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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 2  |  Page : 225-235

Research progress on the pharmacological mechanisms of chinese medicines that tonify Qi and activate blood against cerebral ischemia/reperfusion injury


1 Beijing University of Chinese Medicine, Graduate School; Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing Key Laboratory of Pharmacology of Chinese Materia, Beijing 100091, China
2 Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing Key Laboratory of Pharmacology of Chinese Materia, Beijing 100091, China
3 NICM Health Research Institute, Western Sydney University, Westmead, NSW 2751, Australia
4 Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing Key Laboratory of Pharmacology of Chinese Materia, Beijing 100091; NICM Health Research Institute, Western Sydney University, Westmead, NSW 2751, Australia

Date of Submission10-Aug-2020
Date of Acceptance29-Dec-2020
Date of Web Publication13-May-2021

Correspondence Address:
Jian-Xun Liu
Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing Key Laboratory of Pharmacology of Chinese Materia, Beijing 100091; NICM Health Research Institute, Western Sydney University, Westmead, NSW 2751
Australia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_21_21

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  Abstract 


Cerebral ischemia-reperfusion injury (CIRI) refers to a pathological phenomenon that aggravates the injury after the restoration of blood perfusion and oxygen supply to the cerebral ischemia-induced tissues and organs, with a relatively high incidence. The traditional Chinese medicine (TCM) believes that Qi deficiency and blood stasis are the cause of CIRI. Therefore, Chinese medicine for tonifying Qi and activating blood is regarded as an important choice for the treatment of CIRI. In recent years, it has been found that many Chinese herbal medical ingredients and compound Chinese medicine (CCM) have significant anti-CIRI effects, and their mechanisms of action mainly include improving brain blood supply, neuroprotection, regulating signal pathways such as TLR4/HO-1/Bcl-2, protecting mitochondrial function, regulating related protein levels, and regulating oxidative molecule levels. This article summarizes and introduces the pharmacological mechanisms of Tonifying-Qi and activating-blood Chinese medicine and CCM which have the function of anti-CIRI. Our goal is to provide effective reference for further researches on the cerebral protection of related TCMs or compounds and their clinical application.

Keywords: Cerebral ischemia-reperfusion injury, compound Chinese medicine, ingredients of traditional Chinese medicine, Qi deficiency and blood stasis, Tonifying Qi and activating blood


How to cite this article:
Zheng XY, Zhang YH, Song WT, Chang D, Liu JX. Research progress on the pharmacological mechanisms of chinese medicines that tonify Qi and activate blood against cerebral ischemia/reperfusion injury. World J Tradit Chin Med 2022;8:225-35

How to cite this URL:
Zheng XY, Zhang YH, Song WT, Chang D, Liu JX. Research progress on the pharmacological mechanisms of chinese medicines that tonify Qi and activate blood against cerebral ischemia/reperfusion injury. World J Tradit Chin Med [serial online] 2022 [cited 2022 Aug 8];8:225-35. Available from: https://www.wjtcm.net/text.asp?2022/8/2/225/315765




  Introduction Top


The incidence of ischemic cerebrovascular disease is increasing yearly worldwide, and the condition severely impacts human health and quality of life. The disease is characterized by high prevalence, high mortality, a high recurrence rate, and a high disability rate. The brain, which needs a constant supply of oxygen and adenosine triphosphate (ATP) to maintain normal functional metabolism, is the most sensitive organ to hypoxia. Once cerebral ischemia and hypoxia are induced by various factors, cells and nerves are damaged, resulting in sensory, motor, and cognitive dysfunction and even leading to death. In the Western medicine, the pathological mechanism of cerebral ischemia/reperfusion injury (CIRI) can be divided into two steps: ischemia and reperfusion. During ischemia, blockage of arterial blood flow leads to a lack of oxygen carried by red blood cells and obstruction of the electron transport chain in the mitochondria, which in turn lead to decreased ATP production in mitochondria and the occurrence of anaerobic metabolism.

Anaerobic metabolism also causes the production of antioxidants in cells. Due to the decrease in ATP production, the function of the sodium and potassium pump is impaired, which further leads to hyperosmosis, cell swelling, and hydrogen ion retention in cells, which reduce intracellular pH values. Then, cells become prone to rupture. In the second step, reperfusion (when blood flow and oxygen supply are restored in ischemic tissues), the production of reactive oxygen species (ROS) increases, which leads to oxidative stress, a local inflammatory response and DNA damage. The local inflammatory response and oxidative stress aggravate cell structural damage, ultimately leading to cell death.[1] Compared with ischemia, reperfusion can be better controlled, and drugs that inhibit the progression of reperfusion injury may be better choices for the treatment of patients with CIRI than drugs that limit ischemia.[2]

CIRI is an important cause of diseases such as ischemic stroke, cerebral edema, cerebral hemorrhage, and neuronal death.[3] The mechanism of CIRI is very complex, and many factors are believed to be involved,[4] including mainly oxidative stress, apoptosis, mitochondrial function damage, excitotoxicity, calcium overload, and the inflammatory response.[5],[6] In addition, the reperfusion injury phase lasts for several days, causing apoptosis of nerve cells and further aggravating brain injury.

Scholars worldwide are actively conducting research to determine how to prevent and treat CIRI. Traditional Chinese medicine (TCM) has a long history of use for the treatment of cerebrovascular diseases,[7] and contemporary Chinese medicine (CCM) strategies and treatments have also made much progress. In TCM, it is theorized that Qi and blood are the main factors affecting ischemia/reperfusion (I/R). Qi is the commander of blood, and blood is the mother of Qi; Qi can generate blood, move blood and control blood. Therefore, ischemia and hypoxia lead to Qi deficiency, obstruction of blood circulation, and ultimately blood stasis.[8] In terms of CIRI, it is believed that the Qi deficiency and blood stasis described in TCM correspond to a lack of oxygen supply and decreased production of ATP in the Western medicine. Ultimately, these conditions all lead to neuronal cell death and other outcomes. In TCM, individuals seeking to treat I/R mainly use treatment strategies such as Qi tonification, Qi supply, blood activation, and blood stasis removal. Previous studies have shown that Chinese medicines that tonify Qi and activate blood have significant therapeutic effects on CIRI. This article summarizes the TCM and CCM mechanisms for Qi tonification and blood activation against CIRI.


  Traditional Chinese Medicine Components Top


Astragaloside IV

Huang Qi (Radix Astragali) is a TCM known for its Qi-tonifying effects. Astragaloside IV (AS-IV, 3-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyranosyl-cycloastragenol (CAG), molecular formula: C14H68O14) is one of the main effective components of Huang Qi.[9] AS-IV has a wide range of pharmacological effects, such as cardioprotective, antiviral, antibacterial, antifibrotic, antidiabetic, and immunomodulatory effects[10] and can achieve anti-inflammatory and antioxidant pharmacological activity by inhibiting the TLR4 signaling pathway.[11] In the treatment of cerebrovascular disease, AS-IV can reduce cerebral infarct area, promote angiogenesis, protect blood–brain barrier (BBB) integrity[10] and reduce neuronal apoptosis.[12] The specific mechanism involves activation of the HIF/vascular endothelial growth factor (VEGF)/Notch signaling pathway through miRNA-210 and activation of the JAK2/STAT3 pathway to inhibit neuronal apoptosis caused by cerebral I/R.[13],[14] AS-IV can inhibit the upregulation of Fas, FasL, Caspase-8, and Bax/Bcl-2 mRNA expression and inhibit the protein expression of the apoptosis factors Caspase-8, Bid, Caspase-3 and Cyto-C after cerebral I/R. All the above findings suggest that AS-IV may reduce the apoptosis induced by I/R by inhibiting the death receptor pathway and the activation of key factors in the mitochondrial pathway.[13] Combined treatment with AS-IV and Panax notoginseng saponins (PNSs) can ameliorate pathological changes after cerebral ischemia, reduce cerebral infarct areas in rats, and reduce behavioral scores indicating nerve function defects.[15] Combination of AS-IV with ginsenoside Rg1, ginsenoside Rb1 and notoginseng R1 can enhance antagonism of I/R injury and oxidative stress injury, and the mechanism may be related to coactivation of the Nrf2/HO-1 signaling pathway after cerebral I/R.[16] In addition, AS-IV can be combined with paeoniflorin (PF) to reduce ischemic brain edema by activating the JNK and ERK pathways to inhibit the expression of connexin 43.[17]

Cycloastragenol

Cycloastragenol (CAG) is produced by the metabolism of AS-IV in the body[18] and is regarded as the active form of AS-IV. Cycloastragenol (CAG) has been shown to have a variety of pharmacological effects, including telomerase-activating, antiaging, antifibrotic, hepatoprotective, antiapoptotic, antibacterial and anti-inflammatory effects.[19],[20],[21] Experiments have shown that Cycloastragenol (CAG) can reduce cerebral infarct volume in a dose-dependent manner, significantly improve functional defects, and effectively prevent neuronal loss in mice with middle cerebral artery occlusion. Cycloastragenol (CAG) inhibits the mRNA expression of proinflammatory cytokines (including tumor necrosis factor-alpha [TNF-α] and interleukin [IL]-1 β) and inhibits the activation of microglia and astrocytes in ischemic brains. These findings prove that Cycloastragenol (CAG) does have a neuroprotective effect against ischemic brain injury in mice and that its effect is related to upregulation of SIRT1 and inhibition of apoptosis and neuroinflammation in ischemic brains.[22]

Ginsenoside

Ginsenosides, found in roots, stems, leaves, and other parts, are the stem extracts and major active ingredients of the TCMs Ren Shen (Radix Ginseng) and San Qi (Panax notoginseng). Ginsenosides are tetracyclic triterpene compounds that can be roughly divided into three types according to their different structures: The protopanaxadiol type (including ginsenoside Ra1, Ra2, Ra3, Rb1, Rb2, Rb3, Rc, Rd, Rg3, and Rh2), the protopanaxatriol type (Re, Rf, Rg1, Rg2, and Rh1), and the oleanolic acid type (ginsenoside Ro). A literature review found that ginsenosides Rg1, Rb1, Rh2, Rg3, Rg5, Rd, and Re all have protective effects against CIRI, reducing neuronal damage at different levels and protecting mitochondrial function. The mechanism of action involves the inhibition of TLR4/MyD88, which regulates innate and adaptive immune inflammatory signals and activates SIRT1, and ginsenosides Rb1 and Rg3 have the strongest therapeutic effects.[23]

Ginsenoside Rg1, which has a neuroprotective effect on the central nervous system, can promote hippocampal neurogenesis, improve neuroplasticity, and enhance learning and memory. Ginsenoside Rg1 also has anti-inflammatory, antiaging, and antitumor effects.[24],[25],[26] Experiments have shown that ginsenoside Rg1, as a ginsenoside neuroprotective agent, can ameliorate the nerve injury caused by CIRI in rats, reduce blood–brain barrier (BBB) damage and edema in rats, downregulate aquaporin 4 (AQP4) expression, and play a role in neuroprotection against CIRI.[27],[28] Notably, the PPARγ/HO-1 signaling pathway plays important roles in mediating apoptosis and inflammation and is also a therapeutic target of ginsenoside Rg1 in the context of CIRI that can upregulate the expression of PPARγ and activate the PPARγ/HO-1 signaling pathway.[29]

By inhibiting the neuroinflammatory reaction of MMP-9-and NOX4-derived free radicals, ginsenoside Rb1 protects the integrity of the blood–brain barrier (BBB), which reduces the cerebral infarct area after ischemic stroke and cerebral I/R and alleviates nerve function damage.[30] Studies have found that a combination of ginsenoside Rb1 and emodin has a better effect than either compound alone and that these compounds exert synergistic neuroprotective effects by regulating the expression of aquaporin 4 (AQP4) and Cx43 after cerebral I/R.[31]

Ginsenoside Rd can significantly reduce cerebral infarct volumes and improve neuron survival rates after ischemia, protect against I/R injury in rats and cultured neurons by inhibiting hyperphosphorylation of the NR2B subunit and reduce the expression level of the NR2B subunit in the cell membrane.[32] Ginsenoside Rd can also protect mitochondria after cerebral I/R, reduce the generation of mitochondrial hydrogen peroxide, hyperpolarize mitochondrial membrane potential, reduce redox imbalance, and have a neuroprotective effect.[33]

Ginsenoside Rg3 can exert neuroprotection by inhibiting apoptosis under the conditions of CIRI. Its mechanism may be related to the regulation of the protein and mRNA levels of Bax and Bcl-2.[34] After oral administration of ginsenoside Rg3, the main metabolite processed by human intestinal flora is ginsenoside Rh2. Ginsenoside Rh2 can significantly reduce the sizes of large infarct areas caused by middle cerebral artery occlusion and can inhibit ischemic brain injury caused by inflammatory reactions.[35]

In summary, in terms of CIRI, the protective effects of ginsenosides are related to their molecular structures, which determine their mechanisms of action.

Salvianolic acid

Salvianolic acid is the main water-soluble compound in the TCM Dan Shen (Salvia miltiorrhiza), which can be divided into many kinds of compounds with different structures. The two most common types of salvianolic acid are salvianolic acid A (SalA) and B (SalB). Salvianolic acid has cardiovascular-protective,[36] arteriole circulation-improving,[37] hepatoprotective,[38] neuroprotective,[39] and anticancer effects[40] and is widely used in the clinical treatment. Salvianolic acid has beneficial effects against CIRI, for example, it reduces cortical infarct volumes, prevents apoptosis, increases mitochondrial membrane potential, and reduces the damage to mitochondrial structure and function. The specific mechanism may involve the regulation of mtCx43 through the PI3K/ Protein kinase B (AKT) pathway.[41]

Senkyunolide I

Senkyunolide I (SEI) is an effective component derived from the TCM Chuan Xiong (Rhizoma Ligustici Chuanxiong), which has been widely used in the treatment of stroke and migraine in China.[42] SEI has been proven to treat migraines in the early stage,[43] and some studies have found that SEI is detectable in various tissues after the administration of Z-ligustilide (LIG),[44] indicating that SEI is the major metabolite of LIG. LIG has been confirmed to have anti-CIRI effects.[45] Therefore, it was hypothesized that SEI also has anti-CIRI effects. The experimental results showed that SEI can improve neurological defects, reduce cerebral edema, and reduce infarct areas. The mechanism of action is that SEI can induce Nrf2 nuclear translocation and enhance HO-1 and NQO1 expression by upregulating the phosphorylation of ERK1/2, thus significantly activating the Nrf2/ARE pathway, significantly increasing the ratio of Bcl-2/Bax and inhibiting the expression of cleaved Caspase 3 and Caspase 9.[42]

Hydroxylsafflor yellow A

Hydroxylsafflor yellow A (HSYA), a water-soluble compound found in the TCM Hong Hua (Flos Carthami), has been shown to have antioxidant properties[46] and to improve mitochondrial energy metabolism.[47] Studies have indicated that Hong Hua extract (HSYA) also beneficially affects cerebral ischemia injury and provides neuroprotection. Experiments have shown that rats treated with HSYA show fewer neurological defects, less oxidative damage, and smaller infarct volumes than those not treated with HSYA. The protective effect of this compound may be achieved through scavenging of free radicals and inhibition of reperfusion during mitochondrial permeability transition pore opening.[48]

In addition, many other studies have shown that combinations of Hong Hua injections (composed mainly of HSYA) and other TCM injections can exert therapeutic effects on CIRI and stroke. For example, the combination of a Huang Qi injection and a Hong Hua injection can remove blood stasis and improve cerebral infarction.[49] HSYA and Danshensu (DSS) have significant synergistic neuroprotective effects on CIRI that are related to anti-inflammatory and antioxidant pathways.[50]

Paeoniflorin

PF is a TCM that activates blood and relieves pain. PF is a terpene glycoside (C23H28O11) and an important bioactive ingredient in Shao Yao (Paeonia lactiflora Pall). PF has a variety of pharmacological effects, such as antitumor, hepatoprotective, antioxidative, anti-inflammatory, anti-platelet aggregation, vasodilatory, and anti-ischemic injury effects.[51] PF has been found to be useful in the treatment of cerebrovascular diseases; for example, PF can reduce early brain injury after subarachnoid hemorrhage[52] and reduce the cerebral infarct size and the number of inflammatory cells. In the treatment of CIRI, PF can reduce neurological deficit scores, improve motor function, reduce nicotinic acetylcholine receptor α4 β2-immunoreactive cell counts, and increase nicotinic acetylcholine receptor α7-immunoreactive cell counts. The above results show that the mechanism of PF involves inhibition of neurological apoptosis and inflammation and amelioration of neurological deficits.[53]

Levo-tetrahydropalmatine

Levo-tetrahydropalmatine (L-THP) exists in Corydalis spp. L-THP has analgesic, sedative, hypnotic and blood-activating effects.[54] It is an effective ingredient of a TCM commonly used to treat migraine and dizziness, and it is also an effective drug for the treatment of drug addiction.[55] Previous studies have shown that L-THP can regulate the expression of Bcl-2 and Bax, ameliorate cerebral infarction and inhibit neuronal apoptosis.[56] Albumin leakage, increased cerebral water content, decreased cerebral blood flow, cerebral infarction, and neurological deficits caused by cerebral I/R can be improved by L-THP therapy. In addition, L-THP administration before cerebral I/R can reduce damage to the blood–brain barrier (BBB) in rats and exert a protective effect against acute CIRI.[57] Furthermore, L-THP can enhance the expression of Bcl-2; reduce the content of Bax, Caspase-3 and PARP; and inhibit overexpression of c-Abl. L-THP pretreatment can also lead to improved nerve function in rats after cerebral I/R, reduce infarct volumes and brain edema, and inhibit nerve cell apoptosis in rats after cerebral ischemia.[58] Therefore, it is possible that L-THP is a reliable therapeutic agent for the treatment of ischemic stroke.

Ferulic acid

Ferulic acid (FA) is commonly found in Chinese herbs such as Dang Gui (Radix Angelicae Sinensis) and Chuan Xiong (Rhizoma Ligustici Chuanxiong) and is an effective active ingredient in the treatment of cardiovascular and cerebrovascular diseases. It has functions such as free radical-scavenging, antioxidative, anti-platelet aggregation, nerve-protective, and immune function-enhancing functions.[59] FA has therapeutic properties for myocardial I/R[60] and renal I/R.[61] In terms of cerebral I/R, FA can inhibit Ca2+ influx, ROS production and apoptosis, exerting significant protective effects against ischemic injury in vivo and in vitro. In addition, FA can reduce memory impairment by inhibiting the TLR4/MyD88 signaling pathway and provide protection against oxidative stress and apoptosis caused by CIRI.[62] Other studies have shown that FA plays a regulatory role in Bax-induced apoptosis that is related to inhibition of the Caspase-3-dependent apoptosis pathway mediated by cytochrome C through activation of the P38MAPK/p90RSK/CREB/Bcl-2 signaling pathway.[63] FA thus plays anti-inflammatory, antioxidant, and antiapoptotic roles. The above content about traditional Chinese medicine components is shown in [Table 1].
Table 1: Components of Traditional Chinese medicine against cerebral ischemia-reperfusion injury and mechanism of action

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  Contemporary Chinese Medicine Top


BuYangHuanWu Tang

BuYangHuanWu Tang (BYHWT) is composed of Huang Qi (Radix Astragali), Dang Gui (Radix Angelicae Sinensis), Chi Shao (Radix Paeoniae Rubra), Di Long (Lumbricus), Chuan Xiong (Rhizoma Ligustici Chuanxiong), Hong Hua (Flos Carthami), Tao Ren (Semen Persicae), and other TCMs, most of which tonify Qi and activate blood. BuYangHuanWu Tang (BYHWT) is a classic TCM formulation. Given its Qi-tonifying and blood-activating effects, it is often used to treat Qi deficiency syndrome and blood stasis caused by stroke. A variety of bioactive ingredients have been found in BuYangHuanWu Tang (BYHWT), including ligustrazine, amygdalin (Amy), HSYA, PF, FA, kaempferol (Kaem), LIG, and AS-IV, among others.[64] Studies have shown that BuYangHuanWu Tang (BYHWT) exerts its ischemic stroke-ameliorating activity by modulating multiple targets with multiple components.[65] BuYangHuanWu Tang (BYHWT) treatment combined with bone marrow mesenchymal stem cell transplantation may repair damaged blood vessels and tissue pathologies caused by cerebral I/R by upregulating the expression of VEGF and Ki-67. VEGF and Ki-67 are expressed to a certain extent after cerebral ischemia, suggesting that angiogenesis and cell proliferation are self-protective mechanisms.[66] BuYangHuanWu Tang (BYHWT) also regulates angiogenesis in ischemic areas by increasing VEGF, transforming growth factor-β, and angiogenin 1 expression.[67] Notably, BuYangHuanWu Tang (BYHWT) increases VEGF and ITGαvβ3 expression and microvascular density in ischemic brains. Elevated levels of VEGF and ITGαvβ3 enhance angiogenesis and improve nerve function, suggesting that administering VEGF to promote angiogenesis after stroke may have therapeutic effects and reduce infarct volumes.[68]

Qishen Yiqi Formula

Qishen Yiqi formula (QSYQ) is composed of Huang Qi (Radix Astragali), Dan Shen (Salvia miltiorrhiza), San Qi (Panax notoginseng), and Jiang Xiang (Dalbergia odorifera), all of which are Qi-tonifying and blood-activating drugs. QSYQ is usually made into capsules. QSYQ contains many active ingredients, including DSS, protocatechualdehyde, caffeic acid (CA), rosmarinic acid (RA), SalA, SalB, ginsenoside Rg1, and ginsenoside Re, among others.[69] At present, it is often used to treat chronic heart failure, myocarditis, myocardial infarction, myocardial fibrosis, myocardial I/R injury, and other cardiovascular diseases.[70],[71] Studies have shown that the active ingredients QSYQ prescriptions, such as astragaloside, ginsenoside, and salvianolic acid, help prevent CIRI.[28],[72],[73] In addition, the research has indicated that QSYQ pretreatment can improve neurological deficits, reduce cerebral infarct volumes, reduce cerebral edema, and protect the blood–brain barrier (BBB). The specific mechanism of action may involve downregulation of IFNG-γ, IL-6, TNF-α, nuclear factor kappa B (NF-κB) p65, and TLR-4 mRNA expression to inhibit the neuroinflammatory response and upregulation of TGF-β1 mRNA expression in ischemic brain tissue.[73]

Nao Xin Tong Capsule

Nao Xin Tong Capsule (NXT) is composed of 16 TCMs, including Huang Qi (Astragalus Membranaceous), Dan Shen (Salvia miltiorrhiza), Dang Gui (Angelica archangelica), Chi Shao (Radix Paeoniae Rubra), Chuan Xiong (Rhizoma Ligustici Chuanxiong), Tao Ren (Semen Persicae), Hong Hua (Flos Carthami), Mo Yao (Commiphora myrrha Engl.), Ru Xiang (Olibanum), Ji Xue Teng (Stem Caulis Spatholobi), Niu Xi (Radix Achyranthis Bidentatae), Gui Zhi (Ramulus Cinnamomi), Sang Zhi (Ramulus Mori), Di Long (Lumbricus), Shui Zhi (Hirudo), and Quan Xie (Scorpio). It is a commonly used medicine in the clinical treatment of cerebrovascular diseases. It was developed based on the prescription of BuYangHuanWu Tang (BYHWT), a classic TCM prescription.[74] Thus far, more than 100 compounds, including flavonoid aglycones and derivatives, amino acids, lactones, phenanthrenequinones, terpenes and others, have been detected in NXT. The main bioactive components include PF, Amy, CA, FA, SalB, and AS-IV, among others.[75],[76] NXT can reduce neurological dysfunction after CIRI, improve the morphology of cerebral microvascular endothelial cells,[77] decrease apoptosis and necrosis of cerebral microvascular endothelial cells, increase mitochondrial membrane potential and reduce infarct volumes and cerebral edema. The protective mechanism may be related to antioxidant and anti-inflammatory effects mediated by downregulation of the expression of LOX-1, pERK1/2, and NF-κB.[78]

Cerebralcare Granule

Cerebralcare Granule (CG) is composed of 11 medicinal materials, including Dang Gui (Radix Angelicae Sinensis), Chuan Xiong (Rhizoma Ligustici Chuanxiong), Bai Shao (Radix Paeoniae Alba), Shu Di Huang (Radix Rehmanniae Preparata), Gou Teng (Ramulus Uncariae cum Uncis), Ji Xue Teng (Caulis Spatholobi), Xia Ku Cao (Spica Prunellae), Jue Ming Zi (Semen Cassiae), Zhen Zhu Mu (Concha Margaritifera), Yan Hu Suo (Rhizoma Corydalis), and Xi Xin (Herba Asari). CG is often used to treat headaches and dizziness caused by cerebrovascular disease. Major active ingredients of this Chinese medicine, such as Dang Gui, Chuan Xiong and Bai Shao, have been proven to have anti-CIRI effects.[42],[53],[79] The active ingredients include protocatechuic acid, chlorogenic acid, CA, PF, FA and RA.[80] Studies have shown that by interfering with the degradation of tight junction proteins and the expression of caveolin-1 in vascular endothelial cells, CG can reduce cerebral edema caused by focal cerebral I/R; reduce microcirculation disorder, blood–brain barrier (BBB) damage, and cerebral infarction and neurological deficits;[81],[82] regulate inflammatory mediators; and improve blood rheology and coagulation indicators.[2]

Tong Xin Luo Capsule

Tong Xin Luo Capsule (TXL) is composed of 11 TCMs, including Ren Shen (Radix Ginseng), Shui Zhi (Hirudo), Quan Xie (Scorpio), Chi Shao (Radix Paeoniae Rubra), Chan Tui (Periostracum Cicadae), Tu Bie Chong (Eupolyphaga seu Steleophaga), Wu Gong (Scolopendra), Tan Xiang (Lignum Santali Albi), Jiang Xiang (Dalbergiae odorifera), Ru Xiang (Olibanum), Suan Zao Ren (Semen Ziziphi Spinosae), and Bing Pian (Borneolum Syntheticum). The main chemical components of TXL include PF ginsenoside Rg1, ginsenoside Rb1, jujuboside A, and jujuboside B.[83] Clinically, TXL is often used to treat coronary heart disease, angina pectoris, ischemic stroke, and other diseases. Previous studies have shown that TXL can improve endothelial function, reduce blood lipid levels, stabilize atherosclerotic plaques, promote angiogenesis, and inhibit inflammation and apoptosis.[84] In terms of CIRI, TXL can significantly improve nerve function, reduce cerebral infarct areas, reduce neuronal injury and significantly reduce neuronal apoptosis. The mechanism involves activation of the PI3K/Akt pathway; significant upregulation of the expression levels of p-PDKl, p-Akt, p-c-Raf, and p-BAD and downregulation of the expression levels of cleaved Caspase 3.[83] The above content about contemporary Chinese medicine is shown in [Table 2].
Table 2: Anti-cerebral Ischemia-reperfusion compound Chinese medicines and their mechanism of action

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  Summary Top


The above research shows that the main effects of TCMs in CIRI treatment are Qi tonification, blood circulation activation and blood stasis removal. Medicines that tonify Qi and activate blood circulation have very good therapeutic effects on CIRI, which involves Qi deficiency and blood stasis. With regard to pharmacological mechanisms, some TCMs treat CIRI by regulating signaling pathways; for example, AS-IV can activate the HIF/VEGF/Notch signaling pathway and the JAK2/STAT3 pathway to inhibit neuronal apoptosis caused by cerebral I/R; ginsenoside Rg1 can activate the PPARγ/HO-1 signaling pathway; SEI can activate the Nrf2/ARE pathway; and TXL can treat CIRI by activating the PI3K/Akt pathway. Other compounds can regulate mRNA and protein levels. For example, AS-IV can inhibit upregulation of Fas, FasL, Caspase-8, and Bax/Bcl-2 mRNA expression and inhibit the protein expression of apoptosis factors such as Caspase-8, Bid, Caspase-3, and Cyto-C after cerebral I/R; ginsenoside Rg3 can regulate the mRNA and protein levels of Bax and Bcl-2; L-THP regulates the expression of bcl-2 and bax, reduces the content of Bax, caspase-3 and PARP, and inhibits overexpression of c-Abl; QSYQ can downregulate the mRNA expression of IFNG-γ, IL-6, TNF-α, NF-κB p65 and TLR-4; and TXL can significantly upregulate the expression of p-PDK1, p-Akt, pc-Raf and p-BAD and downregulate the expression of cleaved caspase 3. In addition, a variety of other pharmacological mechanisms are involved in the treatment of CIRI; for example, Cycloastragenol (CAG) inhibits activation of microglia and astrocytes in ischemic brains, and PF reduces the counts of nicotinic acetylcholine receptor α4 β2-immunoreactive cells and increases the numbers of nicotinic acetylcholine receptor α7-immunoreactive cells. The listed mechanisms are only representative examples mentioned in the article. These findings will provide insights for future research on the mechanisms of the CIRI-ameliorative effects of TCMs used to tonify Qi and activate blood.

A number of experiments have proven that combined application of Qi-tonifying and blood-activating medicines is often better than the application of the single drugs, for example, combined treatment with total Astragalus extract.[85] or AS-IV combined with PNSs can significantly improve cerebral injury caused by ischemia. In addition, combined treatment with AS-IV and ginsenoside Rg1, ginsenoside Rb1 and notoginsenoside can enhance the antagonistic effects of the individual compounds on I/R and oxidative stress injury. This evidence suggests that the use of compatible TCMs to activate blood circulation and tonify Qi is another major direction for CIRI research.

The published literature indicates that some TCMs can prevent I/R injury at multiple sites (the myocardium/intestine/kidneys/spinal cord). For example, Astragalus polysaccharide can treat myocardial I/R injury by regulating inflammation.[86] Ginsenoside Rb1 has been used for the treatment of I/R injury in the brain,[31] myocardium,[87] and spinal cord;[88] for the treatment of remote lung injury caused by intestinal I/R;[89] and for liver injury[90] and kidney injury.[91] CA is an effective substance abundantly present in Salvia miltiorrhiza. It has protective effects on the brain,[92] kidneys,[93] and liver[94] and can prevent damage induced by I/R. Given the multi-targeted effects of TCMs, it can be boldly speculated that Qi-tonifying and blood-activating drugs with anti-cerebral I/R effects can act on multiple sites and have good efficacy against I/R injury at various sites.

The literature reveals that most of the active ingredients in TCM prescriptions are medicines for Qi tonification and blood activation. Therefore, we can speculate that researchers exploring treatments for I/R injury in the future should consider other medicines that tonify Qi and activate blood. Future research should also investigate other TCM ingredients that have been found to treat CIRI.

Financial support and sponsorship

This work is supported by Beijing Key Laboratory of Traditional Chinese Medicine Pharmacology and the National Natural Science Foundation of China (No. 81873041).

Conflicts of interest

There are no conflicts of interest.



 
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