The optimal treatments for CI involve administering thrombolysis promptly within the treatment time frame, and quickly and efficiently rebuilding microvascular collateral circulation. Reinstating blood reperfusion in the ischemic region and penumbra is also a critical intervention. If CBF is not restored in time, microcirculation abnormalities in the ischemic core and penumbra will be closely associated with inflammatory cell infiltration, microthrombosis, vascular endothelial cell damage, and other variables. Cerebral edema resulting from IS exacerbates microcirculatory disruptions by compressing capillaries, underscoring the importance of minimizing microcirculatory disturbances post-ischemia. Furthermore, enhancing CBF in the ischemic penumbra is equally crucial during the acute phase of CI (Kulik et al., 2008; Przykaza, 2021).

Tau is a crucial active ingredient in BC that increases CBF in cerebral ischemic tissue (Zhou et al., 2004; Wang et al., 2016). Following CI, the interaction between extracellular matrix metalloproteinase inducer and platelet glycoprotein VI can lead to intravascular fibrin deposition and platelet adhesion, and subsequent microthrombus formation (Seizer et al., 2009; Jin et al., 2017). According to research, Tau helps reduce secondary thrombosis of microvessels post-CI, aiding in facilitating reperfusion. Furthermore, Tau can mitigate the risk of hemorrhagic transformation following recombinant tissue-type plasminogen activator (rt-PA) treatment by inhibiting the extracellular matrix protease-inducible factor-dependent matrix metalloproteinase-9 (MMP-9) pathway in cerebral tissue post-ischemia (Jin et al., 2018).

Earlier studies have indicated that platelet aggregation is a significant contributor to thrombosis. Tau can stimulate the release of endogenous arachidonic acid (AA) triggered by collagen and inhibit the synthesis of thromboxane A2 (Chen et al., 1991). Tau also demonstrates a notable inhibitory impact on platelet aggregation, which is induced by adenosine diphosphate (ADP), collagen, and AA. In addition, the combination of Tau with tetrandrine or neferine has the potential to further suppress platelet aggregation, which is induced by ADP, collagen, and AA (Huang and Rao, 1995; Qi and Rao, 1995). Hypertension, a major risk factor for CI, has a complex interplay with microcirculatory disturbances, contributing to endothelial dysfunction and hypoperfusion due to increased shear stress (Feihl et al., 2009; Cipolla et al., 2018). In patients with essential hypertension, Tau can lower blood pressure. Moreover, Tau helps to prevent the increase of serum Ca²⁺ in spontaneously hypertensive rats on a high-salt diet, leading to reduced blood pressure (Dawson Jr et al., 2000; Militante and Lombardini, 2002; El Idrissi et al., 2013).

When combined with indapamide, Tau has the ability to significantly reduce blood pressure in spontaneously hypertensive rats and also shorten the duration of the dosing cycle. The mechanism is to affect the intracellular Ca²⁺ concentration, then promote the phosphorylation of endothelium-derived nitric oxide (NO) synthase, and increase the release of NO. Thus, leading to blood vessel relaxation and a reduction in blood pressure (Zhao Y. Y. et al., 2018). Research has also revealed that Tau exerts a non-endothelium-dependent vasodilatory effect, which is through the concentration-dependent inhibition of the contraction. The contraction is that isolated porcine coronary artery rings induced by KCl, histamine, 5-hydroxytryptamine, and extracellular Ca²⁺ (Zhang et al., 2009).

In clinical settings, the combination of BCS with conventional drugs, such as antiplatelet medications, has been shown to effectively reduce intracranial pressure and improve circulation for CI. This combined approach yields significant therapeutic benefits, improving neurological deficit scores, blood lipid profiles, and hemorheological parameters (Cai et al., 2004).

Overall, the above findings indicate that BCS and Tau have the effects of alleviating microcirculation disturbance after CI and promoting complete reperfusion. The therapeutical effects are achieved by inhibiting thrombosis and dilating blood vessels during the acute stage injury of CI.

Glutamate and aspartate are examples of excitatory amino acids (EAA), while gamma-aminobutyric acid (GABA) and glycine (Gly) are examples of inhibitory amino acids (IAA). All of these are neurotransmitters in the central nervous system. Following the occurrence of CI, neurons release large amounts of EAA, such as glutamate and aspartate. Due to insufficient ATP supply and diminished EAA reuptake, the accumulation of EAA triggers excitatory neurotoxicity by stimulating their respective receptors. This cascade of events is linked to inflammatory responses, oxidative stress, leading to neuronal demise (Deng et al., 2004; Korde et al., 2007; Xu et al., 2007; Li X. X. et al., 2016). Therefore, it is imperative to counteract the detrimental effects of amino acid overstimulation to alleviate the immediate damage caused by CI.

Tau serves as a prevalent inhibitory neurotransmitter in the central nervous system (Huxtable, 1992). Studies indicate that Tau in NBC comprises approximately 4.71% of the total amino acid content (Wen et al., 2020). Noticeably, Tau exhibits an anti-EAA toxicity effect (Wu and Prentice, 2010) by reducing neuronal excitability through the activation of γ-aminobutyric acid type A receptors (GABA_AR), increasing Cl⁻ influx, and hyperpolarizing the cell membrane (Wang G. H. et al., 2007). Additionally, Tau can mitigate hypoxia induced by focal CI, or the influx of Ca²⁺ caused by N-methyl-D-aspartate (NMDA). By modulating the transmembrane movement of Ca²⁺, stabilizing the intracellular Ca²⁺ concentration, enhancing the energy barrier, and inhibiting the release of glutamate and aspartic acid (Asp), Tau aids in reducing EAA neurotoxicity (Sun et al., 2008; Zhao et al., 2012). Furthermore, TUDCA has been demonstrated to lower serum glutamate levels and inhibit EAA toxicity in rats subjected to transient CI in animal studies (Bian et al., 2019). Other studies demonstrated that NBC could elevate the levels of IAA, such as GABA and Gly in the rat brain striatum, thereby exert anti-EAA toxicity (Liu P. et al., 2010).

The aforementioned findings indicate that the active components of Tau and TUDCA exert anti-EAA toxicity by reducing EAA levels, activating GABA_AR, and increasing IAA content, thereby eliciting protective effects on the brain (Figure 2).

CI/RI is closely associated with oxidative stress as a prominent pathological mechanism. Upon the occurrence of CI, an excess of reactive oxygen species (ROS) is generated. These ROS disrupt the delicate balance of the intracellular oxidation-antioxidation system. Besides, the excessive accumulation of ROS causes oxidative damage to lipids, proteins, and tissue cells. This oxidative stress triggers various signaling pathways, including mitochondrial and endoplasmic reticulum pathways, leading to the release of Cyt-C and apoptosis-inducing factors, ultimately resulting in nerve cell apoptosis (Wang and Huang, 2012; Rodrigo et al., 2013; Orellana-Urzúa et al., 2020). Thus, mitigating oxidative stress injury contributes to alleviating symptoms during the acute stage of CI.

BR, a key active component of bile components, serves as a potent antioxidant (Suh et al., 2018). It effectively reduces oxidative damage by enhancing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxide (GSH-Px). Furthermore, it diminishes the levels of oxidative injury markers, including malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) (Zhang et al., 2016). BV displays the ability to inhibit the generation of superoxide anion (O₂ ^·-), lower lipid peroxidation levels, and reduce DNA oxidative damage. Additionally, it decreases MDA and 8-OHdG content while downregulating the expression of inducible nitric oxide synthase (iNOS) (Deguchi et al., 2008; Li et al., 2017).

CA, contained in BC, has been shown to elevate SOD levels and reduce MDA content following oxygen-glucose deprivation/reperfusion (OGD/R) in the neurovascular unit (NVU), exerting antioxidant effects (Li C. X. et al., 2020). TUDCA is one of the essential bile acid components of BC. It has the ability to reduce serum MDA and oxidized low-density lipoprotein levels, enhance antioxidant SOD and GSH-Px levels, and modulates oxidative stress injury through the Nrf2-VLDLR pathway in rats with transient middle cerebral artery occlusion (Bian et al., 2019). HDCA, present in BC, plays a significant role in regulating oxidative stress post-OGD/R in the NVU and exhibits an antioxidative stress injury effect (Li C. X. et al., 2019).

Although Tau within BC does not directly scavenge O₂ ^·-, it can eliminate other oxygen radicals, such as hydroxyl radicals, thereby reducing tissue damage caused by oxygen radicals. This action enhances SOD, total anti-oxidant capacity (T-AOC), and GSH-Px levels, reduces MDA content, and inhibits the activity of nicotinamide adenine dinucleotide phosphate (NADPH) to confer antioxidant effects (Raschke et al., 1995; Hanna et al., 2004; Sun et al., 2008; Fang and Peng, 2013; Han et al., 2016; Zhu et al., 2016; Cai et al., 2018). Furthermore, BCS has been shown to enhance cellular tolerance to hypoxia, suppress free radical generation, and modulate neurotransmitters. These effects are linked to the augmentation of SOD and GSH-Px activity as well as T-AOC by BCS (Cai et al., 2007). Collectively, the findings suggest that BR, BV, TUDCA, HDCA, and Tau, as the active components of BCS or NBC, have antioxidant effects against stress injuries. These mechanisms involve scavenging oxygen free radicals or enhancing antioxidant activity (Figure 3).

Excessive local inflammatory response tends to worsen brain damage during CI, leading to a poor prognosis (Lawrence, 2009; Cheng et al., 2020). Following CI, the build-up of ROS triggers the activation of complement, platelets, and endothelial cells, resulting in inflammatory substances generation such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). Moreover, necrotic neurons release nucleosides that stimulate purine receptors on microglia and circulating macrophages. The process leads to the aggregation of inflammatory cells and the infiltration of neutrophils (Iadecola and Anrather, 2011; Fluri et al., 2015). According to research, Nuclear factor-κB (NF-κB) is activated by the phosphorylation of inflammatory transcription factors during inflammation. This activation allows NF-κB to enter the nucleus and regulate cytokine expression, leading to the production of numerous adhesion molecules. Simultaneously, inflammatory factors and adhesion molecules further induce NF-κB phosphorylation, intensifying the inflammatory response (Sun et al., 2014; Zhao H. et al., 2018). Therefore, anti-inflammatory measures are crucial for alleviating adverse symptoms following CI-reperfusion.

Different researches have revealed that CA, UDCA, TUDCA, HDCA, and Tau present in BC, possess anti-inflammatory properties that can reduce levels of TNF-α, IL-6, and IL-1β in CI. Additionally, these compounds demonstrate the capacity to inhibit the activation of NF-κB and mitigate the inflammatory response (Joo et al., 2003; Zhu et al., 2004; Hua et al., 2009; Wang and Xu, 2017; Bian et al., 2019; Li C. X. et al., 2020).

Among these constituents, CA has been shown to suppress TNF-α and IL-1β expression post-CI, reducing monocyte chemoattractant protein-1 (MCP-1) expression at the site of CI. Moreover, CA has the ability to impede microglia activation and the aggregation of monocyte macrophages to the injury site (Zhu et al., 2004; Hua et al., 2009; Li C. X. et al., 2020). Furthermore, UDCA has shown the ability to lower NO levels, decrease IL-1β and TNF-α expression, and inhibit microglia activation (Joo et al., 2003).

Specifically, TUDCA has the ability to stimulate adenylate cyclase and enhance cyclic adenosine monophosphate (cAMP) expression. TUDCA activates Takeda G-protein receptor 5 (TGR5) in microglia and triggers cyclic adenosine-dependent protein kinase A and cyclic adenosine-independent protein kinase A pathways to regulate the transcription of pro- and anti-inflammatory proteins. TUDCA also reduces the levels of high-sensitivity c-reactive protein (hs-CRP), TNF-α, and interleukin-8 (IL-8) through transcription and translation inhibition. Additionally, it negatively regulates the Nrf2 inflammatory pathway, contributing to its anti-inflammatory effects (Yanguas-Casás et al., 2017; Bian et al., 2019). Additionally, HDCA significantly reduces inflammatory response in NVU following OGD/R, and may exert anti-inflammatory effects through its conversion to bile acids like CA and TUDCA (Li C. X. et al., 2019).

Furthermore, Tau acts as a suppressive amino acid in the brain, suppressing NF-κB activation, and preventing neutrophil infiltration and neuron apoptosis by hindering microglia activation in ischemic tissues. Tau also hinders NO production, suppresses pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as adhesion molecules like intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and prostaglandin E2 (PGE2) (Luo et al., 2004; Yang et al., 2006; Sun et al., 2011; Wang and Xu, 2017; Wang et al., 2018). BV, another essential bile pigment in BC, exerts anti-inflammatory effects by down-regulating inflammatory mediators expression, including TNF-α, IL-6, IL-1β, and iNOS mRNA, and negatively regulating heme oxygenase-1 mRNA expression (Li et al., 2017; 2021).

Clinical studies have indicated that BCS is effective in reducing the inflammatory response in patients with CI, thereby decreasing neurological damage and providing neuroprotective effects (Wang et al., 2021).

In summary, the active constituents of BC, CA, UDCA, TUDCA, HDCA, and Tau exhibit anti-inflammatory effects. They achieve that by suppressing the production of inflammatory factors IL-1β, IL-6, and TNF-α. Additionally, these active constituents reduce the expression of MCP-1 at ischemic sites, lower NO levels, increase cAMP and activate TGR5. Furthermore, they regulate the transcription of pro- and anti-inflammatory proteins, reduce hs-CRP, inhibit microglia activation, suppress ICAM-1, VCAM-1, and PGE2, decrease iNOS mRNA, and regulate heme oxygenase-1 mRNA expression (Figure 4).

The BBB is a complex structure consisting of cerebral microvascular endothelial cells, endothelial cell occluding, and claudin, intercellular zonula occludens-1 (ZO-1), astrocyte terminal foot, pericyte, and basement membrane (Mark and Davis, 2002; Lampugnani and Dejana, 2007). More importantly, the BBB is responsible for maintaining the overall stability of the central nervous system and safeguard the brain from the infiltration of detrimental substances.

When CI occurs, the BBB function is compromised, leading to increased permeability. This allows harmful substances and cytokines to enter the brain to penetrate the brain tissue, causing damage (Marı́n-Teva et al., 2004; Choi et al., 2008; 2008; Hjort et al., 2008). Noticeably, when large amounts of matrix metalloproteinases are released, the tight junctions of the BBB are impaired, and permeability is increased (Vecsernyés et al., 2014). Additionally, increased expression of water channel proteins like aquaporin-4 (AQP-4) can result in hemorrhagic brain edema (Zhang H. et al., 2020; Shi et al., 2021). Additionally, endothelial cells express amounts of inflammatory substances such as TNF-α, IL-6, IL-1β, and ICAM. These substances enhance the permeability of vascular endothelial cells and contribute to the accumulation, adhesion, and infiltration of leukocytes in the area affected by infarction. Furthermore, ICAM-1-mediated neutrophil adhesion after reperfusion blocks microcirculatory channels and exacerbates tissue damage in CI (Amantea et al., 2007; Tuttolomondo et al., 2008; Vakili et al., 2011; Treda et al., 2016). Therefore, protecting the BBB’s integrity is crucial in enhancing the therapeutic effect of cerebral ischemia-reperfusion and alleviate patients’ symptoms.

Tau has been shown to reduce secondary brain injury after CI by down-regulating the expression of matrix metalloproteinases-3 (MMP-3) in brain-injured rats, thereby protecting the BBB (Li et al., 2010). Moreover, GUDCA inhibits the activation of MMP-9 and caspase-9 in a model of superoxide dismutase-1-induced neuronal degeneration, thereby exerting a protective effect on the BBB (Vaz et al., 2015). Additionally, the CA can protect the BBB function following NVU OGD/R. The mechanism is associated with the reduction of serum factor permeability coefficient and the increase in transepithelial electrical resistance (TEER) value and Gamma-glutamyl transferase activity (γ-GT) (Li C. X. et al., 2020).

Furthermore, investigation revealed that BC and its active constituents, including Tau, TUDCA, and UDCA, can decrease lactate dehydrogenase levels, increase γ-GT content, raise TEER values, and decrease fluorescein sodium permeability coefficient. These medications alone can lower the expression levels of inflammatory factors TNF-α, IL-6, and IL-1β, and reduce the protein expression of MMP-2 and MMP-9. Among them, Tau alone can stimulate the protein expression of tight junction protein ZO-1, occludin, and claudin-5 (Zhang et al., 2019). Combining Tau with UDCA can inhibit the MyD88/NF-κB pathway, while Tau and TUDCA combination can suppress the P38MAPK pathway, thereby exerting cerebral protective effects (Xu et al., 2017).

In conclusion, BC and its bioactive constituents, such as Tau, GUDCA, CA, TUDCA, and UDCA, collectively inhibit caspase-9 activation, reduce serum factors permeability coefficient, improve TEER and γ-GT activity, decrease inflammatory factors expression, block the MyD88/NF-κB and P38MAPK pathways, and promote the expression of tight junction proteins such as ZO-1, occludin, and claudin-5. These mechanisms play a crucial role in protecting the BBB’s integrity.

Apoptosis plays a crucial role in neuronal death following CI. After CI, the brain has two important regions that are independent of ischemia: the ischemic core and the ischemic penumbra (Kulik et al., 2008). Insufficient ATP supply renders Ca²⁺-related transporter proteins ineffective. Conversely, when EAA is released and binds to EAA receptors on the postsynaptic membrane, it induces cell depolarization. This leads to a significant influx of Ca²⁺, triggering the activation of Ca²⁺ proteases, the hydrolysis of cellular proteins, and ultimately resulting in neuronal death (Radak et al., 2017; Sekerdag et al., 2018).

The accumulation of calcium ions within cells can potentially induce the release of Cytochrome C (CytC) in mitochondria, which activates caspase-9 and the final executor protein caspase-3. This process leads to the breakdown of functional proteins within cells, causing DNA damage, and ultimately initiating apoptosis (He et al., 2020; Tuo et al., 2022). In addition, cell injury induces endoplasmic reticulum stress, which is an important site for intracellular protein translation, synthesis, modification, folding, and storage of Ca²⁺. This stress will lead to the accumulation of unfolded proteins, disrupting Ca²⁺ homeostasis, and ultimately resulting in a further increase in intracellular Ca²⁺ concentration (Xu et al., 2017). Thus, the mitigation of symptoms during the subacute phase of CI and the enhancement of recovery outcomes are significantly influenced by preventing neuronal cell death.

Additionally, CA has been shown to inhibit the expression of caspase-9, caspase-3, and Bax after NVU OGD/R while increasing the expression of Bcl-2, exerting an anti-apoptotic effect (Li C. X. et al., 2020). Different researches have shown that Tau effectively prevents cell death and tissue damage by suppressing Bax activity, thus preventing the release of Cyt-C from mitochondria to the cytoplasm. Tau safeguards mitochondrial function, inhibits caspase-3 and calpain activity, and enhances the production of the anti-apoptotic protein Bcl-2. These actions help regulate the Bax/Bcl-2 ratio, ultimately resulting in anti-apoptotic effects (Schaffer et al., 2002; Zhang, 2006; Sun et al., 2011; Zhu et al., 2016).

Furthermore, Tau has been found to suppress endoplasmic reticulum stress by inhibiting the activation of transcriptional activator 6 and inositol-requiring enzyme-1 molecular pathways (Gharibani et al., 2013). TUDCA, as an important component of BC, inhibits the phosphorylation activation of protein kinase R-like endoplasmic reticulum kinase, eukaryotic initiation factor 2α, and transcriptional activator 4 expression in cortical and hippocampal regions. TUDCA also blocks caspase-12-dependent endoplasmic reticulum stress-mediated apoptosis (Rodrigues et al., 2002; Xu et al., 2017; Chen et al., 2020).

The active constituents of BC, BR, and BV, play a crucial role in inhibiting apoptosis. This is achieved by reducing the levels of caspase-3, Bax, and other proteins associated with apoptosis, while simultaneously elevating the concentration of Bcl-2 (Zhang et al., 2016; Li et al., 2021). A study demonstrated that pretreatment with BCS reduced brain swelling, damaged tissue size, neuronal cell death, and neurological impairments in rats. BCS also decreased the number of dying neurons, possibly by suppressing caspase-9 and caspase-3 activity, and Cyt-C release. This inhibition of mitochondria-mediated apoptotic signaling contributed to CI/RI reduction (Lu et al., 2020).

Overall, these findings highlight that the active components of BC, CA, Tau, TUDCA, BV, and BR, can protect mitochondria, inhibit endoplasmic reticulum stress, impede apoptosis, and exert neuroprotective effects through various mechanisms of action (Figure 5).

The process of angiogenesis plays a crucial role in restoring blood oxygen supply to injured brain tissue and mitigating damage from IS. Additionally, within the central nervous system, there exists a significant interplay between blood vessels and axons. Angiogenesis also plays a crucial role in the growth of axons and the generation of new neurons, ultimately facilitating the development and differentiation of neurons. These contribute to restoring typical brain function (Millikan, 1970; Hatakeyama et al., 2020). Hence, the promotion of angiogenesis is crucial for brain function repair during the recovery phase following an IS.

Vascular endothelial growth factor (VEGF) has mitogenic and anti-apoptotic effects on endothelial cells and plays a pivotal role in angiogenesis and remodeling in the restoration stage of IS (Melincovici et al., 2018). According to research, Hypoxia-inducible factor (HIF-1α) plays a key role in promoting angiogenesis after IS by regulating the expression of downstream genes (Shi, 2009). Moreover, Angiotensin-1 (Ang-1) has been found to promote cerebral angiogenesis after IS through the Mas/eNOS-dependent pathway, reduce ischemic tissue injury, and enhance its tolerance to subsequent ischemia (Jiang et al., 2014).

Studies demonstrated that Tau presence in ischemic brain tissue enhances the production of HIF-1α mRNA, thereby promoting angiogenesis, microcirculation reconstruction, and reducing ischemic brain tissue damage following IS (Wang H. R. et al., 2007). Additionally, BCS activates 3-carboxyphosphatidylinositol kinase (p-PI3K) and serine/threonine protein kinase (p-Akt) proteins, leading to an upregulation in the expression of p-PI3K, p-Akt protein, and PI3K mRNA. This activation results in increased levels of serum VEGF and Ang-1 (Ren et al., 2023). Furthermore, BCS modulates the HIF-1α/VEGF and PI3K/AKT pathways, thus aiding in the restoration of normal brain function post-IS (Zhang et al., 2019).

In conclusion, BCS and its active component Tau promote angiogenesis following IS by modulating HIF-1α/VEGF and PI3K/Akt pathways, thereby contributing significantly to the restoration of normal brain function subsequent to an IS.

CI can lead to limited endogenous neurogenesis within the body, failing to adequately repair nerve damage following ischemia. The rehabilitation and reconstruction of neurological function play a vital role in the treatment of IS. Studies have indicated that stem cell-based therapy, which includes cell transplantation and stimulating endogenous neurogenesis, holds promise as a potential strategy for repairing and regenerating damaged brains. This innovative approach may offer a secondary treatment window for IS patients (Zhu et al., 2018).

Tau, a natural amino acid found in the brain, has been demonstrated to exert positive effects on brain growth and development (Huxtable, 1992; Tochitani, 2017). In cases of CI/RI, Tau has been shown to enhance the expression of neural stem cell factor (SCF) mRNA in the cortex, striatum, and paraventricular zone. Moreover, it promotes nestin expression and augments the population of neural stem cells during the ischemic recovery process (Zhang et al., 2008; Zang et al., 2011).

Tau facilitates the proliferation and differentiation of hippocampal neural stem cells induced by glutamic acid (Glu). This was achieved by activating the brain-derived neurotrophic factor (BDNF)/ERK/CREB signaling pathway and repairing brain injury after CI (Zhou, 2019). BDNF plays a crucial role in neuronal growth and development. Upon binding to the tyrosine kinase B receptor (TrkB), BDNF triggers downstream signaling pathways such as mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) and PI3K/Akt, governing neuronal proliferation and differentiation (Choo et al., 2017; Li C. X. et al., 2020).

As one of the important free bile acids present in BC, HDCA can effectively protect NVU in NVU ODG/R. HDCA might achieve this by promoting the expression and release of BDNF and glia cell line-derived neurotrophic factor (GDNF), thereby fostering neural recovery (Li C. X. et al., 2019). Moreover, Nerve growth factor (NGF) contributes to nerve growth. After an IS, the content of NGF in brain tissue decreases, weakening the body’s protective effect. One study demonstrated that BCA can increase the content of NGF and aid in nerve recovery in the recovery stage of IS (Li and Li, 2004).

In conclusion, BC and its active constituents have a significant impact on restoring nerve function after IS. This is achieved by stimulating SCF mRNA production, activating the BDNF/ErK/CREB signaling pathway, boosting BDNF and GDNF expression, and facilitating neuronal repair.

Quantitative indicators play a crucial role in evaluating the neurological function and consciousness status of stroke patients. For instance, a higher National Institute of Healthstroke scale (NIHSS) score indicates that a stroke may lead to more severe neurological dysfunction. Building upon the NIHSS, the Full Outline of UnResponsiveness (FOUR) score considers indicators such as breathing pattern, eye movements, and swallowing reflex in patients. In clinical practice, the use of BCS in the treatment of IS with impaired consciousness can significantly reduce the NIHSS score, improve the FOUR score, indicating a marked enhancement in the neurological function and consciousness status of patients. Additionally, BCS is safe and stable, with a low incidence of adverse reactions (Chen, 2022).

Furthermore, a lower Glasgow Coma Scale (GCS) score indicates more severe neurological damage. Newly clinical research found that BCS can increase the GCS score and improve the prognosis of patients with IS accompanied by impaired consciousness (Wu et al., 2023). It is noteworthy that Coma Recovery Scale-Revised (CRS-R) is used to assess patients’ cognitive function and neurological function. One study demonstrated that BCS can increase the CRS-R score, improving the cognitive function of patients with IS and impaired consciousness (Chen, 2022). Otherwise, a lower Modified Rankin Scale (mRS) score indicates a better consciousness state in patients. In a new clinical study, treatment with BCS for IS patients can lower the mRS score, leading to a favorable prognosis (Wu et al., 2023).

Clinical studies have shown that elevated levels of cholesterol, triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) are closely associated with the occurrence of stroke. For example, abnormal levels of erythrocyte sedimentation rate (ESR), hematocrit (HCT), whole blood viscosity (WBV), and fibrinogen (FIB) can lead to abnormal blood viscosity, resulting in reduced blood rheology. Otherwise, clinical trials found that BCS has been shown to significantly improve cholesterol, TG, and LDL-C levels, alleviate symptoms of acute IS, promote the recovery of neurological function, improve CBF, and enhance clinical treatment outcomes (Liao, 2020). Additionally, BCS can lower HCT, WBV, and FIB levels, improve blood viscosity, and enhance blood circulation (Liu X. Y. et al., 2010).

Serum levels of hs-CRP, neuron specific enolase (NSE), and S-100β protein are commonly used to evaluate neurological damage. Hs-CRP serves as an inflammatory marker, and elevated levels indicate the presence of an inflammatory response in patients. S-100β protein levels can reflect the severity of central nervous system inflammatory responses. The serum levels of hs-CRP and NSE are associated with the severity and prognosis of IS. Noticeably, NSE can serve as a quantitative index of central nervous system damage (Pandey et al., 2014; Selçuk et al., 2014). Clinically, BCS can reduce serum levels of hs-CRP, NSE, and S-100β protein, effectively reducing central nervous system inflammatory responses, alleviating neurological damage, improving medium-to-long-term prognosis, and possessing high clinical utility (Wang et al., 2021).

To date, BC and BC-related preparations have been widely used in IS treatment. According to a research, mice were divided into three groups in the laboratory, and after an 8-h fast, they were orally administered 12.5% BC at doses of 10 g/kg, 15 g/kg, and 20 g/kg, respectively. In a 7-day acute toxicity experiment, none of the groups exhibited signs of toxicity, with normal eating and bowel movements observed (Yuan et al., 1992). Currently, data on in vivo and clinical toxicity experiments of BC are still lacking. Therefore, it is necessary to conduct in vivo and clinical research on the potential toxicity of BC, which will be crucial to determine its safe dosage.