Banxia-Baizhu-Tianma Decoction Combined with Acupuncture for Cerebral Ischemic Stroke: A Narrative Review

Introduction

Cerebral ischemic stroke (CIS), characterized by the stenosis or occlusion of cerebral arteries leading to reduced or interrupted local cerebral blood flow, subsequent brain tissue ischemia-hypoxia, and neuronal damage, is a leading cause of adult disability and the second most common cause of cardiovascular disease-related mortality worldwide.¹ Without timely and effective intervention, CIS can progress to irreversible cerebral infarction, resulting in a series of neurological dysfunctions such as hemiplegia, speech disorders, hemianesthesia, and cognitive impairment, which severely compromise patients’ quality of life.² Globally, the social and economic burden imposed by CIS is escalating annually due to population aging, changes in lifestyle, and the increasing prevalence of risk factors such as hypertension, diabetes, and hyperlipidemia.³ It is estimated that the number of CIS patients will continue to rise in the coming decades, making it a major public health challenge requiring urgent attention.⁴

Contemporary pathophysiological studies have confirmed that CIS is a complex, multi-step cascade reaction involving multiple cell types, include neurons, astrocytes, microglia, vascular endothelial cells and molecular pathways; The key pathological mechanisms include energy metabolism disorders, glutamate excitotoxicity, oxidative stress, calcium overload, inflammatory responses, blood-brain barrier (BBB) disruption, neuronal apoptosis, and autophagy imbalance.^5,6 Among these, the inflammatory response and oxidative stress are core drivers of the progression of ischemic brain injury, as they trigger a series of secondary damage cascades that exacerbate neuronal loss and neurological dysfunction.⁷ Additionally, the prognosis of CIS is unsatisfactory due to its high recurrence rate, especially the high risk of early recurrence within 3 months after onset, which further increases the difficulty of clinical treatment and rehabilitation.⁸

In clinical practice, conventional Western medical treatments for CIS mainly include emergency thrombolysis, endovascular interventional therapy, anti-platelet aggregation, anti-arteriosclerosis, and rehabilitation training.⁹ While these interventions can effectively restore cerebral blood flow in the acute phase and reduce the scope of infarction to a certain extent, they have significant limitations: thrombolysis and interventional therapy have strict time windows, and only a small proportion of patients can receive timely treatment; long-term use of anti-platelet and anti-lipid drugs may cause adverse reactions such as bleeding and liver and kidney function damage; moreover, these treatments are often ineffective in improving long-term neurological sequelae, and a considerable number of patients still suffer from persistent motor, sensory, and cognitive impairments.¹⁰

Traditional Chinese medicine (TCM) has a long history of treating CIS, which is categorized under the rubric of “apoplexy” in TCM theory. TCM holds that the pathogenesis of CIS is mainly related to the deficiency of vital qi, and the invasion of pathogenic factors such as wind, phlegm, and blood stasis, which block the meridians and collaterals and impair the functions of the zang-fu organs.¹¹ Therefore, the core therapeutic principles for CIS in TCM are resolving phlegm, dispelling wind, promoting blood circulation, dredging collaterals, invigorating qi, and nourishing the liver and kidney. Over thousands of years of clinical practice, TCM has developed a variety of effective prescriptions and therapeutic techniques for CIS. Banxia-Baizhu-Tianma Decoction (BBTD), recorded in the classic TCM work “Yi Xue Xin Wu” by Chen Guopeng in the Qing Dynasty, is a classical formula with the effects of resolving phlegm, calming wind, invigorating the spleen, and eliminating dampness. Its composition is scientifically compatible: Pinellia ternata (Banxia) eliminates dampness and resolves phlegm; Gastrodia elata (Tianma) extinguishes wind and calms the liver; Atractylodes macrocephala (Baizhu) and Poria cocos (Fuling) invigorate the spleen and eliminate dampness; Exocarpium Citri Grandis (Juhong) resolves phlegm and regulates qi; Zingiber officinale (Shengjiang), Ziziphus jujuba (Dazao), and Glycyrrhiza uralensis (Gancao) harmonize the properties of the other herbs.¹² Due to its precise efficacy in targeting the key pathogenesis of CIS (phlegm and wind blocking collaterals), BBTD has been used in the clinical treatment of CIS and its sequelae, and modern pharmacological studies have confirmed its significant neuroprotective and vascular-protective effects.¹³ Acupuncture, as a characteristic therapeutic technique of TCM, involves stimulating specific acupoints to regulate the circulation of qi and blood, dredge meridians, and restore the balance of yin and yang. Endorsed by the World Health Organization (WHO) as an effective alternative and complementary therapy for CIS, acupuncture has been validated by a large number of preclinical and clinical studies to improve neurological function, alleviate spasms, enhance muscle strength, and promote rehabilitation in CIS patients.^14–16 The therapeutic effects of acupuncture are mediated by multiple mechanisms, including regulating neurotransmitter release, inhibiting inflammatory responses, promoting angiogenesis, and protecting neurons from ischemic damage.¹⁷

In recent years, the combination of TCM herbs and acupuncture has become a research hotspot in CIS treatment, as it integrates the systemic regulation of herbs and the targeted stimulation of acupuncture, achieving synergistic therapeutic effects that are superior to monotherapy.¹⁸ In a word, leveraging the complementary advantages of herbal medicine and acupuncture, BBTD and acupuncture can effectively improve cerebral perfusion, reduce inflammatory markers, enhance motor function, and ameliorate the quality of life of CIS patients. However, there remains a lack of comprehensive and systematic reviews that focus on the therapeutic efficacy and synergistic mechanisms of BBTD combined with acupuncture in the treatment of CIS. Therefore, this review aims to systematically summarize the latest advances in the pathophysiology of CIS, elaborate on the distinct and complementary therapeutic mechanisms of BBTD and acupuncture, analyze the synergistic effects of their integrated application, and discuss the current limitations and future research directions. In doing so, it intends to provide a robust theoretical basis for the clinical translation and in-depth investigation of this integrative TCM strategy in CIS management.

Epidemiology

Stroke is a cerebrovascular disease characterized by sudden onset, high incidence, high recurrence rate, high disability rate, and high mortality rate, which poses a serious threat to global human health.² According to the Global Burden of Disease Study (GBD) 2019, the global prevalence of CIS reached 101 million, and the age-standardized incidence rate of stroke was 150.5 per 100,000 population.¹⁹ Notably, the epidemiological characteristics of CIS exhibit significant regional and demographic differences: while the prevalence of stroke in high-income countries remained relatively stable from 1990 to 2019, the prevalence of CIS in low- and middle-income countries increased significantly, especially among individuals aged 15–49 years.³ This trend may be related to the rapid economic development, changes in lifestyle, and the increasing prevalence of risk factors such as hypertension and diabetes in low- and middle-income countries.²⁰

In China, CIS is a major public health problem with a high disease burden. Studies have shown that the age-standardized incidence rate of stroke in China is 226 per 100,000 population, and the overall lifetime risk of stroke is 39.9%, ranking first in the world.²¹ A 2019 special survey on stroke epidemiology in China found that the incidence of first-time stroke was approximately 345.1 per 100,000 population, with an age-standardized incidence rate of 247 per 100,000.²² In addition, there is a significant urban-rural difference in the incidence of CIS in China: the incidence of stroke among rural residents (298.2 per 100,000) is significantly higher than that among urban residents (203.6 per 100,000), which may be attributed to the relatively backward medical and health conditions, insufficient health education, and higher prevalence of risk factors in rural areas.²²

Traditionally, CIS has been regarded as a disease that mainly affects the elderly. However, in recent years, the incidence of CIS in young and middle-aged people (15–49 years old) has shown an obvious upward trend, which has attracted widespread attention from the medical community.²³ It is estimated that the incidence of CIS in young adults accounts for 15%-18% of all CIS cases worldwide.²⁴ Unlike the declining incidence of stroke in the elderly population, the incidence and hospitalization rate of acute ischemic stroke in young people have been increasing year by year.²⁵ A study conducted in Finland involving 1008 young CIS patients aged 15–49 years found that the incidence of CIS in young adults was 10.8 per 100,000 population, and the incidence increased sharply after the age of 40.²⁶ In China, the annual incidence rate of stroke among people aged 18–45 years is 97.7 per 100,000 population, indicating a relatively high risk of CIS in young Chinese individuals.²⁷

The main risk factors for CIS include non-modifiable factors and modifiable factors, such as hypertension, diabetes, hyperlipidemia, atrial fibrillation, smoking, alcohol consumption, physical inactivity, unhealthy diet, abdominal obesity, etc. Among these, hypertension is the most important modifiable risk factor for CIS, accounting for approximately 54% of all stroke cases.²⁸ For young CIS patients, the main risk factors include hypertension, hyperlipidemia, smoking, alcohol consumption, atrial fibrillation, and hyperhomocysteinemia. Compared with elderly CIS patients, young CIS patients often have a longer life expectancy, and the disease may render them incapacitated during their most productive years, imposing a heavier economic burden on families and society.²⁹

In summary, CIS has a high global incidence, mortality, and disability rate, and its epidemiological characteristics are constantly changing with the times. The increasing incidence of CIS in young and middle-aged people and low- and middle-income countries highlights the urgency of strengthening the prevention and treatment of CIS. Given the limitations of conventional Western medical treatments, exploring effective alternative and complementary therapies such as TCM has important clinical significance and social value for reducing the disease burden of CIS.

Pathogenesis

CIS is a complex pathophysiological process involving multiple cell types and molecular pathways. The core pathological event is the sudden reduction or interruption of cerebral blood flow due to cerebral artery stenosis or occlusion, leading to brain tissue ischemia-hypoxia, which further triggers a series of cascade reactions resulting in neuronal damage and neurological dysfunction.² Brain tissue has a high demand for glucose and oxygen, and it can only maintain normal physiological functions with a continuous supply of blood flow. Once cerebral blood flow is interrupted, brain tissue will suffer irreversible damage within a short time.³⁰ The pathological process of CIS can be divided into two stages: the acute ischemic stage and the secondary damage stage. The acute ischemic stage is mainly characterized by energy metabolism disorders and neuronal necrosis in the ischemic core area, while the secondary damage stage is dominated by inflammatory responses, oxidative stress, and BBB disruption, which further expand the scope of brain damage.³¹

Energy metabolism disorders are the initiating factors of ischemic brain injury. After the onset of CIS, the interruption of cerebral blood flow leads to the depletion of oxygen and glucose in the ischemic core area, resulting in the failure of mitochondrial oxidative phosphorylation, a sharp decrease in adenosine triphosphate (ATP) production, and an increase in adenosine monophosphate (AMP) levels.³² The decrease in ATP levels leads to the dysfunction of ion pumps on the cell membrane, resulting in the imbalance of ion homeostasis, which further triggers a series of pathological reactions such as glutamate excitotoxicity and calcium overload.³³ AMP-activated protein kinase (AMPK), as a cellular energy sensor, plays a key role in regulating energy metabolism during CIS. Under low-energy conditions, AMPK is phosphorylated and activated, which can increase ATP production by promoting glucose uptake and glycolysis, and reduce ATP consumption by inhibiting anabolic reactions, thereby maintaining cellular energy homeostasis and protecting neurons from ischemic damage. However, excessive activation of AMPK may also promote neuronal apoptosis, indicating that the role of AMPK in CIS is complex and needs further clarification.^34,35

Glutamate excitotoxicity is a key mechanism of neuronal damage in CIS. Glutamate is the most important excitatory neurotransmitter in the central nervous system, which is essential for neuronal growth, maturation, and synaptic plasticity.³⁶ Under normal physiological conditions, the concentration of glutamate in the synaptic cleft is maintained at a low level through reuptake mechanisms. After the onset of CIS, energy metabolism disorders lead to the dysfunction of glutamate transporters on the cell membrane, resulting in the accumulation of glutamate in the synaptic cleft and the overactivation of glutamate receptors.³³ The overactivation of N-methyl-D-aspartate receptors leads to the massive influx of Ca²⁺ and Na⁺ into neurons, resulting in neuronal depolarization, edema, and necrosis. At the same time, the increase in intracellular Ca²⁺ concentration triggers the activation of multiple calcium-dependent enzymes, which further promotes neuronal apoptosis, autophagy, and the release of inflammatory factors, exacerbating brain tissue damage.³⁷

Oxidative stress is another important mechanism of secondary brain damage in CIS. Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the body’s antioxidant capacity, leading to the accumulation of ROS and RNS, which cause damage to proteins, lipids, and nucleic acids.³⁸ After the onset of CIS, the decrease in mitochondrial oxidative phosphorylation and the activation of NADPH oxidase lead to the massive production of ROS in ischemic brain tissue.³⁹ Excessive ROS can cause lipid peroxidation of cell membranes, leading to membrane damage and increased permeability; it can also damage DNA and proteins, leading to the dysfunction and apoptosis of neurons, astrocytes, and vascular endothelial cells.⁴⁰ In addition, ROS can trigger the activation of inflammatory signaling pathways, promoting the release of pro-inflammatory factors and exacerbating the inflammatory response.⁴¹ The body’s antioxidant system can scavenge excessive ROS and reduce oxidative stress damage. However, during CIS, the antioxidant capacity of brain tissue is significantly reduced, resulting in the accumulation of ROS and severe oxidative stress damage.⁴²

Calcium overload is closely related to glutamate excitotoxicity and oxidative stress, and is a key link in the progression of ischemic brain injury.⁴³ Ca²⁺ is an important second messenger in cells, which is involved in various physiological processes such as nerve signal transduction, neuronal nutrition and development, and mitochondrial energy metabolism. Under normal physiological conditions, the concentration of intracellular Ca²⁺ is maintained at a low level (100–200 nmol/L) through the joint action of ion pumps and ion channels.⁴⁴ After the onset of CIS, the overactivation of glutamate receptors leads to the massive influx of extracellular Ca²⁺ into neurons, and the dysfunction of the endoplasmic reticulum and mitochondria leads to the release of intracellular stored Ca²⁺, resulting in intracellular calcium overload.⁴⁵ Calcium overload can trigger a series of cascade reactions: it can activate calpain, which degrades cytoskeletal proteins and leads to neuronal necrosis; it can promote the release of cytochrome c from mitochondria, triggering the apoptotic pathway; it can also activate nitric oxide synthase (NOS), leading to the excessive production of nitric oxide (NO), which reacts with ROS to form peroxynitrite, a highly toxic substance that exacerbates neuronal damage.⁴⁶

Inflammatory responses play a crucial role in the secondary damage of CIS. After the onset of CIS, damaged brain tissue and neurons release damage-associated molecular patterns (DAMPs), which can activate immune cells in the central nervous system.⁴⁷ Astrocytes and microglia are the main immune cells in the brain: activated astrocytes undergo hypertrophy and proliferation, and secrete a variety of pro-inflammatory factors (TNF-α, IL-6, IL-1β), chemokines, and ROS, which promote the recruitment of leukocytes into the brain and exacerbate the inflammatory response;⁴⁸ activated microglia exhibit two phenotypes: pro-inflammatory M1 and anti-inflammatory M2. M1-type microglia secrete a large number of pro-inflammatory factors and cytotoxins, which exacerbate neuronal damage, while M2-type microglia secrete anti-inflammatory factors and neurotrophic factors, which promote tissue repair and neuronal regeneration.^49,50 The balance between M1 and M2 phenotypes of microglia is crucial for the progression of ischemic brain injury.

The TLR4/NF-κB signaling pathway is a key regulatory pathway of the inflammatory response in CIS.⁵¹ TLR4, a transmembrane protein belonging to the Toll-like receptor family, is widely expressed on astrocytes, microglia, and vascular endothelial cells. After binding to DAMPs, TLR4 is activated, which further activates downstream signaling molecules, leading to the phosphorylation and degradation of IκB, and the nuclear translocation of NF-κB; NF-κB is a key transcription factor that regulates the expression of a variety of pro-inflammatory factors, chemokines, and adhesion molecules, thereby amplifying the inflammatory response and exacerbating brain tissue damage.⁵²

BBB disruption is another important pathological feature of CIS, which is closely related to the inflammatory response and oxidative stress.⁵³ The BBB is composed of vascular endothelial cells, tight junctions, astrocyte endfeet, and pericytes, and plays a crucial role in maintaining the stability of the central nervous system microenvironment. After the onset of CIS, the inflammatory response and oxidative stress damage the tight junctions between vascular endothelial cells, leading to increased BBB permeability. This allows plasma proteins, leukocytes, and other substances to infiltrate into the brain parenchyma, resulting in brain edema, increased intracranial pressure, and further exacerbation of neuronal damage.⁵⁴ Matrix metalloproteinase-9 (MMP-9) is a key enzyme that mediates BBB disruption. MMP-9 can degrade the extracellular matrix components of the BBB, leading to the destruction of the BBB structure and increased permeability.⁵⁵ Studies have shown that the level of MMP-9 is significantly increased in CIS, and targeted inhibition of MMP-9 can reduce BBB disruption and brain edema, thereby protecting ischemic brain tissue.⁵⁶

Neuronal apoptosis and autophagy are important forms of programmed cell death in CIS. Apoptosis is a regulated cell death process that plays an important role in the development and homeostasis of the nervous system. After the onset of CIS, various pathological factors, such as glutamate excitotoxicity, oxidative stress, inflammatory response, which can trigger neuronal apoptosis through the extrinsic pathway and intrinsic pathway.⁵⁷ The intrinsic pathway is the main apoptotic pathway in CIS: oxidative stress and calcium overload damage mitochondria, leading to the release of cytochrome c, which forms an apoptosome with Apaf-1 and caspase-9, and activates caspase-3, thereby triggering neuronal apoptosis.⁵⁸ Autophagy is a process of degrading and recycling intracellular damaged organelles and proteins, which is maintained at a low level under normal physiological conditions. During CIS, autophagy is activated in response to energy metabolism disorders and oxidative stress, Moderate autophagy can help neurons remove damaged organelles and proteins, maintain cellular homeostasis, and promote cell survival; however, excessive autophagy can lead to the degradation of essential cellular components, resulting in neuronal death.⁵⁹ The balance between apoptosis and autophagy is crucial for the survival of ischemic neurons.

In summary, the pathogenesis of CIS is a complex, multi-dimensional cascade reaction involving energy metabolism disorders, glutamate excitotoxicity, oxidative stress, calcium overload, inflammatory responses, BBB disruption, neuronal apoptosis, and autophagy imbalance. These mechanisms interact with each other and promote the progression of ischemic brain injury. Therefore, effective CIS treatment strategies need to target multiple pathophysiological pathways simultaneously.

Treatment of Cerebral Ischemic Stroke with Traditional Chinese Medicine

Banxia-Baizhu-Tianma Decoction

As a classical TCM formula for treating “apoplexy” caused by phlegm and wind blocking collaterals, BBTD has been widely used in the clinical treatment of CIS for centuries. Modern pharmacological studies have confirmed that BBTD exerts robust neuroprotective, anti-inflammatory, antioxidant, and vascular-protective effects through multi-targeted and multi-pathway regulation, which is consistent with the complex pathogenesis of CIS.⁶⁰ The therapeutic effects of BBTD on CIS are mainly reflected in the following aspects:

Inhibiting Inflammatory Response

Inflammatory response is a core driver of the progression of ischemic brain injury, and inhibiting the inflammatory response is an important strategy for CIS treatment. BBTD has been shown to inhibit the inflammatory response by regulating the expression of inflammatory factors and inflammatory pathways.⁶¹ Studies have found that BBTD can downregulate the serum and brain tissue levels of pro-inflammatory factors such as TNF-α, IL-6, and IL-1β in CIS patients and upregulate the level of anti-inflammatory factor IL-10, thereby reducing the degree of inflammatory damage.⁶² The mechanism by which BBTD inhibits the inflammatory response is mainly related to the regulation of the TLR4/NF-κB signaling pathway. BBTD can inhibit the activation of TLR4 and NF-κB, reduce the nuclear translocation of NF-κB, and thereby inhibit the transcription and expression of pro-inflammatory factors.¹²

Each constituent herb of BBTD also plays an important role in inhibiting the inflammatory response. For example, Pinellia ternata can mitigate hippocampal damage and enhance cognitive function in epileptic rats through antioxidant and anti-inflammatory pathways;⁶³ Gastrodia elata can reduce the level of pro-inflammatory factors in the brain tissue of CIS rats and inhibit the activation of microglia;⁶⁴ Atractylodes macrocephala can inhibit neuroinflammation and prevent cerebral ischemia by suppressing the janus kinase 2 / signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway;⁶⁵ Exocarpium Citri Grandis can inhibit the expression of inflammatory factors in rats with cerebral ischemia-reperfusion (I/R) injury, exerting neuroprotective and anti-inflammatory effects;⁶⁶ jujube polysaccharides, the active component of Ziziphus jujuba, exhibit strong anti-inflammatory properties, which can reduce the level of inflammatory factors and alleviate brain tissue inflammation.⁶⁷

Antioxidative Stress and Anti-Apoptosis

Oxidative stress and neuronal apoptosis are crucial mechanisms underlying ischemic brain injury, and BBTD exerts significant neuroprotective effects by enhancing antioxidant capacity and inhibiting neuronal cell damage as well as apoptosis.⁶⁰ Gao et al⁶⁰ have demonstrated that BBTD can elevate the activity of key antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), in the brain tissue of animal models Meanwhile, this decoction effectively reduces the level of malondialdehyde (MDA), thereby scavenging excessive ROS and mitigating oxidative stress-induced damage. In addition to its antioxidant effects, BBTD can inhibit neuronal apoptosis by regulating the expression of apoptosis-related proteins. Specifically, BBTD upregulates the expression of the anti-apoptotic protein Bcl-2 and downregulates the expression of pro-apoptotic proteins such as Bax and caspase-3, which further inhibits the mitochondrial apoptotic pathway and ultimately reduces neuronal apoptosis.⁶⁰

The active components of BBTD’s constituent herbs also contribute to its antioxidant and anti-apoptotic effects. For example, gastrodin, the main active component of Gastrodia elata, has been shown to increase the level of brain-derived neurotrophic factor (BDNF) and stimulate neurogenesis, while exerting antioxidant and anti-apoptotic effects on ischemic brain tissue;⁶⁸ baicalein, a flavonoid component of BBTD, can exert antioxidant, anti-apoptotic, and anti-excitotoxic effects, and protect mitochondria from oxidative damage;⁶⁹ flavonoids in Glycyrrhiza uralensis can promote cell proliferation, reduce apoptosis, and maintain BBB integrity by combating oxidation and inhibiting endoplasmic reticulum stress;⁷⁰ The active component gingerol in ginger exhibits protective effects against focal cerebral ischemia in rats. Kongsui and Jittiwat demonstrated that 6-geranone, as the primary active derivative of gingerol, exerts in vivo protective effects against cerebral ischemia by protecting the antioxidant defense system and activating anti-apoptotic pathways, which is consistent with its role in mitigating ischemic brain injury.⁷¹

Protecting Vascular Endothelial Function and BBB Integrity

Vascular endothelial dysfunction and BBB disruption are important pathological features of CIS, and protecting vascular endothelial function and BBB integrity is crucial for reducing the progression of ischemic brain injury.⁷² Studies have found that BBTD extract can promote the proliferation of vascular endothelial cells, inhibit endothelial cell apoptosis, and enhance the antioxidant and anti-inflammatory activities of endothelial cells.⁶¹ BBTD can also regulate the levels of vascular endothelial active substances: it can increase the level of NO, a vasodilator, and reduce the level of endothelin-1 (ET-1), a vasoconstrictor, thereby improving cerebral blood flow and reducing vascular resistance.⁷³ In addition, BBTD can reduce the level of MMP-9 in CIS patients, inhibit the degradation of the extracellular matrix of the BBB, and maintain BBB integrity, thereby reducing brain edema and secondary brain damage.⁷⁴

The constituent herbs of BBTD also play important roles in protecting vascular endothelial function and BBB integrity. For example, Poria cocos can significantly increase cerebral blood flow in rats after ischemia-reperfusion, reduce infarct volume and brain water content, and alleviate neuronal injury by protecting vascular endothelial function;⁷⁵ Atractylodes macrocephala can improve vascular endothelial function by inhibiting the JAK2/STAT3 signaling pathway, thereby reducing vascular inflammation and atherosclerosis.⁷⁶

Regulating Signaling Pathways and miRNAs

The therapeutic effects of BBTD on CIS are also mediated by regulating key signaling pathways and miRNAs.⁷⁷ Studies have found that BBTD can regulate the PI3K/Akt signaling pathway, which is an important survival signaling pathway in cells. BBTD can upregulate the expression of PI3K and p-Akt, and downregulate the expression of downstream apoptotic-related proteins, thereby promoting neuronal survival and inhibiting apoptosis.⁷⁸ Consistent with this finding, a recent in vivo study on MCAO rat models further confirmed that BBTD intervention can significantly upregulate the protein expression of PI3K and p-Akt in ischemic brain tissue, while downregulating the expression of apoptotic proteins such as Bax and Caspase-3, which provides additional experimental evidence for the regulatory role of BBTD in the PI3K/Akt signaling pathway.¹² In addition, BBTD can regulate the JAK2/STAT3 signaling pathway, inhibit the activation of astrocytes and microglia, and reduce neuroinflammation.⁶⁵

MiRNAs are small non-coding RNAs that play important roles in regulating gene expression and are closely involved in the pathophysiological processes of CIS, including neuronal apoptosis, neuroinflammation, and vascular dysfunction.⁷⁹ Accumulating evidence has shown that BBTD can specifically regulate the expression of multiple miRNAs and their target genes in CIS, thereby mediating its neuroprotective and anti-inflammatory therapeutic effects. For example, BBTD can significantly upregulate the expression of miRNA-124, a key neuroprotective miRNA highly expressed in the brain, which directly targets and suppresses TLR4 translation, thereby abrogating the excessive activation of the TLR4/NF-κB signaling pathway. This molecular regulation leads to a significant reduction in the release of proinflammatory cytokines including IL-1β and TNF-α, and inhibits the hyperactivation of microglia.⁸⁰ Concomitantly, BBTD elevates the expression of miR-138-5p, which modulates its downstream target genes to block the JAK2/STAT3 signaling pathway; this secondary anti-inflammatory cascade further mitigates inflammatory infiltration in the ischemic penumbra and preserves neuronal structural and functional integrity. In terms of vascular protection, angiogenesis promotion and cerebral microcirculation improvement, BBTD upregulates miR-217 expression, which directly targets and represses KLF5 gene expression, the consistent with findings that miR-21 is involved in the regulation of apoptosis and angiogenesis.⁸¹ This regulation inhibits vascular endothelial cell apoptosis, enhances the integrity of the vascular endothelial barrier, and accelerates angiogenesis in the ischemic brain region, thereby effectively improving cerebral microcirculatory perfusion, alleviating ischemic brain tissue damage, and ultimately ameliorating the clinical prognosis of patients with CIS.⁸² Additionally, the core mechanisms by which BBTD modulates miRNA expression involve indirect regulation of inflammation-related signaling cascades, which further amplifies its neuroprotective efficacy. BBTD can fine-tune the expression of specific miRNAs to indirectly downregulate both protein and mRNA levels of IL-6 in the ischemic penumbra, thereby inhibiting IL-6-mediated inflammatory responses and reducing cerebral infarct volume. This downstream effect of miRNA-mediated inflammatory pathway regulation further refines the mechanistic framework of BBTD, whereby its anti-inflammatory and neuroprotective properties are predominantly mediated by the targeted modulation of miRNA expression profiles.⁸³

Improving Mitochondrial Energy Metabolism

Studies have found that the active ingredient of Gastrodiae Rhizoma in BBTD can protect the ultrastructure of mitochondria in ischemic brain tissue, inhibit mitochondrial swelling and membrane potential loss, and improve the activity of mitochondrial respiratory chain complexes (I, II, III, IV), thereby increasing ATP production and reducing energy metabolism disorders.⁸⁴ BBTD can also regulate the AMPK signaling pathway, which is a key regulator of energy metabolism, and promote glucose uptake and utilization, thereby improving cellular energy supply.⁸⁵ In addition, BBTD can reduce the production of ROS in mitochondria, inhibit mitochondrial oxidative stress damage, and protect mitochondrial function.⁶¹

Fu et al⁸⁶ identified 88 chemical components in BBTD using ultra-fast liquid chromatography coupled with quadrupole time-of-flight mass spectrometry, including 19 flavonoids, 8 lactones, 12 triterpenoids, 10 phenols, 14 amino acids, 13 nucleobases and nucleosides, 7 organic acids, and 5 other compounds Among these, flavonoids, lactones, and organic acids are the main active components of BBTD, which are responsible for its multi-targeted therapeutic effects on CIS.⁸⁷ For example, baicalein and stigmasterol have been shown to exert significant neuroprotective effects by inhibiting inflammation, oxidative stress, and apoptosis.^88,89 These active components act synergistically to enhance the overall therapeutic efficacy of BBTD on CIS.

Acupuncture

Acupuncture, as a characteristic therapeutic technique of TCM, has been widely used in the clinical treatment of CIS and its sequelae. Endorsed by the WHO as an effective alternative and complementary therapy for CIS, acupuncture exerts therapeutic effects by stimulating specific acupoints to regulate the circulation of qi and blood, dredge meridians, and restore the balance of yin and yang. Modern scientific research has confirmed that acupuncture exerts neuroprotective, anti-inflammatory, anti-excitotoxic, and pro-angiogenic effects through multi-targeted and multi-pathway regulation, which can effectively improve neurological function and prognosis in CIS patients.⁹⁰ The therapeutic mechanisms of acupuncture on CIS are mainly reflected in the following aspects:

Inhibiting Glutamate Excitotoxicity and Calcium Overload

Glutamate excitotoxicity and calcium overload are key mechanisms of ischemic brain injury, and acupuncture can effectively inhibit these pathological processes.⁹¹ Studies have found that acupuncture can reduce the concentration of glutamate in the synaptic cleft of ischemic brain tissue by promoting the reuptake of glutamate by astrocytes and inhibiting the release of glutamate from presynaptic terminals This reduces the overactivation of N-methyl-D-aspartic acid receptor (NMDA) receptors, thereby inhibiting the massive influx of Ca²⁺ into neurons and alleviating calcium overload.^92,93 Acupuncture can also regulate the function of ion channels and pumps: it can enhance the activity of Na⁺/K⁺-ATPase and Ca²⁺-ATPase on the cell membrane, promote the efflux of intracellular Ca²⁺, and maintain ion homeostasis.⁹³ In addition, acupuncture can inhibit the release of Ca²⁺ from the endoplasmic reticulum and promote the uptake of Ca²⁺ by mitochondria, thereby further reducing intracellular calcium overload and protecting neurons from excitotoxic damage.⁹⁴ Clinical studies have shown that acupuncture can significantly improve the neurological function of CIS patients by inhibiting glutamate excitotoxicity.

Inhibiting Inflammatory Response and Oxidative Stress

Inflammatory response and oxidative stress are core drivers of the progression of ischemic brain injury, and acupuncture exerts therapeutic effects by inhibiting these processes.⁹⁵ Acupuncture can regulate the expression of inflammatory factors: it can downregulate the levels of pro-inflammatory factors such as TNF-α, IL-6, and IL-1β in the serum and brain tissue of CIS patients and animal models, and upregulate the level of anti-inflammatory factor IL-10.⁹⁶ The mechanism by which acupuncture inhibits the inflammatory response is mainly related to the regulation of the TLR4/NF-κB signaling pathway. Acupuncture can inhibit the activation of TLR4 and NF-κB, reduce the nuclear translocation of NF-κB, and thereby inhibit the transcription and expression of pro-inflammatory factors.⁹⁷ In addition, acupuncture can regulate the phenotype of microglia and astrocytes: it can promote the polarization of microglia from M1 to M2, and inhibit the activation and proliferation of astrocytes, thereby reducing neuroinflammation.^98,99 Acupuncture also has significant antioxidant effects. It can increase the activity of antioxidant enzymes such as SOD, GSH-Px, and CAT in the brain tissue of CIS animal models, reduce the level of MDA, and scavenge excessive ROS.⁹⁵ This reduces oxidative stress damage to neurons, astrocytes, and vascular endothelial cells, and protects the structure and function of brain tissue. Studies have found that electroacupuncture can significantly improve the antioxidant capacity of ischemic brain tissue and reduce oxidative stress damage by regulating the Nrf2/ARE signaling pathway, which is a key antioxidant signaling pathway.¹⁰⁰ The choice of acupoints and stimulation parameters has an important impact on the anti-inflammatory and antioxidant effects of acupuncture. For example, electroacupuncture at Quchi (LI11) and Zusanli (ST36) has been shown to significantly reduce the level of pro-inflammatory factors and enhance antioxidant capacity in CIS rats, thereby reducing cerebral infarct volume and improving neurological function.¹⁰¹

Promoting Angiogenesis and Cerebral Blood Flow

Restoring cerebral blood flow and promoting angiogenesis are crucial for the treatment and rehabilitation of CIS. Acupuncture can promote angiogenesis and improve cerebral blood flow by regulating the expression of angiogenic factors and protecting vascular endothelial function.¹⁰² Studies have found that acupuncture can upregulate the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiopoietin-1 (Ang-1) in the ischemic brain tissue of CIS animal models.¹⁰³ Acupuncture can also protect the ultrastructure of microvessels in the ischemic brain region, inhibit vascular endothelial cell apoptosis, and maintain vascular integrity.¹⁰⁴

Acupuncture can also improve cerebral blood flow by regulating cerebral hemodynamics. It can dilate cerebral blood vessels, reduce vascular resistance, and increase cerebral blood flow velocity and blood flow volume.¹⁰⁵ Clinical studies have shown that acupuncture can significantly improve cerebral perfusion parameters in CIS patients, especially in the ischemic penumbra region.¹⁰⁶ This helps to restore the blood supply to the ischemic brain tissue, reduce neuronal damage, and promote neurological function recovery.

Promoting Neurogenesis and Synaptic Plasticity

Promoting neurogenesis and synaptic plasticity is an important strategy for the long-term rehabilitation of CIS patients. Acupuncture can promote neurogenesis and synaptic plasticity by regulating the expression of neurotrophic factors and neurotransmitters.¹⁰⁷ Studies have found that acupuncture can upregulate the expression of BDNF and NGF in the ischemic brain tissue of CIS animal models.¹⁰² Research demonstrates that acupuncture can enhance synaptic quantity and dendritic spine density in ischemic brain regions by upregulating synaptic-associated proteins such as synaptophysin and postsynaptic dense protein 95, while improving synaptic transmission function. This mechanism repairs ischemia-induced synaptic structural damage and functional abnormalities, establishing structural and functional foundations for neurological recovery. Acupuncture regulates the balance of multiple neurotransmitters and receptors, optimizing inter-synaptic signal transmission efficiency to indirectly promote synaptic plasticity, thereby supporting the restoration of motor and cognitive functions. Additionally, acupuncture modulates the activation status of astrocytes and microglia, reducing inflammatory cytokine release to prevent synaptic damage. Simultaneously, it stimulates glial cells to secrete neurotrophic factors, improving the synaptic microenvironment and creating favorable conditions for enhanced synaptic plasticity, ultimately achieving indirect neuronal protection.¹⁰⁸ This enhances the connection between neurons and promotes the reconstruction of neural circuits, thereby improving neurological function such as motor and cognitive function.

Regulating Signaling Pathways

The therapeutic mechanisms of acupuncture on CIS are mediated by multiple signaling pathways. In addition to the TLR4/NF-κB and Nrf2/ARE signaling pathways mentioned earlier, acupuncture can also regulate the PI3K/Akt, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) signaling pathways.¹⁰⁹ The PI3K/Akt signaling pathway is an important survival signaling pathway that can promote neuronal survival and inhibit apoptosis. Acupuncture can upregulate the expression of PI3K and p-Akt, thereby activating this signaling pathway and protecting ischemic neurons.¹¹⁰ The ERK signaling pathway is involved in the regulation of cell proliferation, differentiation, and survival. Acupuncture can activate the ERK signaling pathway, promote the proliferation and differentiation of NSCs, and enhance neurogenesis; The JNK signaling pathway is a pro-apoptotic signaling pathway. Acupuncture can inhibit the activation of the JNK signaling pathway, reduce neuronal apoptosis, and protect ischemic brain tissue.¹¹¹

In summary, acupuncture exerts therapeutic effects on CIS through multiple mechanisms, including inhibiting glutamate excitotoxicity and calcium overload, reducing inflammatory response and oxidative stress, promoting angiogenesis and cerebral blood flow, enhancing neurogenesis and synaptic plasticity, and regulating key signaling pathways. These mechanisms are closely related to the complex pathophysiology of CIS, and acupuncture can target multiple links simultaneously to achieve comprehensive therapeutic effects. The choice of acupoints, stimulation modalities, and stimulation parameters are important factors affecting the therapeutic efficacy of acupuncture, and further standardization studies are needed to optimize the acupuncture treatment protocol for CIS.

Banxia-Baizhu-Tianma Decoction Combined with Acupuncture

CIS, a neurological disease with persistently high global morbidity and mortality, involves complex pathophysiological processes including inflammatory response, oxidative stress, neuronal apoptosis, vascular injury, and neural circuit disruption. Single therapeutic regimens often fail to achieve comprehensive pathological intervention.¹⁸ In clinical practice, the combined application of TCM compound BBTD and acupuncture has become an important strategy for CIS treatment. This combined model organically integrates the systemic regulation advantages of BBTD and the targeted stimulation characteristics of acupuncture, significantly improving therapeutic efficacy through multi-link and multi-target synergistic effects, which is superior to single BBTD treatment or single acupuncture treatment.¹¹² The synergistic therapeutic effect of BBTD combined with acupuncture is centered on the complementarity of their therapeutic mechanisms: both can effectively inhibit inflammatory response, oxidative stress, glutamate excitotoxicity, and neuronal apoptosis during CIS pathogenesis, while promoting angiogenesis and neurogenesis. However, they act on different links and molecular targets of these pathological pathways, forming a synergistic complementarity to achieve more comprehensive and efficient pathological intervention and functional repair.

Kang et al¹¹³ conducted an animal experiment to systematically explore the synergistic therapeutic effect of acupuncture combined with TCM (oral Banxia Baizhu Tianma Decoction combined with Taoren Honghua Decoction, belonging to the category of BBTD) on a rat model of cerebral infarction, and clarified the regulatory roles of short-chain fatty acids (SCFAs) and interleukin-17 (IL-17) in this therapeutic process The study adopted a randomized grouping design, dividing rats into four groups: acupuncture monotherapy group, TCM monotherapy group, acupuncture-TCM combined treatment group, and blank control group. Therapeutic effects and mechanisms were analyzed through multi-index detection. The results showed that compared with the monotherapy groups and the blank control group, the combined treatment group had a significant reduction in cerebral infarct volume, obvious improvement in neurological deficit symptoms, and effective alleviation of pathological damage in ischemic brain tissue. At the mechanistic level, the combined intervention significantly upregulated the overall level of SCFAs in rats and inhibited the abnormal expression of IL-17 in ischemic brain tissue, with regulatory effects significantly superior to either monotherapy. This study further confirmed that acupuncture combined with BBTD-type TCM exerts a significant synergistic neuroprotective effect on cerebral infarction in rats, and its mechanism may be mediated by regulating the SCFAs/IL-17 axis to alleviate ischemic brain injury.

A clinical controlled trial conducted in 2015 enrolled 216 CIS patients, with BBTD monotherapy as the control, to systematically evaluate the therapeutic effect of BBTD combined with acupuncture.¹¹⁴ The study took blood viscosity, plasma viscosity, plasma fibrinogen level, and platelet adhesion rate as core detection indicators, and counted the disease improvement rate of patients in both groups. The results showed that after treatment, the improvement of the above hemorheological indicators in the combined treatment group was significantly better than that in the BBTD monotherapy group, suggesting that combined treatment can more effectively improve the hypercoagulable state of CIS patients and provide guarantee for the recovery of blood supply to ischemic brain tissue. In addition, the disease improvement rate of the combined treatment group (89.8%) was significantly higher than that of the monotherapy group (72.2%), further confirming the advantage of combined treatment.

Wang et al¹¹⁵ conducted a high-quality RCT with optimized study design, providing more reliable evidence for the clinical application of BBTD combined with acupuncture The study enrolled 60 CIS patients, who were equally divided into the acupuncture plus BBTD group and the acupuncture monotherapy group (30 patients in each group) using a randomized stratified design, with an intervention cycle of 8 weeks. The study systematically compared the therapeutic effects of the two groups from multiple dimensions, including inflammatory factor levels, blood lipid profiles, cerebral perfusion parameters, motor function, activities of daily living, and adverse reaction rates. The results showed that both groups had significant clinical improvement after treatment, but the improvement effect of the combined treatment group was more significant: In terms of inflammatory factors, the levels of TNF-α, CRP, and IL-6 in both groups were significantly reduced, but the reduction amplitude was more significant in the combined treatment group (P<0.05), suggesting that combined treatment can more effectively inhibit the neuroinflammatory response after CIS; In terms of lipid metabolism, the levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) in both groups were significantly decreased, and the blood lipid levels in the combined treatment group were lower than those in the acupuncture monotherapy group (P<0.05), indicating that combined treatment helps improve dyslipidemia in CIS patients, reduce vascular plaque formation, and lower the risk of disease recurrence; In terms of cerebral perfusion, the cerebral blood flow velocity, mean transit time, and peak time in both groups were significantly improved, and the cerebral perfusion parameters of the combined treatment group were better (P<0.05), indicating that combined treatment can more effectively restore the blood supply of ischemic brain tissue and reduce ischemic-hypoxic injury; In terms of neurological function, the Fugl-Meyer Assessment score and Barthel Index of both groups were significantly increased, and the scores of the combined treatment group were significantly higher than those of the monotherapy group (P<0.05), confirming that combined treatment can more effectively promote the recovery of motor function and activities of daily living in CIS patients.

Another clinical controlled trial conducted in 2023 focused on the efficacy comparison between BBTD combined with acupoint embedding and conventional rehabilitation therapy, further expanding the clinical application scenarios of BBTD combined with acupuncture-based therapies.¹¹⁶ The study enrolled 72 CIS patients, divided into the control group and the treatment group. The control group received standard drug treatment and conventional rehabilitation training, while the treatment group additionally received BBTD and acupoint embedding treatment on the basis of the control group, with a treatment course of 2 weeks. The study took neurological deficit score, Barthel Index, and total clinical effective rate as core evaluation indicators. The results showed that after treatment, the neurological deficit scores of both groups were significantly decreased, and the Barthel Index was significantly increased (P<0.05), indicating that both treatment regimens can improve the neurological function of CIS patients. However, the improvement degree of the treatment group was more significant: its neurological deficit score was significantly lower than that of the control group, and the Barthel Index was significantly higher than that of the control group (P<0.05). Moreover, the total clinical effective rate of the combined treatment group (94.4%) was significantly higher than that of the control group (77.8%), fully confirming the advantage of BBTD combined with acupoint embedding in the treatment of CIS.

An in-depth analysis of the synergistic mechanism of BBTD combined with acupuncture in the treatment of CIS shows that its core lies in the complementary regulation of the two on the pathophysiological process of CIS, which can be specifically divided into four key aspects: First, synergistic anti-inflammatory effect. BBTD inhibits the initiation and amplification of inflammatory response by regulating two core signaling pathways, TLR4/NF-κB and JAK2/STAT3;^12,65 acupuncture not only inhibits the activation of the TLR4/NF-κB signaling pathway but also regulates microglial polarization, promoting the transformation of microglia from a pro-inflammatory phenotype to an anti-inflammatory phenotype.^97,98 The combined application of the two can target different links of the inflammatory response, both blocking the activation of upstream pathways and regulating the functional phenotype of immune cells, forming a synergistic anti-inflammatory effect, comprehensively reducing the release of pro-inflammatory factors such as TNF-α, CRP, and IL-6, and alleviating the damage of neuroinflammation to ischemic brain tissue. Second, synergistic antioxidant and anti-apoptotic effects. BBTD enhances the body’s antioxidant capacity and inhibits neuronal apoptosis by regulating the PI3K/Akt signaling pathway and upregulating the activity of antioxidant enzymes such as SOD, GSH-Px, and CAT;^60,78 acupuncture exerts similar antioxidant and anti-apoptotic effects by regulating the Nrf2/ARE and PI3K/Akt signaling pathways.^100,110 The synergistic effect of the two can further enhance the ability to resist oxidative stress, inhibit the programmed death of ischemic neurons, reduce neuronal loss, and lay a foundation for the recovery of neurological function. Third, synergistic promotion of angiogenesis and cerebral blood flow recovery. BBTD improves vascular endothelial function and promotes the formation of new blood vessels in ischemic areas by regulating the expression levels of VEGF and NO;⁷³ acupuncture also upregulates VEGF expression and dilates cerebral blood vessels to improve cerebral blood circulation.^103,105 The combination of the two can more effectively restore the blood supply of ischemic brain tissue by synergistically upregulating angiogenic factors and dual regulating vascular tone, improving the perfusion status of the ischemic penumbra, which is crucial for preventing the expansion of infarct size and promoting the repair of ischemic brain tissue. Fourth, synergistic promotion of neurogenesis and synaptic plasticity. BBTD promotes the proliferation and differentiation of neural stem cells and accelerates neurogenesis by regulating the expression of BDNF and miRNAs;^80,81 acupuncture enhances neurogenesis ability and improves synaptic structure and function to enhance synaptic plasticity by upregulating the levels of BDNF and NGF.^102,108 The synergistic effect of the two can further promote the regeneration and repair of neural circuits by synergistically increasing the level of neurotrophic factors and coordinately regulating the expression of genes related to neurogenesis and synaptic function, thereby improving the long-term neurological function of CIS patients and promoting the process of functional rehabilitation.¹⁸

Although BBTD combined with acupuncture (or its derivative acupoint embedding) has shown significant synergistic therapeutic advantages in the treatment of CIS, providing new ideas and schemes for the clinical treatment of CIS, combined with the results of existing basic experiments and clinical studies, this combined therapy still has many defects and limitations, which need to be further solved in future studies to promote its clinical transformation and standardized application. Four main limitations exist in current studies on BBTD combined with acupuncture for CIS. First, clinical trials generally have methodological flaws: the 2015 (216 patients)¹¹⁴ and 2023 (72 patients)¹¹⁶ trials lacked rigorous blinding and had small sample sizes, while the 2021 high-quality RCT (60 patients)¹¹⁵ also had limited sample size, and most studies were single-center without long-term follow-up. Second, the specific synergistic molecular mechanisms remain unclear; Kang et al¹¹³ suggested mediation via the SCFAs/IL-17 axis, but related molecular pathways and cross-talk between BBTD- and acupuncture-regulated pathways are unelucidated Third, basic animal study results lack clinical validation, with interspecies differences limiting translation. Fourth, the combined regimen lacks standardization, with heterogeneous intervention parameters (treatment courses, acupoints, BBTD types/dosages)^113,115,116 and long-term safety remains unevaluated.

In summary, BBTD combined with acupuncture has significant synergistic effects in the treatment of CIS, whose core lies in the multi-link and multi-target complementary regulation of the two on the pathophysiological process of CIS. Existing basic experiments and clinical studies have initially confirmed the effectiveness and feasibility of this combined therapy. However, at the same time, this combined therapy still has limitations such as imprecise methodology, unclear molecular mechanisms, insufficient clinical transformation, and lack of standardized regimens. Future studies should focus on the above deficiencies, conduct high-quality RCTs with multi-center, large-sample, and long-term follow-up to optimize the study design; further explore the molecular mechanisms of synergistic treatment to clarify key regulatory targets and signaling pathways; strengthen the connection between basic experiments and clinical studies to promote the clinical transformation of research results; establish a unified standardized scheme for combined treatment, and systematically evaluate its long-term safety, so as to provide more sufficient evidence support for the standardized application of BBTD combined with acupuncture in the treatment of CIS, further improve the therapeutic effect of CIS, and improve the prognosis of patients.

Conclusion

This review systematically summarizes the therapeutic mechanisms of BBTD and acupuncture in the treatment of CIS, and explores the potential value of their combined application. CIS is a complex cerebrovascular disease characterized by a multi-link, multi-pathway pathophysiological process, involving inflammatory response, oxidative stress, glutamate excitotoxicity, calcium overload, BBB disruption, neuronal apoptosis and other key pathological links. Conventional Western medical treatments have certain limitations in improving long-term neurological sequelae and reducing disease burden, while TCM represented by BBTD and acupuncture provides a unique and effective alternative approach through multi-targeted, multi-pathway regulatory effects.

BBTD, as a classic TCM formula with the effects of resolving phlegm, calming wind, invigorating the spleen and eliminating dampness, exerts therapeutic effects on CIS by inhibiting inflammatory response, enhancing anti-oxidative stress capacity, protecting vascular endothelial function and BBB integrity, promoting neuronal survival, improving mitochondrial energy metabolism, and regulating miRNAs expression. Acupuncture, a characteristic TCM therapy endorsed by the World Health Organization, exerts significant neuroprotective effects by inhibiting glutamate excitotoxicity and calcium overload, reducing inflammatory response and oxidative stress, promoting angiogenesis and cerebral blood flow, and enhancing neurogenesis and synaptic plasticity through regulating key signaling pathways such as PI3K/Akt, ERK and JNK. Preliminary clinical observations suggest that the combined application of BBTD and acupuncture may have better therapeutic effects than single therapy, which may be related to their overlapping regulatory effects on the pathophysiological mechanisms of CIS. However, it should be emphasized that the current evidence for the synergistic effect of their combined application is mainly based on preliminary clinical observations and preclinical studies, and high-quality large-sample, multi-center clinical trials are still needed to further verify this.

Despite the progress made in the research on BBTD and acupuncture for CIS treatment, there are still obvious limitations. Most of the existing studies are preclinical animal experiments or small-sample clinical studies; the research on the material basis of BBTD’s therapeutic effects is not comprehensive enough; the selection of acupoints, stimulation methods and parameters in acupuncture therapy lack unified standards; and the research on the synergistic mechanism of BBTD combined with acupuncture is mostly focused on a single or several signaling pathways, and the comprehensive regulatory network involving multiple molecules, cells and pathways has not been fully elucidated. In conclusion, BBTD and acupuncture have significant potential in the treatment of CIS, and their combined application is expected to provide a more effective therapeutic strategy for CIS patients. Future research should focus on conducting high-quality large-sample, multi-center clinical trials to verify the clinical efficacy of their combined application, clarify the material basis of BBTD’s therapeutic effects and the specific synergistic mechanism between BBTD and acupuncture, standardize the application scheme of acupuncture, and further improve the academic rigor and clinical application value of this therapeutic strategy, so as to provide more reliable treatment options for global CIS patients and contribute to reducing the global disease burden of CIS.