Research Progress on the Effects and Mechanisms of Traditional Chinese Medicine in Protecting Against Cerebral Ischemia-Reperfusion Injury-Liaoning Chaohua Pharmaceutical Co., Ltd.

Research Progress on the Effects and Mechanisms of Traditional Chinese Medicine in Protecting Against Cerebral Ischemia-Reperfusion Injury

Release Date:

2021-03-20

Research Progress on the Effects and Mechanisms of Traditional Chinese Medicine in Protecting Against Cerebral Ischemia-Reperfusion Injury

Abstract: Ischemic cerebrovascular disease is one of the major threats to human health and survival, characterized by high incidence and mortality. The primary clinical approach is to restore blood reperfusion to the ischemic brain region as early as possible, thereby reestablishing oxygen and nutrient supply to the cerebral tissue. However, the restoration of blood flow often exacerbates pathological damage in the ischemic tissue and the nervous system, leading to worsening clinical symptoms and resulting in cerebral ischemia-reperfusion injury. The pathophysiological processes underlying this injury are highly complex, involving multiple mechanisms, and represent a critical challenge that must be addressed in the clinical management of ischemic cerebrovascular disease. Traditional Chinese medicines exhibit multi-component, multi-pathway, and multi-target effects, conferring unique therapeutic advantages and potential for treating cerebral ischemia-reperfusion injury, which is driven by intricate pathogenic mechanisms. Taking the bioactive constituents of traditional Chinese medicines, along with their mechanisms of action and molecular targets, as the starting point, this review summarizes research conducted over the past decade on traditional Chinese medicines with anti-ischemia-reperfusion injury properties, with the aim of providing a reference for the further scientific development and clinical application of therapeutic agents targeting this condition.

Cerebrovascular diseases are among the major conditions that pose a significant threat to human health and survival worldwide, with cerebral ischemia being the most common manifestation. Cerebral ischemia arises primarily from vascular occlusion, leading to reduced cerebral blood flow and inadequate oxygen supply to brain tissue, resulting in tissue injury. The longer the duration of ischemia, the more severe the brain damage; therefore, early restoration of blood reperfusion to the ischemic region through thrombolysis or mechanical recanalization is crucial. However, while these therapeutic interventions can reopen occluded cerebral vessels, they often exacerbate pathological damage to ischemic tissue and the nervous system, sometimes even rendering it irreversible, thereby worsening clinical symptoms. This phenomenon is known as cerebral ischemia-reperfusion injury (CIRI).

The pathogenic mechanisms of CIRI are highly complex, involving multiple processes such as calcium overload, mitochondrial dysfunction, inflammatory responses, apoptosis, accumulation of reactive oxygen species, and excessive release of excitatory amino acids. ^[1] . During the onset and progression of CIRI, brain tissue in the ischemic region, deprived of adequate blood and oxygen supply, relies on anaerobic glycolysis for energy production, leading to Na ^plus ,K ^plus -Reduced ATPase activity leads to an increase in intracellular sodium ions (Na ^plus ) and calcium ions (Ca ²^plus ) Concentration increases. Accompanied by Ca ²^plus As the concentration increases, the excitatory amino acid neurotransmitter glutamate is released in large quantities. When glutamate binds to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, it further promotes Ca ²^plus Intracellular accumulation leads to mitochondrial dysfunction. When glutamate interacts with N -Methyl- D -Aspartic acid ( N -methyl- D Binding to aspartate (NMDA) receptors triggers the production of large amounts of reactive oxygen species and reactive nitrogen species, thereby inducing oxidative stress and nitrosative stress–mediated damage. This, in turn, impairs blood–brain barrier permeability, upregulates the expression of autophagy-related factors, and leads to disruption of the blood–brain barrier and enhanced cellular autophagy. Furthermore, during CIRI, activation of microglia, astrocytes, and macrophages results in the release of abundant pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, which further exacerbates the inflammatory response. These various factors are intricately interwoven at multiple stages of CIRI onset and progression, acting both as causes and effects of one another and mutually influencing each other. Collectively, they promote neuronal injury, necrosis, or apoptosis in brain tissue. The principal pathological mechanisms of CIRI are illustrated in Figure 1.

In the theoretical framework of traditional Chinese medicine, CIRI is classified under the category of “stroke.” Traditional Chinese medicine has long recognized stroke, and through clinical practice has gradually developed a relatively comprehensive understanding of its etiology and pathogenesis, syndrome differentiation and classification, as well as therapeutic approaches, thereby establishing an effective treatment system. The Complete Works of Jingyue records: “Symptoms such as numbness and insensitivity in stroke arise because blood and qi fail to reach the affected areas, resulting in a loss of sensation to pain and itch; when qi is deficient, numbness occurs; when blood is deficient, stiffness ensues. Persistent numbness may lead to hemiplegia, atrophy, and eventual progressive deterioration.” The Treatise on Symptoms, Causes, and Pulse Diagnosis states: “The causes of hemiplegia include stagnation of qi and blood stasis, with obstruction of the pulse channels preventing normal circulation, or excess stomach heat giving rise to phlegm that obstructs the meridians.” According to traditional Chinese medical theory, the pathogenesis of this condition involves qi stagnation and blood stasis, qi deficiency leading to failure to control the blood, obstruction of the collaterals, or blockage of the brain orifices; blood stasis and kidney deficiency are considered the fundamental etiological factors. The basic therapeutic principles for this condition include promoting blood circulation and resolving stasis, tonifying qi and invigorating blood, clearing heat and detoxifying, transforming phlegm and unblocking the collaterals, opening the orifices and awakening the spirit, nourishing yin and generating body fluids, calming the liver and suppressing wind, and strengthening the spleen and tonifying the kidneys. ^[2] Based on the theoretical framework of traditional Chinese medicine regarding “stroke,” modern medicine has further elucidated the anti-CIRI effects and underlying mechanisms of various Chinese herbal medicines with distinct therapeutic properties. Herbal formulas that tonify qi, invigorate blood circulation, and resolve blood stasis—grounded in the pathogenic mechanism of “qi stagnation and blood stasis”—exert their therapeutic effects through antioxidant activity, inhibition of apoptosis, and antagonism of inflammatory responses. ^[3-4] ; Traditional Chinese medicines with heat-clearing and detoxifying properties, based on the pathogenic mechanism of “toxin-induced collateral damage,” exert their therapeutic effects by inhibiting inflammatory responses and enhancing superoxide dismutase activity, among other mechanisms. ^[5-6] Traditional Chinese medicines that resolve phlegm and unblock the collaterals, based on the pathogenesis of “phlegm obstruction of the meridians,” exert their therapeutic effects by inhibiting inflammatory responses and modulating endoplasmic reticulum stress, among other mechanisms. ^[7-8] Traditional Chinese medicines that tonify the spleen and kidney based on the pathogenic mechanism of “qi deficiency leading to failure to control blood” can enhance the activity of antioxidant enzymes and inhibit lipid peroxidation-induced damage, exerting their therapeutic effects through mechanisms such as antioxidant protection and free-radical scavenging. ^[9] Traditional Chinese medicines that open orifices and awaken the spirit, based on the pathogenesis of “orifice closure and concealment of the Shen, with the Shen unable to guide qi,” can exert anti-CIRI effects by inhibiting inflammatory responses and oxidative stress. ^[10-11]。

In recent years, the incidence, mortality, and disability rates associated with cerebral ischemia–reperfusion injury (CIRI) have remained persistently high, posing a serious threat to human life, health, and quality of life. Currently, clinical practice primarily relies on thrombolytics, calcium channel blockers, free-radical scavengers, and excitatory amino acid modulators, which aim to treat CIRI by targeting specific pathological mechanisms in its pathogenesis. However, limitations such as a narrow therapeutic time window and single-target action constrain the clinical utility of these agents in the management of CIRI. ^[12] In recent years, research has demonstrated that traditional Chinese medicines and their compound formulations, owing to the diverse structural diversity of their chemical constituents, can exert holistic interventions on the pathological processes underlying cerebral ischemia-reperfusion injury (CIRI) through multiple targets and pathways, thereby exhibiting unique advantages and considerable therapeutic potential in the treatment of CIRI. Consequently, studies on the prevention and treatment of CIRI with traditional Chinese medicine have garnered increasing attention. This review takes the bioactive constituents of traditional Chinese medicines and their mechanisms of action as the starting point, summarizing the research advances over the past decade concerning traditional Chinese medicines with anti-CIRI effects and their underlying mechanisms. The aim is to provide a theoretical basis for drug development targeting CIRI and to lay a scientific foundation for further in-depth research on the use of traditional Chinese medicine in the prevention and treatment of CIRI.

1 Treatment CHARACTERISTICS of a single herbal ingredient

In the pharmacological history of treating ischemic stroke, traditional Chinese medicines belonging to the categories of blood-activating, heat-clearing, tonifying, dampness-drying, and liver-calming agents have demonstrated favorable therapeutic effects through mechanisms such as promoting blood circulation to remove stasis and unblock the collaterals, clearing heat, draining fire, and detoxifying; tonifying the kidney and replenishing qi; dispelling wind and eliminating dampness; transforming phlegm and unblocking the bowels; and harmonizing the ying and wei. Modern research has further revealed that the principal active fractions or constituents in these single herbs—such as ginsenosides in ginseng, gastrodin in Gastrodia elata, and angelica polysaccharides in Angelica sinensis—also exhibit notable therapeutic efficacy against cerebral ischemia-reperfusion injury (CIRI).

1.1 Gastrodia elata

Tianma Gastrodia Rhizome For the orchid plant Gastrodia elata Gastrodia elata The dried tuber of Bl. possesses the effects of calming wind and arresting convulsions, leveling liver yang, dispelling wind, and unblocking the meridians; it exerts anti-CIRI activity by mitigating oxidative stress–induced injury, inhibiting apoptosis, and reducing neurotoxicity. Gastrodia elata primarily contains gastrodin and phenolic constituents. Studies have shown that gastrodin markedly suppresses the excessive expression of central nervous system–specific proteins following CIRI, thereby exerting an anti-CIRI effect; the lipid-soluble phenolic components of Gastrodia elata confer neuroprotection by modulating the expression level of calmodulin-dependent protein kinase II; and p-hydroxybenzaldehyde in Gastrodia elata achieves anti-CIRI activity by inhibiting apoptosis. ^[13-15] . In addition, Chen Tingting et al. ^[16] Furthermore, the mechanisms of action related to oxidative stress and neurotoxicity were investigated to explore the differences in the protective effects against CIRI among Tianma powders of varying particle sizes. The results demonstrated that Tianma powders of all specifications improved neurological function in CIRI rats; notably, the 500-mesh ultrafine Tianma powder exhibited a more pronounced neuroprotective effect compared with other particle-size grades.

1.2 Angelica

Angelica Angelicae Sinensis Radix Angelica sinensis, a plant of the Apiaceae family Angelica sinensis The dried roots of (Oliv.) Diels possess the effects of tonifying blood and promoting blood circulation, regulating menstruation, and relieving pain, and can exert neuroprotective effects by promoting angiogenesis, alleviating oxidative stress-induced damage, inhibiting inflammatory responses, and modulating apoptosis and autophagy. Polysaccharides and volatile oils are its major chemical constituents. Cheng et al. ^[17] The study found that treatment with 0.5 and 1 mg of Angelica sinensis water extract significantly increased the survival rate of hippocampal CA1 neurons in a rat model of cerebral ischemia-reperfusion injury, suggesting that the neuroprotective effects of Angelica sinensis water extract in CIRI are primarily mediated by activation of the phosphorylated serine-threonine kinase/p-Bad and phosphorylated serine-threonine kinase/cAMP-response element-binding protein/brain-derived neurotrophic factor signaling pathways, thereby preserving mitochondrial integrity and inhibiting apoptosis. Furthermore, the study demonstrated that the volatile oil components of Angelica sinensis can exert anti-CIRI effects by activating the phosphorylated protein kinase B/mammalian target of rapamycin (p-Akt/mTOR) signaling pathway, which in turn modulates autophagy-related proteins. ^[18] Angelica polysaccharides also exhibit pronounced neuroprotective effects, which are likely closely associated with anti-inflammatory activity, antioxidant properties, inhibition of neuronal apoptosis, and promotion of angiogenesis. ^[19-20]。

1.3 Rhubarb

Rhubarb Rhei Radix and Rhizome For the plant Rheum palmatum Rheum palmatum L., Rheum tanguticum R. tanguticum Maxim. ex Balf., or medicinal rhubarb R. officinale The dried roots and rhizomes of Rheum palmatum possess a range of therapeutic effects, including purgation to eliminate accumulated pathogenic factors, clearing heat and draining fire, cooling the blood to detoxify, removing blood stasis to unblock the channels, and promoting diuresis to resolve jaundice. These effects are mediated by inhibiting oxidative stress, inflammatory responses, and apoptosis, thereby protecting ischemic brain tissue. The main constituents of Rheum palmatum are anthraquinones. Studies have shown that anthraquinones constitute the primary pharmacological basis for the anti-CIRI activity of Rheum palmatum, with their mechanism of action closely associated with antioxidant and anti-inflammatory effects. ^[21] Furthermore, compounds such as chrysophanol and emodin have been found to exert neuroprotective effects in the CIRI rat model by, respectively, inhibiting the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway and modulating mitochondrial protein acetylation levels, thereby regulating the adenosine monophosphate-activated protein kinase/glycogen synthase kinase 3β (AMPK/GSK3β) and phosphatase and tensin homolog deleted on chromosome ten/phosphatidylinositol 3-kinase/Akt signaling pathways. ^[22-25]。

1.4 Tripterygium wilfordii

Tripterygium wilfordii Tripterygii Radix Tripterygium wilfordii, a plant of the Celastraceae family Tripterygium wilfordii The dried roots of Hook. f. possess the effects of dispelling wind and eliminating dampness, promoting blood circulation and unblocking the collaterals, reducing swelling and relieving pain, as well as killing parasites and detoxifying; these effects are primarily mediated through inhibition of inflammatory responses and apoptosis, along with modulation of the immune system, thereby exerting anti-CIRI activity. Tripterygium wilfordii mainly contains terpenoid constituents, with triptolide being its principal active component. Bai et al. ^[26] Studies have shown that triptolide intervention can significantly improve neurological function in rats subjected to the CIRI model, suggesting that triptolide exerts its protective effect against CIRI by inhibiting the activation of the nuclear factor-κB (NF-κB) signaling pathway. Furthermore, other studies indicate that triptolide’s anti-CIRI effects are closely associated with the regulation of the expression of caspase-3, inducible nitric oxide synthase, and TNF-α, as well as with the NF-κB/p53–mediated positive regulation of apoptosis via the p53 up-regulate modulator of apoptosis (PUMA) signaling pathway. ^[27-29]。

Furthermore, as early as the 19th century, studies had already demonstrated that ginsenosides are present in ginseng. ^[30-36] , Notoginsenosides in Panax notoginseng ^[37-39] 1. Ligustrazine and ligustilide in Chuanxiong ^[40-43] , Salvia miltiorrhiza ^[44-49] and Scutellaria ^[50-55] It is believed that the active ingredients of traditional Chinese medicines or individual herbal formulas exert a protective effect on CIRI. In recent years, research has revealed that crocin ^[56-57] 1. Total glucosides of white peony ^[58] , Paeoniflorin ^[59-60] , Paeonol ^[61] , Anemarrhena saponin ^[62] 1. Total flavonoids of Patrinia villosa ^[63] , Peimine A ^[64] , Rhynchophylline ^[65] , β-caryophyllene ^[66-67] 1. Hawthorn Total Flavonoids ^[68] , Vitexin ^[69]、 Z -Myrrh sterone ^[70] , 11-oxo-β-acetyl boswellic acid ^[71] , Astragaloside ^[72] 1. Puerarin ^[73-74] , Poria acid ^[75] , Shikonin ^[76-77] , Gallic acid ^[78] , Naringin ^[79-80] , Resveratrol ^[81-82] , Total Flavonoids of Propolis ^[83-84] , Luteolin ^[85] , Ginkgolide ^[86-88] , Curcumin ^[89-91] 1. Goji berry polysaccharides ^[ninety-two] It has also been confirmed that the active ingredients or effective fractions of traditional Chinese medicines exhibit good therapeutic efficacy against CIRI, as shown in Table 1.

2 Treatment CHARACTERISTICS Chinese herbal medicine pairs

Chinese medicinal herb pairs are relatively fixed combinations of two herbs commonly used in clinical practice; they represent the fundamental form of herbal compatibility and serve as an important bridge linking individual herbs to formulated prescriptions. ^[93] Studies have found that many traditional Chinese medicine herb pairs exhibit significant protective effects against CIRI, such as the Danshen–Honghua pair and the Danggui–Chuanxiong pair.

2.1 Salvia miltiorrhiza - Red Flower Herbal Pair

Both danshen and safflower are classified as blood-activating and stasis-resolving traditional Chinese medicines, and their combined formulation is one of the commonly used herb pairs in TCM compound formulas. This herb pair exhibits effects such as promoting blood circulation to remove stasis, unblocking the meridians, and relieving pain, and is widely applied in the clinical treatment of gynecological and cardiovascular diseases. Recent studies have shown that this herb pair exerts its anti-CIRI effects primarily by inhibiting oxidative stress and inflammatory responses and by alleviating endoplasmic reticulum stress. Chen Yulin et al. ^[94] Four major bioactive constituents—danshensu, salvianolic acids A and B, and hydroxysafflor yellow A—were selected as the experimental targets from Salvia miltiorrhiza and Carthamus tinctorius to investigate the anti-CIRI effects of the Salvia–Carthamus herbal pair. The results demonstrated that this herbal pair effectively attenuates brain tissue damage induced by cerebral ischemia-reperfusion. Furthermore, it is hypothesized that the Salvia–Carthamus pair exerts neuroprotective effects through anti-inflammatory mechanisms and modulation of endoplasmic reticulum stress. Xia Ying ^[95] This study investigated the anti-CIRI activities of two constituents—danshensu and hydroxysafflor yellow A—and determined their optimal therapeutic ratio. The results showed that the treatment group receiving a 1:1 combination of danshensu and hydroxysafflor yellow A exhibited a significant improvement in neurological function scores in the rat model compared with the control group. Furthermore, other studies have demonstrated that the combined use of danshen and safflower is markedly more effective in treating CIRI than either herb used alone, thereby further elucidating the scientific rationale underlying the principle of herbal pairings in traditional Chinese medicine. ^[96]。

2.2 Frankincense - Myrrh medicinal pair

Frankincense and myrrh both belong to the category of traditional Chinese medicines that promote blood circulation and relieve pain; when combined, they address both qi and blood, enhancing their effects in promoting blood circulation, alleviating pain, reducing swelling, and fostering tissue regeneration. This combination demonstrates remarkable clinical efficacy in treating conditions such as traumatic injuries and joint pain, and it can also exert favorable neuroprotective effects by promoting angiogenesis. 11-Keto-β-acetylfrankincense acid and Z -Myrrh sterone is the primary active constituent in frankincense and myrrh for the treatment of CIRI; studies have shown that these two constituents alone already exhibit good therapeutic efficacy when administered to CIRI model rats. Wang Jitao et al. ^[97] To 11-carbonyl-β-acetyl boswellic acid and Z - A study was conducted to investigate the therapeutic effects of the combined application of myrrh sterone, and the results demonstrated that the concurrent administration of these two components significantly attenuated neurological functional impairment in CIRI model rats, with a clear dose–response relationship. The underlying mechanism may involve the modulation of protein expression of vascular endothelial growth factor (VEGF) and delta-like ligand 4 (DLL4).

2.3 Astragalus - Red Flower Herbal Pair

Astragalus membranaceus is renowned for its effects of tonifying the middle jiao, replenishing qi, and strengthening the spleen, making it a commonly used qi-tonifying herbal medicine in clinical practice. Safflower, on the other hand, is widely employed for its ability to invigorate blood circulation, unblock the meridians, disperse stasis, and relieve pain, serving as a frequently prescribed blood-activating herb. When these two herbs are combined, they demonstrate favorable clinical efficacy in the treatment of syndromes characterized by qi deficiency and blood stasis. The combination of Astragalus and Safflower exerts anti-CIRI effects by inhibiting inflammatory and oxidative stress responses and promoting angiogenesis. According to existing literature, astragaloside IV and astragalus polysaccharides from Astragalus, as well as hydroxysafflor yellow A from Safflower, all exhibit protective effects against CIRI. Studies have shown that the combined use of Astragalus and Safflower yields significantly better therapeutic outcomes for CIRI than either herb alone, with the underlying anti-CIRI mechanism closely associated with the regulation of transforming growth factor expression and the modulation of B-cell lymphoma-2 (Bcl-2) gene expression. ^[98-99]。

2.4 Dang Gui and Chuan Xiong herbal pair

Danggui is renowned for its effects of nourishing and activating blood as well as regulating menstruation and relieving pain, with a primary focus on blood nourishment; in contrast, Chuanxiong excels in promoting qi circulation, activating blood, dispelling wind, and alleviating pain, with qi movement as its principal action. When used together, the two herbs address both blood and qi, thereby enhancing their combined efficacy in tonifying blood and invigorating circulation. Currently, this herbal pair is widely employed in gynecology and cerebrovascular diseases. The combination of Danggui and Chuanxiong exerts therapeutic effects on cerebrovascular disorders by improving neural plasticity and maintaining the stability of the blood–brain barrier. Lin Junbin ^[100] This study investigated the anti-CIRI effects of a combination of Angelica sinensis and Ligusticum chuanxiong by examining their major bioactive constituents—Angelica polysaccharides and ligustrazine. The results demonstrated that treatment with either Angelica sinensis or Ligusticum chuanxiong alone, as well as the combined formulation, all improved neurological function in rats subjected to a focal reperfusion injury model; moreover, the optimal therapeutic efficacy was achieved when Angelica polysaccharides and ligustrazine were administered at a 5:2 ratio. The anti-CIRI effects of Angelica sinensis and Ligusticum chuanxiong appear to be mediated by their ability to modulate neural plasticity and reduce blood–brain barrier permeability. In addition, the study revealed that, over the course of prolonged treatment for CIRI, the extent of brain tissue damage in affected rats progressively diminished. These findings suggest that, in addition to pharmacological intervention, the recovery of neurological function in ischemia-reperfusion–injured brain tissue may also involve an endogenous self-repair process.

In addition, besides the aforementioned pairs of traditional Chinese medicinal herbs that exhibit a favorable protective effect on CIRI, the combination of ginseng and notoginseng is also used. ^[101] 1. Compatibility of Borneol and Chuanxiong ^[102] 1. Combination of Astragalus and Notoginseng ^[103-104] 1. Combination of Chuanxiong and Chi Shao ^[105] 1. Combination of Hawthorn and Notoginseng ^[106] 1. Combination of Herba Asari and Radix Paeoniae Rubra ^[107] Other traditional Chinese medicine herb pairs and their compatibility patterns also demonstrate good therapeutic efficacy for CIRI, as shown in Table 2.

3 Treatment CHARACTERISTICS Traditional Chinese medicine compound

Traditional Chinese medicine compound formulas are the primary form of clinical medication in TCM. Studies have shown that many classic renowned formulas exhibit anti-CIRI effects, such as Buyang Huanwu Tang and Taohong Siwu Tang. In addition, certain modern TCM compound preparations, including Mailuoning Injection and Naobaojian Granules, also confer protective effects against CIRI.

3.1 Bu Yang Huan Wu Tang

Buyang Huanwu Tang originates from the renowned Qing-dynasty physician Wang Qingren’s “Yilin Gaicuo” and is composed of seven traditional Chinese medicinal herbs: Astragalus, Angelica sinensis, Red Peony Root, Sichuan Lovage Rhizome, Peach Kernel, Safflower, and Earthworm. It is a classic formula for treating ischemic cerebrovascular disease with proven clinical efficacy. Buyang Huanwu Tang exerts its anti-CIRI effects by inhibiting platelet activation and excessive glutamate release, thereby attenuating excitotoxicity mediated by excitatory amino acids. Zhao et al. ^[108] Studies have demonstrated that Buyang Huanwu Decoction can markedly alleviate cerebral tissue injury induced by ischemia-reperfusion, and have identified the optimal therapeutic time window for this formulation as within 4 hours of ischemia-reperfusion. This suggests that early administration of Buyang Huanwu Decoction following the onset of CIRI yields superior therapeutic outcomes. Furthermore, it is hypothesized that the therapeutic efficacy of Buyang Huanwu Decoction is associated with its ability to modulate glutamate receptors and inhibit glutamate release. Additional research indicates that the anti-CIRI effects of Buyang Huanwu Decoction may also be mediated by enhancing antioxidant capacity in brain tissue, thereby reducing lipid peroxidation-induced damage; inhibiting platelet aggregation and activation; regulating the PI3K/Akt signaling pathway; and promoting repair of brain tissue following ischemia-reperfusion injury. ^[109-110]。

3.2 Huanglian Jiedu Tang

Huanglian Jiedu Tang is a commonly used clinical heat-clearing formula, composed of four traditional Chinese medicinal herbs—Coptis chinensis, Scutellaria baicalensis, Phellodendron amurense, and Gardenia jasminoides—which exert heat-clearing and detoxifying effects and can drain pathogenic heat-toxins from the three burners. Huanglian Jiedu Tang exerts its anti-CIRI effects by inhibiting oxidative stress and inflammatory responses, modulating energy metabolism and mitochondrial function, and suppressing cell apoptosis. Previous studies have reported that components such as baicalin in Scutellaria baicalensis exhibit notable anti-CIRI activity. Wang et al. ^[111] Adopt ¹ H-NMR metabolomics combined with multivariate statistical analysis was used to comprehensively evaluate the anti-CIRI effects of Huanglian Jiedu Tang. Serum and brain tissue samples from rats were ¹ H-NMR data demonstrate that Huanglian Jiedu Tang can markedly alleviate the metabolic dysregulation induced by CIRI, improving the levels of metabolic products such as lactate, glucose, and creatinine. It exerts neuroprotective effects by restoring brain tissue to a normal state through mechanisms including mitochondrial membrane protection, modulation of neurotransmitter systems, and antioxidant and anti-inflammatory actions. Furthermore, its protective effect against cerebral injury caused by ischemia-reperfusion is mediated, in part, by activation of the PI3K/Akt signaling pathway, which upregulates the expression of hypoxia-inducible factor-1α and thereby inhibits ischemia-reperfusion–induced neuronal apoptosis. ^[112-114]。

3.3 Rehmannia Decoction

Dihuang Yinzi is a traditional herbal formula composed of 12 medicinal ingredients—Rehmannia glutinosa preparata, Morinda officinalis, Cornus officinalis, Dendrobium, Cistanche deserticola, Aconitum, Schisandra, Cinnamomum cassia, Poria cocos, Ophiopogon japonicus, Acorus tatarinowii, and Polygala tenuifolia—according to the principles of Traditional Chinese Medicine. It exerts effects such as nourishing kidney yin, tonifying kidney yang, opening orifices, and transforming phlegm, and can exert anti-CIRI activity by promoting neural stem cell proliferation, alleviating oxidative stress-induced damage, inhibiting apoptosis, and facilitating angiogenesis. In modern clinical practice, Dihuang Yinzi has also been increasingly recognized as one of the effective prescriptions for treating CIRI. Studies have shown that Dihuang Yinzi can improve neurological function in CIRI model rats by activating the Notch signaling pathway, with a certain dose–response relationship. ^[115] Furthermore, studies have shown that Dihuang Yinzi can significantly increase the expression levels of Bax, Bcl-2, Caspase-3 proteins, and VEGF in the brain tissue of rat models of ischemia-reperfusion injury, suggesting that Dihuang Yinzi may mitigate neurological dysfunction caused by ischemia-reperfusion through antioxidant effects, inhibition of neuronal apoptosis, and promotion of angiogenesis. ^[116]。

3.4 Tongxinluo Capsules

Tongxinluo Capsules are a traditional Chinese medicine compound formulation composed of 12 herbal ingredients: ginseng, leech, whole scorpion, earthworm, centipede, cicada slough, red peony root, sandalwood, borneol, agarwood, frankincense, and sour jujube seed. They exert the effects of tonifying qi, promoting blood circulation, unblocking collaterals, and relieving pain, and are currently widely used in clinical practice for the treatment of cardiovascular and cerebrovascular diseases. The mechanisms by which Tongxinluo Capsules exert their therapeutic effects in ischemic stroke include inhibiting inflammatory responses, improving blood–brain barrier permeability, and promoting angiogenesis. Gao Zhijie et al. ^[117] This study employed a combination of animal experiments and network pharmacology to investigate the protective effects of Tongxinluo Capsules on cerebral ischemia-reperfusion injury (CIRI) and to elucidate their underlying mechanisms. In the animal experiments, neurological behavioral scores, the extent of brain injury, and the area of cerebral infarction were used as evaluation indices. The results demonstrated that Tongxinluo Capsules exerted a significant protective effect on the brain tissue of CIRI rats, with a clear dose–response relationship. To further identify the bioactive chemical constituents in Tongxinluo Capsules responsible for their therapeutic efficacy and to explore their mechanisms of action, network pharmacology was applied to screen 132 active components from the 12 herbal ingredients of Tongxinluo Capsules, which were found to overlap with 240 genes involved in cerebral ischemia–target pathways. According to the network pharmacology analysis, key target genes for the treatment of CIRI by Tongxinluo Capsules include recombinant cAMP-dependent protein kinase A catalytic subunit alpha (PRKACA), adenylate cyclase 1, and dopamine D2 receptor; moreover, cAMP and the cyclic guanosine monophosphate/cyclic guanosine monophosphate–dependent protein kinase (cGMP/PKG) signaling pathways are identified as the primary pathways through which Tongxinluo Capsules exert their therapeutic effects. These findings provide a solid theoretical foundation for in-depth investigation of the mechanisms of action of Tongxinluo Capsules. In addition, studies have shown that Tongxinluo Capsules can effectively protect the blood–brain barrier, thereby exerting a preventive effect against CIRI. ^[118]。

In addition to the aforementioned compound preparations, research has found that the Huoxue Kaiqiao Decoction ^[10-11] 3. Sanhuang Xiexin Tang ^[119] 1. Peach Red Four-Ingredient Decoction ^[120-122] 1. Xuefu Zhuyu Tang ^[123] , Hou’s Black Powder ^[124] , Qingnao Yiyuan Decoction ^[125] , Astragalus and Ginseng Qi-Boosting Formula ^[126] , Shenxiong Huayu Capsules ^[127-130] , Compound Xueshuantong Capsules ^[131] , Dandeng Tongnao Capsules ^[132] , An Nao Tablets ^[133] , Sangqi Shouwu Tablets ^[134] , Xingnao Jing Injection ^[135] 1. Mailuoning Injection ^[136] , Xixian Thrombolytic Preparations ^[137] 1. Gualou Guizhi Granules ^[138-140] , Brain Health Granules ^[141] and Compound Acorus and Polygala Decoction ^[142] Traditional Chinese medicinal compound formulas and modern formulated preparations also exhibit certain neuroprotective effects, as shown in Table 3.

4 Conclusion and Outlook

Previously, the clinical treatment of CIRI has predominantly employed drugs such as nimodipine, edaravone, and dexmedetomidine, which directly target specific pathogenic mechanisms or steps in the CIRI cascade. ^[143-146] Although these drugs exert rapid therapeutic effects, the occurrence of CIRI often involves multiple pathogenic pathways, and its complex pathophysiological mechanisms severely limit their clinical efficacy in treating such diseases.

Traditional Chinese medicines and their compound formulations with CIRI–therapeutic effects contain a diverse array of bioactive constituents with complex structural types, which can synergistically target multiple pathological pathways and molecular targets involved in the onset and progression of CIRI. Even among TCMs that share the same mechanism of action or target, their active ingredients may still exhibit distinct chemical structures. For example, ginsenosides, baicalin, and paeonol, although classified as triterpenoid saponins, flavonoids, and phenolic compounds, respectively, and thus belonging to different structural classes, all exert anti–CIRI effects by improving blood–brain barrier permeability. ^[32,53,61] This opens up further possibilities for the subsequent development of novel anti-CIRI drug candidates derived from traditional Chinese medicine. Moreover, traditional Chinese medicinal formulations—whether involving pairwise or multi-ingredient combinations—often contain a diverse array of bioactive constituents that can exert therapeutic effects on CIRI through multiple pathways and at multiple molecular targets. For example, the combination of Salvia miltiorrhiza and Carthamus tinctorius has been shown to exert anti-CIRI effects by attenuating inflammation and alleviating endoplasmic reticulum stress. ^[94-96] The Buyang Huanwu Decoction exerts its therapeutic effects by inhibiting platelet activation and excessive glutamate release, respectively. ^[108-110] This demonstrates unique therapeutic advantages and potential for CIRI, which is characterized by complex pathogenic mechanisms.

In recent years, traditional Chinese medicine has made numerous noteworthy research advances in the prevention and treatment of CIRI, with many individual active constituents and herbal formulas demonstrating significant therapeutic efficacy in both pharmacological studies and clinical applications. Nevertheless, further in-depth and sustained investigation is still needed in several key areas of CIRI research involving TCM. First, although current studies have shown that diverse structural classes of active constituents in various TCM preparations can target the same molecular pathway in CIRI, the underlying mechanisms remain poorly elucidated; research scope is relatively limited, and the range of outcome measures is comparatively narrow, leaving unclear how these constituents differ or converge in their modes of action on the same target. Clarifying these issues will lay the foundation for developing novel anti-CIRI agents derived from TCM and for substantiating the scientific rationale behind TCM’s anti-CIRI effects. Second, given the complex and multifarious composition of active constituents in both single herbs and herbal formulas, the nature of their interrelationships remains poorly defined, thereby impeding more comprehensive research and broader clinical application of TCM in CIRI management. Future efforts should therefore focus on more precisely identifying the active constituents (or constituent groups) responsible for the anti-CIRI activity of TCM formulations and strengthening investigations into the relationships among these active constituents, as well as between individual herbs and their combinations. Third, it is essential to integrate pharmacological experimentation with clinical validation. Pharmacological studies should combine in vivo and in vitro approaches, leveraging the strengths of modern pharmacology to comprehensively explore the actions and mechanisms of TCM in combating CIRI from multiple angles. Prior to initiating clinical trials, it is advisable to select animal models and experimental systems that closely resemble human clinical cases, so as to conduct thorough investigations and validations of the drug’s mechanism of action, therapeutic window, pharmacokinetics, and pharmacodynamics.

One of the limitations of traditional Chinese medicine in disease treatment is its relatively slow onset of action, which often fails to achieve satisfactory therapeutic outcomes for conditions with a narrow therapeutic window. In contrast, chemical drugs typically have single molecular targets and a higher incidence of adverse reactions; however, their rapid onset of action represents a key advantage over traditional Chinese medicine. Therefore, the rational combination of traditional Chinese medicine and chemical drugs could be explored as a novel approach to research on combating cerebral ischemia-reperfusion injury (CIRI). As research into the pathogenic mechanisms of CIRI continues to deepen, the mechanisms of action, optimal therapeutic time windows, and pharmacokinetic profiles of traditional Chinese medicines and their compound formulations in the context of CIRI are becoming increasingly clear. It is believed that, with the progressive advancement of both basic scientific research and clinical studies, significant breakthroughs will eventually be achieved in addressing the current challenges in the treatment of CIRI.

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