the total catechins (Ohishi et al., 2016) and also the most abundant and active compound in green tea (Zhao et al., 2020). Emerging evidence suggests that EGCG possesses diverse pharmacological activities, including anti-inflammatory (Ohishi et al., 2016; Tasneem et al., 2019), antioxidant (Karas et al., 2017; Guo et al., 2005), anticancer (Baláži et al., 2019), anti-apoptotic (Guo et al., 2005; Weinreb et al., 2004), and neuroprotective (Cheng et al., 2021; Payne et al., 2022) properties, highlighting its therapeutic potential for the treatment of various human diseases (Chakrawarti et al., 2016). EGCG is approved as a dietary supplement in many regions worldwide, including Europe, the United States, Canada, and Japan. However, doses exceeding 600 mg per day may cause liver toxicity (Dekant et al., 2017). Several studies have shown that EGCG exerts important neuroprotective effects against a variety of neurological diseases/disorders such as AD, PD, cerebral edema, and cerebral ischemic injury (Xu et al., 2016; Zhang et al., 2020a; Park et al., 2020). However, due to poor physicochemical stability and low oral bioavailability of EGCG, its clinical application remains limited. Research indicates that certain technologies, such as nanotechnology, can enhance its stability, efficacy, and pharmacokinetics by encapsulating EGCG within nanoparticles (Peng et al., 2025).

Moreover, reports suggest that HIF-1 facilitates endogenous neuroprotection under hypoxic/ischemic conditions. HIF-1 is a heterodimer (including HIF-1a and HIF-1b), with the HIF-1b subunit constitutively expressed and the HIF-1a subunit regulated in an O₂-dependent manner. HIF-1α—the active subunit in HIF-1—is a key regulator of cellular and systemic O₂ homeostasis, and it regulates the expression of multiple genes (Lu and Kang, 2010; Lee et al., 2020). The study by Orly Weinreb et al. systematically revealed the neuroprotective mechanism of EGCG in a human neuroblastoma SH-SY5Y cell model induced by prolonged serum deprivation. Gene expression analysis was utilized to ascertain EGCG effects on protein levels and mRNA expression of the prolyl 4-hydroxylase subunit. The findings demonstrated a reduction in both protein levels and mRNA expression following EGCG treatment. Notably, this enzyme, which belongs to the HIF prolyl hydroxylase family, serves as a key iron oxide sensor for hypoxia perception and can also negatively regulate the stability of multiple enzymes and the degradation of proteins involved in cell survival and differentiation. Subsequent studies have indicated that EGCG may stabilize HIF-1α through various regulatory pathways, including immunoglobulin-heavy-chain binding protein HSP 70 kDa protein 5 (BiP), prolyl 4-hydroxylase, HSP90 beta, and E2 ubiquitin-conjugating enzyme, among others. This mode of regulation corroborates with proteomic data. According to proteomic analyses, EGCG increases the levels of cytoskeleton structural proteins and binding protein 14-3-3 γ, and is involved in regulating intracellular signaling pathways as well as promoting cytoskeleton stability, leading to specific neuroprotective effects in the brain (Weinreb et al., 2007). In addition, the induction of a series of hypoxia-sensitive genes regulated by HIF-1 is also affected by iron chelation. Moreover, both HIF-1 and iron-regulated protein 2 (IRP2) share a common iron-dependent proteasomal degradation pathway through the action of the key iron and O₂ sensors prolyl hydroxylase (Erez et al., 2003; Callapina et al., 2005), whereas EGCG maintains cellular homeostasis by inhibiting both prolyl hydroxylase activity via free iron chelation and inhibiting the degradation of both HIF and IRP2. This mechanism offers a new approach for the management of NDDs (such as AD, PD, and HD) (Mandel et al., 2006).

Activation of the nuclear factor kappa-B (NF-κB)/HIF signaling axis in a hypoxic microenvironment reportedly triggers microglia activation (Liu et al., 2020; Zhang et al., 2021), which not only exacerbates the lipopolysaccharide (LPS)-induced inflammatory cascade but is also associated with the pathological process of plateau brain edema (Zhou et al., 2017). EGCG exhibits multi-targeted regulatory advantages in this segment: First, it reduces the expression of pro-inflammatory factors such as IL-1β and TNF-α by inhibiting the toll-like receptor 4 (TLR4)/NF-κB pathway (Zhong et al., 2019; Liu et al., 2016); second, it constructs a neuroprotective barrier by enhancing the BBB integrity (Wei et al., 2019; Kim et al., 2020a). Consequently, it demonstrates substantial anti-inflammatory and neuroprotective effects in AD models. Similarly, in the CoCl₂-induced hypoxia model of BV2 microglia, EGCG achieved dual regulation of oxidative stress and inflammatory response by synergistically inhibiting the NF-κB pathway and activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1(HO-1) pathway (Kim et al., 2022). In summary, EGCG possibly prevents inflammatory responses and brain oedema in hypoxia-activated microglia through NF-κB pathway inhibition.

In addition to the NF-κB pathway, the importance of the mitogen-activated protein kinase (MAPK) signaling network in the neural injury response cannot be overlooked (Singer et al., 1999; Xia et al., 1995). As a central regulatory network in the response to nerve injury, among MAPKs, the p38 and c-Jun N-terminal kinase (JNK) pathways respond to stress stimuli (including hypoxia, free radicals, and reactive oxygen species [ROS]) (Chen et al., 2018), which promotes neurodegeneration or neuroinflammation, leading to apoptosis or cell death. Moreover, events such as hypoxia, ischemia, and infection may trigger inflammatory responses. Consequently, ischemia and hypoxia induced by long-term chronic hypoperfusion can lead to hyperstimulation of neuroinflammation, resulting in apoptosis, BBB damage, and other pathological changes. These phenomena can lead to the onset and progression of vascular cognitive impairment and dementia (VCID) (Tian et al., 2022). A study by Ashley Payne’s team offered valuable insights, as it confirmed that EGCG, by inhibiting microglial cells from aberrantly activation, effectively blocks the neuroinflammation-apoptosis vicious cycle (Payne et al., 2022), further improving the theoretical framework of its multi-pathway neuroprotective mechanism.

Furthermore, although the precise mechanism through which EGCG exerts its antioxidant effect remains unclear, its substantial capacity for free radical scavenging has been substantiated through pharmacological investigations (Guo et al., 1996; Kondo et al., 1999). Previous studies have reported that EGCG reduces lipid peroxidation damage in synaptosomes (Lin et al., 1998) and has a protective effect against neuronal damage induced by free radicals (Guo et al., 1996). This neuroprotective effect is clinically important because oxidative stress-induced lipid peroxidation not only directly leads to neuronal death (Kruman et al., 1997), but also is the central mechanism of delayed neuronal injury after transient total cerebral ischemia (Kawase et al., 1999). Moreover, animal experiments further confirmed that intraperitoneal injection of EGCG reduced neuronal damage in a dose-dependent manner in the hippocampus of Mongolian gerbils after a transient ischemic attack (Lee et al., 2000). Thus, green tea extract might be an effective preventive agent for ischemia/reperfusion (I/R) brain injury (Hong et al., 2000; Hong et al., 2001).

Complementarily, EGCG can also affect enkephalinase (NEP) activity. As a major amyloid β-peptide (Aβ) degrading enzyme in the central nervous system, NEP ameliorates AD pathology by removing Aβ (Iwata et al., 2000; Iwata et al., 2001; Nalivaeva et al., 2012). A recent meta-analysis revealed a decrease in NEP expression and activity in the cortex of older patients with AD. (Zhang et al., 2017a) I. A. Zhuravin et al. demonstrated that EGCG increased NEP mRNA levels and gene expression in human neuroblastoma NB7 cells under hypoxic conditions. Furthermore, they concluded that EGCG reverses NEP activity reduction caused by prenatal hypoxia in an animal model, and even triggered a double elevation of enzyme activity in the cortex and hippocampus (Zhuravin et al., 2019). These findings validate the neuroprotective effects of EGCG in protein homeostasis regulation, providing a new molecular basis for its application in AD therapy (Table 1).

In summary, EGCG exerts protective effects through multiple mechanisms in various models of neurological injury, demonstrating significant potential as a novel therapeutic agent. Moreover, further research is needed in the future to enhance the physicochemical stability and oral bioavailability of EGCG.

CA, Centella asiatica (L.) Urban, is a perennial herbaceous plant of the Umbelliferae family. It grows in wet or swampy areas in tropical and subtropical regions of the Northern and Southern hemispheres. Native to South Africa, India, Malaysia, Sri Lanka, Madagascar, and Australia, CA is also found in Japan and China (Gray et al., 2018). Phytochemical analyses reveal that principal bioactive constituents of CA comprise triterpenoids, polyphenols, and essential oils. The most important components of medicinal value in CA are pentacyclic triterpenic acids and the corresponding glycosides, mainly including asiatic acid (AA), madecassic acid (MA), asiaticoside (AS), and madecassoside (MS) (Zheng and Qin, 2007). This multifunctional natural product demonstrates remarkable therapeutic versatility, with established applications in wound healing (Diniz et al., 2023), dermatological disorders (Bylka et al., 2014), antimicrobial (Mudaliana, 2021), antiviral (Li et al., 2024a), and venous insufficiency (Incandela et al., 2001) as well as anxiety alleviation and cognitive enhancement (Gray et al., 2024). Its anti-inflammatory (Park et al., 2017) and antioxidant properties (Zhao et al., 2014) play a significant neuroprotective role in neuroprotection, particularly in NDDs and ischemic encephalopathy.

The neuroprotective effects of CA can be categorized into two: in vitro and in vivo. In an in vitro model, the presence of CA resulted in an observable increase in neurite elongation (Soumyanath et al., 2005); whereas, in an in vivo experiment, antioxidant capacity of CA protected the rat brain from age-related oxidative damage, confirming a significant neuroprotective effect (Subathra et al., 2005). Studies have reported that the administration of CA and its extracts exerts a neuroprotective effect on NDDs (primarily AD and PD) by selectively lowering Aβ levels (Dhanasekaran et al., 2009), inhibiting ROS production (Gray et al., 2017), ameliorating mitochondrial dysfunction (Nataraj et al., 2017), and increasing brain-derived neurotrophic factor (BDNF) levels (Nataraj et al., 2017).

Based on the scope of current research, hypoxia could accelerate the pathological progression of AD through the following mechanisms: First, hypoxia promotes the production and accumulation of Aβ, which is an important neurotoxic factor of AD (Peers et al., 2007), and is also commonly regarded as the initiator of AD; Second, hypoxia induces calcium overload by interfering with intracellular calcium homeostasis (Peers et al., 2007; Lall et al., 2019), culminating in neuronal death; moreover, hypoxia fosters the release of large amounts of ROS and proinflammatory mediators through the activation of pro-inflammatory immune cells, such as microglia (Lall et al., 2019), and this neuroinflammatory response further accelerates AD progression. Notably, CA and its active components showed multi-targeted intervention potential for several pathological processes caused by hypoxia, including inhibition of Aβ plaque deposition, regulation of calcium homeostasis imbalance, and modulation of the NF-κB/Nrf2 signaling axis (Hambali et al., 2021). Particularly, in the NF-κB pathway, the research group led by Feng Zhang discovered that mice model of acute hypoxia exhibited significantly elevated levels of NF-κB p50/p65 subunit expression and p-IκBα/IκBα ratio. This finding suggests that hypoxia activates the NF-κB pathway, thereby promoting the release of pro-inflammatory factors (Zhang et al., 2017b). From a mechanistic perspective, NF-κB pathway inhibition prevents NF-κB from dissociating from IκB, which inhibits downstream transcription of related genes and exerts neuroprotective effects. Further, the Nrf2 pathway mediates anti-inflammatory responses through its target gene HO-1 (Li et al., 2014). Notably, the Nrf2 pathway also establishes a bidirectional regulatory network through NF-κB activity inhibition (Chi et al., 2015a). In addition, the anti-inflammatory properties of CA provide neuroprotection against cerebral I/R injury. She Chen et al. found that AS significantly ameliorated I/R-induced memory impairments and inflammatory cascade responses by inhibiting microglia activation and p38 MAPK phosphorylation in the hippocampus (Chen et al., 2014).

Hypoxia-induced neurological dysfunction often involves oxidative stress, and the neuroprotective effects of CA may stem from its antioxidant properties. For example, in a rat model of acute focal middle cerebral artery occlusion (MCAO), CA significantly improved cerebral infarct size and neurological function by scavenging free radicals (Tabassum et al., 2013). Similarly, MS pretreatment exhibited antioxidant and neuroprotective effects in a GT1-7 cell model of hypoxic injury (Li et al., 2016). Notably, the mechanism of neurotrophic factors in hypoxia-induced neurodegeneration is related to oxidative stress (Sharma et al., 2019); moreover, CA regulates the expression of BDNF. Recently, the zebrafish model has provided new insights regarding the anti-hypoxic mechanism of CA. Further, Ariani et al. found that AA treatment improved head development, blood flow rate, and BDNF expression in intrauterine hypoxic zebrafish embryos (Ariani et al., 2023a), which was predicted to be associated with insulin-like growth factor-1 receptor (IGF-1R) signaling (Ariani et al., 2023b). Further studies have shown that CA also alleviates neurological dysfunction in zebrafish larvae by modulating BDNF and vesicular glutamate transporter protein 1 (VGLUT1) expressions under oxygen deprivation (OD) conditions (Ariani et al., 2024). Notably, VGLUT1 overexpression under hypoxia could trigger glutamate excitotoxicity (Daniels et al., 2011). This study also demonstrated that CA resistance to hypoxia-induced oxidative stress is also associated with VGLUT1 expression and that BDNF has a regulatory effect on VGLUT1 (Ariani et al., 2024). Furthermore, research on adult zebrafish suggests that combining CA ethanol extract and intermittent feeding ameliorates neuronal and mitochondrial damage caused by subacute hypoxia (Bindal et al., 2024). Moreover, Rajanikant et al. demonstrated that the neuroprotective effect of AA in a mouse model of permanent MCAO was associated with inhibition of mitochondrial cytochrome c release, suggesting that AA may attenuate cerebral ischemic injury by maintaining mitochondrial function (Krishnamurthy et al., 2009).

The mechanism of brain injury caused by hypoxia and ischemia is reportedly associated with neuronal apoptosis. For example, Tao Sun et al. utilized a neonatal rat cortical neuronal ischemic-hypoxic model to confirm that AS exerted an anti-apoptotic effect by regulating Bcl-2, Bax, and caspase-3 expression and inhibiting lactate dehydrogenase release (Sun et al., 2015). Similarly, a study further revealed that the neuroprotective mechanism of AS against neonatal hypoxic-ischemic encephalopathy (HIE) involved the TLR4/NF-κB/signal transducer and activator of transcription 3 (STAT3) pathway: it inhibited NF-κB phosphorylation and thus downregulated the levels of TNF-α, IL-6, and p-STAT3 by decreasing the levels of TLR4, intercellular cell adhesion molecule-1 (ICAM-1), and IL-18/IL-1β (Zhou et al., 2020). In addition, Yuan Luo et al. found that the apoptosis-inhibitory effect of MS on anti-cerebral I/R injury was also regulated by the NF-κB pathway (Luo et al., 2014). Notably, the effects of CA active ingredients on NF-κB-related pathways combine multiple anti-inflammatory, antioxidant, and anti-apoptotic effects. Similarly, by modulating the nucleotide-binding oligomerization domain containing 2 (NOD2)/MAPK/NF-κB signaling axis (including downregulation of P-ERK1/2, P-JNK, P-p38, P-65, and p-IκBα), AS achieved three major modulations of inflammation, oxidative stress, and apoptosis in MCAO rats (Zhang et al., 2020b) (Table 2).

In short, CA and its extracts showed protective effects against hypoxia-induced nerve damage in many aspects. As a natural product, CA is well tolerated and has no adverse reactions (Songvut et al., 2019), and its potential is noteworthy despite the lack of relevant clinical trials based on the scope of the literature we have reviewed.

Ginkgo (Ginkgo biloba), a deciduous tree of the genus Ginkgo in the family Ginkgoaceae, is native to China and has existed for >200 million years, making it one of the most famous living fossils. Presently, dozens of compounds have been isolated from Ginkgo biloba (Meng et al., 2024). Flavonoids and terpenoids are the major bioactive compounds found in Ginkgo biloba (G. biloba L.). Ginkgolides are unique to Ginkgo and are the principal diterpene terpenoids in the standardized Ginkgo biloba leaf extract EGb 761, including Ginkgolide A (GA), Ginkgolide B (GB), Ginkgolide C (GC), Ginkgolide J (GJ), Ginkgolide K (GK), Ginkgolide L (GL), and Ginkgolide M (GM) (Feng et al., 2019). A distinguishing feature of all ginkgolides is the presence of a five-membered ring (Gachowska et al., 2021). The most studied ginkgolide associated with hypoxia is GB. Notably, ginkgolides possess a wide range of activities such as anti-inflammatory (Li et al., 2023; Shu et al., 2016), antioxidant (Liu et al., 2019a), anti-ischemic (Chi et al., 2015b), and neuroprotective, although they are yet to be found in any other natural plants (Liu et al., 2022; Xia and Fang, 2007; Maclennan et al., 2002). Ginkgo biloba has been recommended for medicinal use for centuries due to its high medicinal value (Hirata et al., 2019; Hassan et al., 2020). In clinical practice, ginkgo biloba extracts have been widely used to treat central nervous system disorders such as AD and cognitive deficits with little to no adverse effects (Chan et al., 2007; Peng et al., 2024; Liu et al., 2019b; Canevelli et al., 2014). This demonstrates that GB is a safe and effective adjunctive treatment option. Scientific studies have demonstrated the neuroprotective effects of ginkgolides against a variety of hypoxia-induced neuronal damage. In summary, emerging evidence reveals the superior neuroprotective potential of ginkgolides.

Zhu et al. successively investigated the neuroprotective effects of ginkgolides against neuronal injury induced by physical and chemical hypoxia. In hypoxic rat pheochromocytoma PC12 cells treated with ginkgolides, the p42/p44 MAPK pathway was activated, and HIF-1α protein expression and modification were upregulated (Li et al., 2008). To further clarify the mechanism of the neuroprotective effect of ginkgolides against cellular hypoxia injury, they investigated the neuroprotective effect of ginkgolides against chemical and physical hypoxia-induced injury in neurons and PC12 cells based on their previous results. Their findings indicated that ginkgolides significantly upregulated HIF-1α protein expression in cortical neurons, while reducing lactate dehydrogenase (LDH) release and enhancing cell viability (Zhu et al., 2007a; Zhu et al., 2007b). Therefore, the neuroprotective effects of ginkgolides against hypoxic injury might be associated with their upregulation of HIF-1α expression in hypoxic neurons.

Hypoxia reportedly reduces the activity of intracellular antioxidant systems, such as superoxide dismutase (SOD). This reduction in activity results in an imbalance between the rates of free radical production and scavenging, leading to oxidative stress (Ramanathan et al., 2005; Kleszczyński et al., 2016). Excess ROS, which are mainly produced by the mitochondria, then trigger a cascade of deleterious effects, including inflammation, neuronal damage, and irreversible brain tissue injury. In the experiments conducted by Wang et al., the activities of antioxidant defense systems, including SOD, glutathione (GSH), catalase, and other antioxidant defenses, were elevated, while malondialdehyde (MDA) concentrations were reduced in the hippocampus of rats in the GB group compared to the plateau group. These findings suggest that GB may have the potential to prevent oxidative stress (Hua et al., 2012). They therefore concluded that GB could attenuate hypoxia-induced neuronal damage in the rat hippocampus by inhibiting oxidative stress and apoptosis (Li et al., 2019). Another related study demonstrated that GB could also activate endogenous cellular antioxidant defenses by enhancing the Nrf2 signaling pathway, thereby restoring the intracerebral microenvironment in ischemic stroke and protecting brain tissues from oxidative damage (YE et al., 2022) (Figure 1).

The underlying mechanism of the neuroprotective effect of GB is not solely attributed to its free radical scavenging properties; it is believed to be more complex and involves the regulation of mitochondrial function. In a recent study, Yile Cao’s research team revealed that GB intraperitoneal injection significantly reduced neuronal loss and apoptosis in a transient MCAO model. In addition, they observed improvements in sensorimotor dysfunction, with these effects potentially being dependent on AMP-activated protein kinase (AMPK)/PTEN-induced putative kinase 1 (PINK1). In vitro experiments further confirmed that GB inhibited mitochondrial pathway apoptosis in an AMPK-dependent manner in hypoxia/glucose-deprived SH-SY5Y cells. In summary, GB protects mitochondrial function and reduces mitochondria-dependent neuronal apoptosis by promoting AMPK activation in neuronal cells, specifically upregulating the expression of PINK 1, which provides a novel target for intervention in ischemic stroke therapy (Cao et al., 2022).

Jian-Ming Zhou’s team has elucidated a novel anti-inflammatory mechanism of ginkgolides through the oxygen glucose deprivation and reoxygenation (OGD/R) model: significantly inhibiting the release of inflammatory factors from BV2 microglial cells through the targeted modulation of the TLRs/MyD88/NF-κB signaling pathway, and this effect demonstrates specific neuroprotective value in the treatment of ischemic stroke (Zhou et al., 2016) (Figure 1). Extensive research has demonstrated that preconditioning for transient, sublethal cerebral ischemia can enhance the brain’s resilience to subsequent ischemia and hypoxia. This phenomenon has been observed to prevent ischemic neuronal damage and exert neuroprotective effects (Liu et al., 1993; Liu et al., 1992; Kato et al., 1991; Kitagawa et al., 1991; Kirino et al., 1991). Experimental evidence showed that ginkgolide treatment induces C6 cells to produce protein expression profiles and MAPK/phosphatidylinositol 3-kinase (PI3K) pathway response patterns similar to those of hypoxic preconditioning, suggesting that it may imitate the neuroprotective programming effect of ischemic preconditioning, providing a theoretical basis for its use as a prophylaxis in ischemic-hypoxic brain injury (He et al., 2008).

In addition, several studies have reported that ginkgolides also have significant effects on extracellular amino acid levels (Thompson et al., 2012; Ahlemeyer and Krieglstein, 2003; Yang et al., 2011). Currently, emerging evidence from in vitro and in vivo experiments suggests that excitotoxicity mediated by excessive release of excitatory amino acids (such as glutamate) is an important neuropathological process in ischemic brain injury (Lai et al., 2014; Taghibiglou et al., 2009; Zhou et al., 2010; Dohmen et al., 2005). In primary cultures of neonatal rat hippocampal neurons and astrocytes, GA and GB protected neurons from glutamate excitotoxicity in a dose-dependent manner (Ahlemeyer and Krieglstein, 2003). This study also indicated that GB and GJ ameliorated apoptotic injury, which is consistent with the findings of GB inhibiting apoptosis in hippocampal neurons mentioned above (Li et al., 2019). Another related study showed that GB reduced ischemia-induced elevation of glutamate, aspartate, and glycine levels and increased extracellular γ-aminobutyric acid (GABA) levels, which means it altered the balance of excitatory and inhibitory amino acid levels in the brain and reduced excitotoxicity in the striatum of rats with MCAO, suggesting that GB ameliorated brain damage caused by cerebral ischemia-reperfusion and significantly reduced the rate of cerebral infarction in reperfused rats (Yang et al., 2011). The potential of ginkgolides to open a new pathway for stroke treatment is evidenced by the finding that it is capable of modulating the amino acid metabolic network in a multidimensional manner (Table 3).

Briefly, the diverse preclinical studies referenced above elucidate the mechanisms governing GB-induced repair of nervous system damage from a range of perspectives. Comprehensive reviews have already detailed clinical trials of GB for the treatment of AD (Pagotto et al., 2024). However, further research is needed to determine more effective administration methods, optimal dosages, and suitable drug formulations and others.

Que is a natural plant pigment widely distributed in fruits and vegetables, particularly abundant in onions and apples (Hertog et al., 1992). Que (3,3′,4′,5,7-pentahydroxyflavone) belongs to the flavonol subclass of polyphenolic compounds, and is structured on the basis of the flavonoid C6 (ring A)-C3 (ring C)-C6 (ring B) backbone as the structural basis (Singh et al., 2021), and modified by glycosylation or methylation to form derivatives such as isoquercitrin, chrysin, rutin, and rhamnetin (Magar and Sohng, 2020). Que has a wealth of bioactivities, such as antioxidant (Hou et al., 2019), anti-inflammatory (Hou et al., 2019), anticancer (Lamson and Brignall, 2000), antimicrobial (Mlcek et al., 2016), and antiviral (Ramos et al., 2006), and has also been considered effective in offering cardiovascular protection (including antihypertensive (Kim et al., 2020b) and anti-atherosclerosis (Marunaka et al., 2017)) and neuroprotection (Luo et al., 2020). In terms of clinical applications, Que has been approved for safety in human use (Okamoto, 2005).

The neuroprotective properties of Que are manifested in several conditions, including NDDs such as AD and PD, and cerebrovascular diseases such as ischemic stroke, as well as specific neonatal neurological disorders such as neonatal hypoxic-ischemic brain damage (HIBD) and hypoxia-induced neonatal seizure (HINS). Protective effects of Que include protection of neurons from neurotoxin damage (Kaur et al., 2019), neuroinflammation inhibition (Jain et al., 2022), and improving memory and cognition (Jain et al., 2022).

Numerous studies have demonstrated the neuroprotective effect of Que against hypoxia-induced neurological injury. Hypoxia exposure induces neurodegeneration through the upregulation of HIF-1α expression. However, in an intermittent low-pressure hypoxia mouse model simulating high altitude, Que reportedly exhibits neuroprotective effects against both acute and chronic hypoxia: at the behavioral level, Que significantly improved poking and upright behavior in mice; at the molecular level, it inhibited the expression of HIF-1α and vascular endothelial growth factor (VEGF), decreased the caspase-3 activity and lowered ubiquitination levels; overall, it reduced hypoxia-induced neurodegeneration (Sarkar et al., 2012).

Furthermore, hypoxia induces oxidative stress, thereby contributing to neurodegeneration. In a model simulating high altitude, Prasad et al. discovered that by increasing the antioxidant level and free radical scavenging enzyme system, Que could reduce the level of ROS and subsequent lipid peroxidation in the hippocampus. It could also reduce the expression of caspase-3 in the hippocampus to decrease neuronal apoptosis, exerting antioxidant and anti-apoptotic effects to reverse low-pressure hypoxia-induced neurodegeneration in the rat hippocampus and enhance memory function (Prasad et al., 2013). In addition, on the effects of hypoxia on memory function, Peng Liu et al. found that Que improved acute low-pressure hypoxia-induced hippocampal mitochondrial and synaptic damage and thus memory impairment, and it was related to the peroxisome proliferator activated receptor γ coactivator-1 (PGC-1)/fibronectin type III domain-containing protein 5 (FNDC5)/BDNF pathway, which was specifically shown to modulate the silencing information regulator 1 (Sirt1), PGC-1, FNDC5, and BDNF expression (Liu et al., 2015). Generally, the above studies point to the significance of Que’s ameliorative effect on hypoxic neurological injury in high-altitude residents. In addition, evidence suggests that neuronal damage and apoptosis are closely associated with calcium dysregulation and calpain activation during hypoxia-induced oxidative stress (Aki et al., 2002). Hypoxia caused by potassium cyanide (KCN) is tissue-toxic. In an in vitro model of primary cultured hippocampal cells established in this manner, Que has shown strong cytoprotective and antioxidant activities, as evidenced by the maintenance of increased GSH levels and the inhibition of hypoxia-induced ROS production and intracellular Ca²⁺ influx. Reducing the activity of μ-calpain, a Ca²⁺-activated intracellular cysteine protease, has also been proposed as a potential therapeutic target for hypoxia-induced neuronal injury (Pandey et al., 2012; Pandey et al., 2016). Notably, hypoxia can lead to the expression of microRNA-122 and subsequent cell inactivation, resulting in apoptosis. Conversely, Que has been observed to enhance cell viability, promote cell proliferation and migration, and inhibit apoptosis. Rui Yan et al. discovered that Que exhibited an inhibitory effect on the damage to PC-12 cells induced by hypoxia. This effect was associated with the downregulation of miR-122 expression and the activation of AMPK and Wnt/β-catenin signaling pathways (Yan et al., 2019).

Hypoxia frequently occurs in conjunction with ischemia, and the inflammatory response and oxidative stress induced by ischemia and hypoxia can further lead to brain injury, such as ischemic stroke and neonatal HIBD, which have been the focus of more frequent research. The neuroprotective effect and mechanism of Que on ischemic stroke have been reviewed and reported in detail: Que may elicit therapeutic effects in cases of ischemic stroke by modulating oxidative stress, inflammation, apoptosis, the BBB, and ion channel regulation as well as the regulation of several signal transduction pathways, including Nrf2, NF-κB, PI3k, MAPK, Sirt1, and Wnt/β-catenin (Zhang et al., 2023) (Figure 1). Neonatal HIBD is also associated with multiple pathways, including oxidative stress, mitochondrial dysfunction, inflammatory response, and apoptosis (You et al., 2023). Several studies on the neuroprotective effect of Que on HIBD have demonstrated that it can promote remyelination, thereby improving cognitive impairment in neonatal rats caused by hypoxia and ischemia (Qu et al., 2014). It can also protect oligodendrocyte precursor cells from damage by activating the PI3K/Akt signaling pathway, downregulating caspase-3 and Bax, and upregulating Bcl-2 (Wang et al., 2011). Moreover, it inhibits the TLR4-mediated NF-κB signaling pathway to reduce brain damage, which is manifested in the partial reversal of this pathway’s representative factors TLR4, p-p65, and p-IκBα (Wu et al., 2019). Kai Le et al. further found that the attenuation of neonatal HIBD by Que was associated with inhibition of the inflammatory response mediated by the TLR4/MyD88/NF-κB signaling pathway and direct inhibition of microglia-derived oxidative stress (Le et al., 2020) (Figure 1). Regarding the TLR4/MyD88/NF-κB signaling pathway, a recent study by Zhaoyan Chen et al. elucidated its deep-rooted mechanism, which involves balancing microglia polarization and inhibiting downstream signaling by decreasing the level of Sirt1-mediated high-mobility-group protein B1 (HMGB1) acetylation (Chen et al., 2025b). In addition, more recent studies have found that Que can attenuate HIBD-induced neurodegeneration by upregulating the number of autophagosomes and the expression of nucleotide-binding domain and leucine-rich-repeat-containing family member X1 (NLRX1) in rat models of HIBD (Xu et al., 2023). Besides, Wu Yan et al. found that Que downregulated the inflammatory response via the TLR4/NF-κB pathway, showing a certain mitigating effect on HINS (Wu et al., 2022) (Table 4).

To summarize, as a natural product with multiple pharmacological effects and therapeutic potential, Que has shown its neuroprotective effect in hypoxic injury. However, with the low solubility and poor bioavailability, a series of problems should be overcome to achieve clinical application.

BBR is a natural isoquinoline alkaloid extracted from Chinese herbs such as Coptis chinensis and Coptis japonica, which has a wide range of pharmacological effects (Calvani et al., 2020; Fatahian et al., 2020; Wang et al., 2021b), including good anti-inflammatory (Wu et al., 2012), anti-cancer (Sun et al., 2022), antiepileptic (Jivad et al., 2024), glycolipid metabolism (Ma et al., 2022), and neuroprotective effects (Zhang et al., 2016a). BBR has a long history in countries like China and India (Kulkarni and Dhir, 2010), and it has long played an important role in the field of Oriental medicine. BBR has a broad range of clinical applications, and various studies conducted over the years have demonstrated its beneficial effects in a variety of neurodegenerative and neuropsychiatric disorders (Yoo et al., 2006; Ji and Shen, 2011; Mohi-Ud-Din et al., 2022).

HIF-1 has been demonstrated to contribute to BBR’s capacity to target hypoxia-induced neurological impairment, a property that is consistent with its mechanism of action in other natural products. As posited by Qichun Zhang et al., the administration of BBR prior to the onset of treatment led to the activation of endogenous neuroprotective mechanisms associated with the sphingosine-1-phosphate (S1P)/HIF-1 pathway, thereby contributing to the protection of neuronal cells from the deleterious effects of hypoxia/ischemia (Zhang et al., 2016a). Notably, in addition to regulating HIF-1α, a select number of studies have demonstrated that BBR exerts anti-apoptotic and neuroprotective effects in ischemia-hypoxia models through multi-target mechanisms. In an ischemic injury model, Hu-Shan Cui et al. discovered that BBR pretreatment significantly inhibited the OGD-induced elevation of p-Bcl-2 levels in organotypic hippocampal brain slice cultures (OHSCs), and this effect was present either before or during simultaneous administration of OGD, indicating that it attenuates neuronal apoptosis by blocking Bcl-2 phosphorylation (Cui et al., 2009). Another in vitro study demonstrated that BBR could effectively lower intracellular ROS levels in PC12 cells, thereby inhibiting the mitochondrial apoptotic pathway, and thus exerting a neuroprotective effect against OGD-induced PC 12 cell injury (Zhou et al., 2008). Its dose-dependent neuroprotective effect is also supported by animal experiments. For example, F Benaissa et al. demonstrated that BBR has anti-stroke potential by intraperitoneally injecting BBR to significantly reduce midbrain ischemic injury and cerebral edema in rats (Benaissa et al., 2009). At the molecular level, BBR reportedly enhances PI3K p55γ promoter activity during cerebral I/R. Furthermore, BBR activates the PI3K/Akt signaling pathway, thereby inhibiting mitochondrial dysfunction. In addition, BBR reportedly reduces the cleavage of the pro-apoptotic protease, caspase-3, and thus inhibits neuronal apoptosis (Hu et al., 2012). Further, Elisa Nicoloso Simões Pires et al. revealed that BBR mediates neuroprotection by regulating the Akt/GSK3β/ERK1/2 survival/apoptosis signaling pathway while inhibiting JNK and caspase-3 activity (Simões Pires et al., 2014). Similarly, Q Zhang et al. found that BBR pretreatment significantly led to a substantial downregulation of HIF-1α, caspase-9, and caspase-3 expression while concurrently elevating the Bcl-2/Bax ratio. This study also suggests that the regulation of apoptosis in cerebral ischemic neurons by BBR may be related to the extent of cellular injury (Zhang et al., 2012). Notably, in addition to the classical apoptotic pathway, BBR also enhances neuroprotection by activating the autophagy pathway. As demonstrated by Qichun Zhang et al., it promotes autophagy by regulating autophagy markers such as LC3-II, Beclin-1, and p62. Moreover, the expression levels of caspase-8, caspase-9, poly ADP-ribose polymerase (PARP), Bcl-2/Bax and other proteins that regulate apoptosis were synergistically regulated, thereby forming an autophagy-apoptosis network (Zhang et al., 2016b). Overall, these findings suggest that BBR has the potential to mitigate the adverse effects of hypoxia/ischemia in neuronal injury (Figure 2).

The systematic analysis of the above multi-target mechanisms provides a theoretical basis for clinical applications. The study by Ke Song et al. further expands the cognitive dimension of BBR’s mechanism of action by utilizing techniques such as network pharmacology, molecular docking, and bioinformatics analysis. The team indicated that BBR may act as a neuroprotective factor by regulating the long non-coding RNA (lncRNA) H19/EGFR/JNK1/c-Jun signaling pathway in hypoxia-induced SH-SY5Y cell injury. This finding elucidates the mechanism of action and therapeutic potential of BBR in ischemic stroke (Azadi et al., 2021). Moreover, its neuroprotective effect is also reflected in the promotion of neovascularization. As demonstrated in experimental studies on animals, BBR has been observed to elicit the HIF-1β/VEGF pathway, resulting in a substantial augmentation of vascular remodeling subsequent to cerebral I/R injury (Liu et al., 2018). Overall, these studies have shown that BBR forms a three-dimensional intervention strategy against ischemic-hypoxic injury by regulating the core pathway of the hypoxic response (HIF-1α/β), remodeling the balance of cell death/survival, and promoting vascular regeneration.

Further, BBR has been demonstrated to affect not only neurons but also oligodendrocytes. Oligodendrocytes are myelin-forming glial cells of the central nervous system that are highly susceptible to ischemia-induced excitotoxic injury, which is primarily because of Ca²⁺ overload. BBR demonstrated a marked capacity to impede ischemia-induced Ca²⁺ elevation in oligodendrocytes. In addition, BBR exerted a substantial effect in attenuating excitotoxic injury and enhancing oligodendrocyte viability during hypoxia-glucose deprivation/reperfusion (Nadjafi et al., 2014a). Furthermore, an excess of intracellular Ca²⁺ induces a series of events, including NO production, which can ultimately result in cell death. The hypothesis that the blockade of NO production by BBR may also be involved in the protection of oligodendrocytes that have been injured by OGD/R is supported by available evidence (Nadjafi et al., 2014b).

In summary, BBR has potent neuroprotective properties. It is evident that BBR is a safe and effective natural product for neurological diseases. However, evidence from clinical investigations is lacking, and further clinical research should be considered in the future (Song et al., 2020).

Curcumin—also known as diferuloylmethane—is a polyphenolic natural product obtained from turmeric (Aggarwal et al., 2003), a perennial herb which originated in India and has been widely used as a spice due to its special flavor and color. It is also often found in tropical and subtropical regions such as Southeast Asia and China (Kotha and Luthria, 2019). Curcumin has a variety of biological activities, including anti-inflammatory (Khan et al., 2012), antioxidant (Kalpravidh et al., 2010), anticancer (Wright et al., 2013), antimicrobial (Wang et al., 2009), antiviral (Mazumder et al., 1995), antiangiogenic (Bhandarkar and Arbiser, 2007), antidiabetic (Chuengsamarn et al., 2012), and anti-autoimmune (Bright, 2007), and it has potential therapeutic effects on a variety of diseases, such as arthritis, diabetes, cancer, acquired immune deficiency syndrome (AIDS), and AD. Moreover, curcumin is utilized in the food industry as both a food additive and coloring agent (Aggarwal et al., 2003). Its non-toxic properties have prompted considerable research interest among scholars in relevant fields. However, the clinical application of curcumin is limited by several challenges, including its low water solubility, rapid metabolism, low bioavailability, and poor stability. As research progresses, special formulations of curcumin, such as nanoparticles, have garnered increased attention.

Recent studies have demonstrated that curcumin exerts neuroprotective effects in models of hypoxia-induced neurological injury. The underlying mechanisms of this neuroprotective response involve three primary pathways: anti-neuroinflammatory, antioxidant, and anti-apoptotic. The present study explores the potential benefits of curcumin in the treatment of NDDs (Armağan and Nazıroğlu, 2021), ischemic stroke (Zhu et al., 2022), neonatal HIE (Rocha-Ferreira et al., 2019), and other neurological disorders. A comprehensive review of the existing literature reveals the valuable role and mechanisms of curcumin.

Oxidative stress and apoptosis are important aspects of hypoxia-induced neurodegeneration. In the hypoxia-induced SH-SY5Y cell model, curcumin reportedly regulates hypoxia-induced ROS overproduction and excessive apoptosis by inhibiting the activation of transient receptor potential melastatin 2 (TRPM2) channels and intra-mitochondrial Zn²⁺ inflow (Armağan and Nazıroğlu, 2021). In addition, curcumin protects HT22 cells exposed to hypoxia from oxidative stress and endoplasmic reticulum (ER) stress, and attenuates apoptosis by modulating the expression of Prdx6 and NF-κB (Chhunchha et al., 2013). The results of the aforementioned studies demonstrated the therapeutic potential of curcumin in the treatment of hypoxia-induced NDDs such as AD and PD. Moreover, curcumin could exert neuroprotective effects against hypoxic injury by reducing neuroinflammation and increasing neurogenesis. In an intermittent hypoxia (IH) model, Bo Wang et al. found that curcumin attenuated IH-induced neuroinflammation and cerebral edema, which was achieved by inhibiting astrocyte aquaporin 4 (AQP4) expression and activating the p38 MAPK pathway (Wang et al., 2018). Based on a network pharmacology study, Yao He et al. discovered that curcumin significantly promoted neurogenesis and attenuated neurological damage by increasing Wnt/β-catenin expression (He et al., 2024a). These studies showed the therapeutic potential of curcumin for obstructive sleep apnea (OSA)-related brain injury. Notably, OSA is more common in patients with stroke or NDDs.

With regard to stroke or cerebral I/R injury, the neuroprotective effects and mechanisms of curcumin have been reported in detail in numerous reviews (Marques et al., 2022; Bavarsad et al., 2019; Fan and Lei, 2022; Du et al., 2023), including anti-inflammatory, antioxidant, and anti-apoptotic activities as well as protection of the BBB and regulation of autophagy and other pathways. These pathways involve a number of signaling pathways, such as Nrf2, PI3K/Akt/mammalian target of rapamycin (mTOR), JAK2/STAT3, and Notch. Recently, Yangyang Wang et al. applied network pharmacology and molecular dynamics to identify five key targets of curcumin against ischemic stroke, including NF-κB1, TP53, AKT1, STAT3, and TNF (Wang et al., 2023), which are mainly related to neuroinflammation, oxidative stress, and apoptosis.

Furthermore, in a study on spinal cord injury, Daverey et al. found that curcumin mediated neuroprotective effects against white matter hypoxic injury by significantly down-regulating the expression of HIF-1α, caspase-9, glial fibrillary acidic protein (GFAP), and neurofilament-H (NF-H), as well as exerting the crosstalk between NF-κB and Nrf2 signaling pathways. This finding provides a novel approach for the treatment of cerebral white matter injury (WMI) (Daverey and Agrawal, 2020).

In a brief, curcumin has important research significance for the neuroprotective properties against hypoxic nerve injury. It is worth noting that in clinical trials related to curcumin and NDDs, a clinical trial related to Amyotrophic Lateral Sclerosis (ALS) showed that nanocurcumin could improve the survival rate of ALS patients, while the results of a clinical trial related to PD did not show the efficacy of curcumin on PD, and the clinical trial of curcumin in combination with IFN β-1a for MS has not been conclusive due to high patient dropout rates and has not confirmed the neuroprotective effect of curcumin (Ghodsi et al., 2022; Petracca et al., 2021; Ahmadi et al., 2018). Although these results reveal that curcumin is well tolerated and safe (Ghodsi et al., 2022; Petracca et al., 2021; Ahmadi et al., 2018), clinical trials are susceptible to a variety of factors, and the efficacy of curcumin needs more clinical data to support it.

Based on the natural products discussed above, we briefly summarize the mechanisms or targets of the neuroprotective effects of these natural products on hypoxia-induced nerve injury (Figure 3).