생명과학회지 (Journal of Life Science)

  • 제32권7호
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  • Pages.550-566
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  • 2022
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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허혈성 뇌졸중 모델에서 혈액-뇌 장벽에 보호효과를 나타내는 한약처방, 한약재 및 활성화합물

Protective Effects of Traditional Korean Medicine Preparations, Herbs, and Active Compounds on the Blood-brain Barrier in Ischemic Stroke Models

  • 신수빈 (부산대학교 한의학전문대학원 한의학과) ;
  • 장석주 (부산대학교 한의학전문대학원 한의학과) ;
  • 이나경 (부산대학교 한의학전문대학원 한의학과) ;
  • 최병태 (부산대학교 한의학전문대학원 한의학과) ;
  • 신화경 (부산대학교 한의학전문대학원 한의학과)
  • Shin, Su Bin (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University) ;
  • Jang, Seok Ju (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University) ;
  • Lee, Na Gyeong (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University) ;
  • Choi, Byung Tae (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University) ;
  • Shin, Hwa Kyoung (Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University)
  • 투고 : 2022.05.26
  • 심사 : 2022.07.15
  • 발행 : 2022.07.30
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초록

뇌졸중은 세계적으로 사망과 장기간인 신체적, 인지적 장애의 주요 원인들 중 하나이며, 매년 약 1,500만명의 사람들에게 영향을 미친다. 뇌졸중의 병태 생리학적 과정은 다수의 사건들이 관여하는 복잡한 과정으로, 그 중 혈액-뇌 장벽(blood-brain barrier: BBB)의 붕괴는 허혈성 뇌손상의 진행에 크게 기여하는 것으로 알려져 있다. 따라서 BBB 붕괴는 뇌졸중의 특징으로 인식되므로 허혈성 뇌졸중에서 BBB 기능 장애를 보호할 수 있는 새로운 치료 전략을 개발하는 것이 뇌졸중 치료에 매우 중요하다. 전통한약은 천연물로 구성되어 있으며, 이는 뇌졸중 치료약 개발을 위한 유망한 원천이 될 수 있다. 실제로 여러 연구에서 뇌졸중에 대한 한의학의 효능이 밝혀져 허혈성 뇌졸중에 대한 한의학적 치료 가치가 부각되고 있다. 본 리뷰에서는 허혈성 뇌졸중으로 인한 BBB 붕괴에 대한 전통적인 한의학의 처방, 탕약, 약재 및 활성 성분의 개선효과에 관한 현재 정보와 기본 메커니즘을 요약 정리하였다. 이러한 연구가 한의학의 신경보호 효과에 대한 추가 조사를 촉진하고 뇌졸중 환자에 대한 한방유래의 임상시험 시행을 활성화하는데 도움이 되기를 기대한다.

Stroke is among the leading causes of death and long-term physical and cognitive disabilities worldwide, affecting an estimated 15 million people annually. The pathophysiological process of stroke is complicated by multiple and coordinated events. The breakdown of the blood-brain barrier (BBB) in people with stroke can significantly contribute to the development of ischemic brain injury. Therefore, BBB disruption is recognized as a hallmark of stroke; thus, it is important to develop novel therapeutic strategies that can protect against BBB dysfunction in ischemic stroke. Traditional medicines are composed of natural products, which represent a promising source of new ingredients for the development of conventional medicines. Indeed, several studies have shown the effectiveness of Korean medicine on stroke, highlighting the value of Korean medicinal treatment for ischemic stroke. This review summarizes the current information and underlying mechanisms regarding the ameliorating effects of the formula, decoction, herbs, and active components of traditional Korean medicine on cerebral ischemia-induced BBB disruption. These traditional medicines were shown to have protective effects on the BBB in many cellular and animal ischemia models of stroke, and experiments in various animal species, such as mice and rats. In addition, they showed brain-protective effects by protecting the BBB through the regulation of tight junction proteins and matrix metalloproteinase-9, reducing edema, neuroinflammation, and neuronal cell death. We hope that this review will help promote further investigation into the neuroprotective effects of traditional Korean medicines and stimulate the performance of clinical trials on Korean herbal medicine-derived drugs in patients with stroke.

키워드

Introduction

Stroke is a neurological abnormality in which blood vessels supplying blood to the brain are blocked or burst, causing damage to the brain. Most strokes are ischemic strokes, with this type accounting for 87% of all strokes [65]. Risk factors for stroke can be categorized as congenital and lifestyle. Age, sex, and race/ethnicity are hereditary risk factors for stroke, while hypertension, smoking, diet, and physical inactivity are among some of the more commonly reported lifestyle-related factors [4]. Stroke is dangerous not only because it can cause death but also because it can leave some people with permanent disabilities. Stroke is the second leading cause of mortality globally, accounting for almost 11% of all deaths, according to the World Health Organization in 2020. In 2017, 6.2 million died due to stroke worldwide [65]. In those who survive, stroke can result in long-term disability, which reduces productivity and increases medical costs, causing economic and psychological burdens on society and individuals. The symptoms of stroke, such as consciousness disorder, half-body exercise paralysis, speech disorder, abdominal vision (one object appears to be two), and dysfunction of swallowing, can make daily life difficult [24]. Furthermore, only one drug has been approved by the Food and Drug Administration to treat stroke [84], and there are many limitations to its use. Although there is a significant enhancement effect when tPA is used within 3 hr, only 6-16% of stroke patients can receive tPA treatment [27]. While many neuroprotective agents have been developed and have shown protective efficacy in stroke animal models, clinical trials have failed to show positive effects in patients with ischemic stroke. Therefore, stroke research is important, and a new paradigm is required.

The pathological process of stroke is complicated, with multiple and coordinated events. A number of pathophysiological events occur following stroke, including energy failure, glutamate excitotoxicity, oxidative stress, leukocyte infiltration, inflammation, breakdown of the blood-brain barrier (BBB), and edema [71]. The BBB is a gateway that strictly regulates the movement of ions, molecules, and cells between the central nervous system (CNS) and systemic circulation [19]. It is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane [3]. In the early stages of damage to the BBB, the tight junction proteins are loosened, and cerebrovascular permeability increases, which causes extravasation and extracellular accumulation of circulatory immune cells and fluid into the cerebral parenchyma [53]. It aggravates inflammation and generates neurotoxicity in the damaged site, thereby resulting in neuron cell death. Therefore, the protection of BBB breakdown is a major strategy for the treatment of damaged brains after ischemic injury.

Traditional medicines are composed of natural products, which represent a promising source of new ingredients for the development of conventional medicines. Indeed, researchers have begun to consult the traditional medicine literature in the search for novel therapeutic strategies [33,52]. Compiled by the Korean royal physician Heo Jun during the 17th century, the Dongui Bogam contains information regarding several prescriptions and systematic screening methods that have been applied to both experimental and clinical settings [16,57]. In addition, several studies have shown the effectiveness of Korean medicine on stroke, highlighting the potential role of Korean medicinal treatment in the treatment of stroke. This review selected recent studies and discussed further considerations for the critical reevaluation of the neuroprotection hypothesis of traditional Korean medicines against BBB disruption in ischemic brain injury. We hope that this review will further help investigate the neuroprotective effects of Korean medicines and stimulate the performance of clinical trials of Korean herbal medicine-derived drugs in patients with stroke.

Structure and function of the BBB

The BBB is a physiological and biochemical barrier that separates the CNS from the systemic circulation, which controls CNS homeostasis and protection of the brain tissue from exposure to potentially toxic substances. The BBB is a specialized barrier that consists of endothelial cells, tight junction proteins, pericytes, astrocytic end-feet processes, and the basement membrane. It is crucial in the regulation of the passage of ions, proteins, and inflammatory cells between the plasma and brain (Fig. 1) [3]. Tight junctions in the brain endothelial cells maintain the integrity of the BBB and consist of different proteins, such as zonula occludens 1 (ZO-1), claudin, and occludins [70]. In acute stroke, there is the degradation of the tight junctions resulting in the loss of vascular integrity [56].

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Fig. 1. Pathological changes in the blood vessels after ischemic stroke.

Astrocytes are the most common glia cell in the CNS and affect the brain’s endothelial cell function, blood flow, and ion balance through close association with cerebrovascular interactions. Their close interaction with endothelial cells within the BBB, particularly via astrocyte end-feet, strengthens the regulation and maturation of the BBB [47]. The astrocyte end-foot protein strongly implicated in BBB function is the water channel aquaporin 4 (AQP4), which is involved in the pathogenesis of cerebral edema, facilitates water movement through the plasma membrane of several cell types in the brain, including endothelial cells, and contributes to permeability regulation [28]. Additionally, astrocytes play a role in mediating neuroinflammation and thus are significant in neuroinflammatory pathologies, including ischemic stroke [17].

Another cell type implicated in promoting BBB function are pericytes. Pericytes are located along the basement membrane of BBB endothelial cells, encircling the vessel wall and promoting overall BBB function. Although pericytes also exist in the peripheral vasculature, the CNS microvasculature has the highest degree of pericyte coverage, potentially contributing to vascular permeability and small vessel stability [20]. They also display an ability to self-renew and differentiate into neural and vascular lineage cells in the setting of stroke [54].

The basement membrane connects endothelial cells to astrocytic end-feet and has been implicated in BBB maintenance. Specifically, damage to the basement membrane caused by increased expression of matrix metalloproteinases (MMPs) is believed to be related to alterations in BBB permeability in numerous pathologies. In particular, MMP-9 plays a key role in protease-mediated physiological and pathological changes in BBB breakdown [59]. In ischemic stroke, increased MMP-9 in the damaged brain is one of the significant causes of BBB breakdown. BBB-constituting cells, including the brain microvascular endothelial cells, astrocytes, and brain pericytes, can release MMP-9 upon thrombin stimulation. Following this breakdown, a sustained increase in permeability likely occurs due to a neuroinflammatory response, which contributes to longer-term or permanent loss of neurological function, combined with other consequences such as brain edema [59].

Protective effects of traditional Korean medicines on BBB disruption in ischemic stroke

Formula and decoction (Table1, Table 2)

(1) Shuanghe-Tang is a traditional Korean medicine formula that has long been utilized to treat fatigue and promote recuperation following sickness in Korea. In a study of focal cerebral ischemia mice, this formula significantly reduced the cerebral infarction volume, decreased BBB breakdown, attenuated edema, and improved neurological and motor functions. Shuanghe-Tang increased the expression of occludin, ZO-1, and aquaporin 4 (AQP4) [31].

Table 1. Composition of the Traditional Korean medicine formulas and decoctions

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Table 2. Traditional Korean medicine formulas and decoctions targeting the BBB in cerebral ischemia rodent models

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BBB: blood-brain barrier, MCAO: middle cerebral artery occlusion, pMCAO: permanent middle cerebral artery occlusion, tMCAO: transient middle cerebral artery occlusion, OGD: oxygen-glucose deprivation, ICH: intracerebral hemorrhage, EB: evans blue, ZO-1: zonula occludens-1, AQP4: aquaporin4, MMP-2/9: matrix metalloproteinase-2/9, PAR-1: protease-activated receptor-1, COL IV: collagen IV, TIMP1: tissue inhibitor of metalloproteinase 1, Alb: albumin, Fga: fibrinogen alpha chain, Trf: transferrin, CaMKII: Ca2+/calmodulin-dependent protein kinase II, VE-Cadherin: vascular endothelial cadherin, HIF-1α: hypoxia-inducible factors 1 alpha, TEER: trans-epithelial electrical resistance, VEGF: vascular endothelial growth factor, JAM-1: junctional adhesion molecules-1, LRP-1: lipoprotein receptor-related protein 1, FITC-dextran: fluorescein isothiocyanate-dextran.

(2) Weisheng-Tang is a traditional Korean formula that has been used in individuals who suffer from exhaustion and indigestion causing diarrhea. Weisheng-Tang significantly reduced infarct volume and edema and improved neurological and motor functions. Weisheng-Tang resulted in less BBB damage via downregulation of the tight junction proteins and suppression of protease-activated receptor-1 (PAR-1) and MMP-9 in the ischemic brain [32].

(3) Sijunzi decoction is widely used to invigorate ‘Qi.’ In the middle cerebral artery occlusion (MCAO) rat model, Sijunzi decoction treatment enhanced neurobehavioural scores and prevented BBB disruption. Permeability of the BBB was maintained by increasing the expression of tissue inhibitor of metalloproteinase 1 (TIMP1) and collagen IV and reducing the expression of MMP-9 and apoptotic rate in the hippocampus [77].

(4) Buyang Huanwu decoction has long been used to treat stroke. It improved the function recovery of MCAO mice, reduced the volume of cerebral infarction, and attenuated BBB disruption. It increased the level of tight junction proteins, ZO-1, and occludin and reduced MMP-2/9 activities and NK cells infiltrating the brain [22]. Moreover, in a study of cerebral ischemia/reperfusion mice, albumin, fibrinogen alpha chain, and transferrin, which increased due to stroke, were reduced by Buyang Huanwu decoction, and the integrity of the BBB was preserved. In addition, neuronal death and apoptotic cell death were also suppressed by Buyang Huanwu [13].

(5) Tong-Qiao-Huo-Xue decoction is a traditional formula that has long been used clinically for stroke treatment. This decoction improved neurological function and reduced the infarct volume and BBB injury in the cerebral ischemia-reperfusion rat model [72]. It protected the permeability of the BBB by increasing the expression of tight junction proteins such as ZO-1, occludin, and claudin-5 and reducing the expression of AQP4 and MMP-9 in MCAO rats [35].

(6) Angong Niuhuang Wan is a traditional formula to treat stroke, but it contains arsenic- and mercury-containing materials, so it should be used carefully. In the MCAO rat model, it reduced the infarct size and protected BBB permeability by increasing the expression of tight junction proteins, including ZO-1 and claudin-5, and inhibiting MMP-2/9 [63].

(7) Qingkailing injection is a traditional Chinese medicine based on Angong Niuhuang Wan. It has been widely used for the treatment of stroke for almost 30 years in China [50]. Qingkailing protects against BBB disruption, improves neurological function, inhibits inflammatory responses, and decreases infarct volume [49,81]. It was shown that tight junction proteins such as ZO-1, claudin-5, vascular endothelial cadherin (VE-Cadherin), and occludin were increased in the transient MCAO mice model [81]. In addition, it reduced apoptosis [49] and the activation of MMP-9 and hypoxia-inducible factor-1 (HIF-1), which affects the structural hardness of the basement membrane and the collapse of the BBB [81]. However, refined Qingkailing was developed due to safety concerns and contains four major components of traditional Qingkailing (baicalin, geniposide, cholic acid, and hyodeoxycholic acid (4.4:0.4:3:2.6)). Refined Qingkailing has been reported to reduce apoptosis, inflammatory response, and infarction rates in cerebral ischemia [50]. Moreover, Qingkailing decreased apoptosis by inhibiting the activation of caspase-3 in the intracerebral hemorrhage rat model [48].

(8) Shuxuetong injection is a formula that consists of leeches (Hirudo nipponica Whitman) and earthworms (Pheretima asperfillum). It has been long used for the treatment of stroke in China. Shuxuetong increased the expression of the BBB tight junction proteins, claudin-5, occludin, and ZO-1 in the oxygen-glucose deprivation/reperfusion (OGD/R) bEnd.3 cell model to prevent the disruption of the BBB, reactive oxygen species (ROS), mitochondrial superoxide production, inflammation via downregulation of NF-κB, vascular endothelial growth factor (VEGF), and p-ERK1/2 [61].

(9) Danhong injection is a traditional Chinese formula composed of Radix Salviae miltiorrhizae and Flos Carthami tinctorii that has been used in the treatment of acute ischemic stroke. Danhong treatment reduced infarct volume and improved neurological deficit in the MCAO rat model. In addition, Danhong decreased neutrophil infiltration and protected the BBB by increasing occludin and reducing MMP-9 [69]. Mannitol, a representative treatment for brain edema, was found to be effective in reducing edema temporarily but can further worsen the destruction of the BBB. However, when mannitol is used in combination with Danhong, BBB destruction was improved by increasing the expression of occludin, junctional adhesion molecules-1 (JAM-1), and ZO-1 and inhibiting the activation of MMP-2/9 [80].

(10) YiQiFuMai injection is a modern formula based on Sheng-Mai-San. It is used to treat microcirculatory disturbance-related diseases in China. In the MCAO mouse model, it reduced the cerebral infarct volume and brain edema and improved neurological behavior outcomes. In addition, it increased ZO-1 and occludin, thereby preventing damage to the BBB [6].

(11) Longshengzhi capsules contain a formula based on Buyang Huanwu decoction and is used at the recovery stage of ischemic stroke in China. It was found to decrease infarct volumes and brain edema and improve neurological deficits via anti-inflammatory effects. It protects against BBB disruption by reducing MMP-2/9, VEGF, and HIF-1α [78].

(12) Tongxinluo capsule is a traditional Chinese medicine approved in China in 1996 for stroke treatment. It attenuates BBB disruption by increasing the expression of tight junction proteins (occludin, claudin-5, and ZO-1), decreasing lipoprotein receptor-related protein 1 (LRP-1), restoring AQP4 polarization loss, and activating the sonic hedgehog (Shh) pathway [8,44,66]. In addition, it was found to have an anti-inflammatory effect, reduce apoptosis, and alleviate pyroptosis [66].

(13) Tongfu Xingshen capsule is a traditional Chinese medicine formula developed in China to treat hemorrhagic stroke. It is known to attenuate BBB deficits and cerebral edema and improve neuronal function by increasing brain-derived neurotrophic factors to proliferate the number of natural stem cells and astrocytes in the intracerebral hemorrhage rat model [18].

Herbs (Table 3)

(1) Lycium barbarum is widely used in traditional Chinese medicine and food supplements. It is known to have health-promoting effects and anti-aging effects. L. barbarum polysaccharides account for more than 40% of the Lycium barbarum fruit extract. L. barbarum polysaccharides decreased the infarct volume, water content, and hemispheric swelling, reduced apoptotic cell and oxidative stress, and improved neurological deficits in the MCAO mouse model. In addition, they attenuated BBB breakdown by downregulation of MMP-9 and AQP4 and up-regulation of occludin [76].

(2) Gastrodia elata Blume has long been widely used in traditional Chinese medicine to treat many neurological disorders, including ischemic stroke. Ethyl acetate extracts of G. elata Blume was found to have a protective effect on cerebral ischemia by reducing apoptosis and inhibiting platelet aggregation. In addition, Gastrodia elata Blume in the MCAO rat model was found to reduce the expression of AQP4 and increase the expression of tight junction proteins such as occludin and claudin-5, illustrating its BBB protective effect. Moreover, it has an anti-inflammatory effect by reducing the release of NO and the activity of nitric oxide synthase (NOS) [25].

(3) Kudiezi injection consists of components extracted from Ixeris sonchifolia Hance. I. sonchifolia H. is used in the treatment of angina, coronary artery diseases, and cerebral infarction in traditional Chinese medicine. Kudiezi prevented ischemic brain injury and BBB disruption by enhancing tight junction proteins (ZO-1, claudin-5, and occludin) and JAM-1 and attenuating the expression and activation of caveolin-1 in the MCAO rat model [10]. In addition to animal studies, a study on patients with acute cerebral ischemia also showed that Kudiezi had anti-inflammatory properties and reduced the expression of MMP-9 [45].

(4) Carthamus tinctorius L. has been known to have a protective effect on myocardial ischemia and cerebral ischemia. It was found that C. tinctorius L. reduced infarct volume and neurological damage via decreasing apoptosis in the MCAO rat model. In addition, it alleviates BBB damage by reducing MMP-2/9 expression and increasing TIMP [9].

(5) Cordyceps sinensis is known to have anti-cancer, anti-oxidant, anti-diabetes, anti-aging, and immunomodulative effects and has been used in traditional Chinese medicine for thousands of years. It was found that C. sinensis extract protects the BBB and ischemic brain injury by reducing apoptosis in the oxygen-glucose deprivation (OGD) brain microvascular endothelial cell (BMEC) model and MCAO rat model [2].

(6) Erigeron breviscapus injection consists of E. breviscapus (Vant.) Hand-Mazz. E. breviscapus has long been used by ethnic minorities in China because of its effectiveness in treating heart and liver diseases and activating blood circulation. E. breviscapus injection was found to reduce infarct size and brain edema and improve neurological function in the MCAO rat model by increasing tight junction proteins (claudin-5 and ZO-1) and suppressing MMP-9 activation and iNOS synthesis [43].

Table 3. Traditional Korean medicine herbs targeting the BBB in cerebral ischemia rodent models

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BBB: blood-brain barrier, BMEC: brain microvascular endothelial cell, MCAO: middle cerebral artery occlusion, OGD: oxygen-glucose deprivation, EB: evans blue, ZO-1: zonula occludens-1, AQP4: aquaporin4, MMP-2/9: matrix metalloproteinase-2/9, TIMP: tissue inhibitor of metalloproteinase, JAM-1: junctional adhesion molecules-1, iNOS: inducible nitric oxide synthase.

(7) Uncaria sinensis is a medicinal herb used in traditional Korean medicine for neurological symptoms and high blood pressure. Pretreatment with partially purified components of U. sinensis restored the integrity of the BBB by reducing MMP-9 and increasing tight junction proteins ZO-1 and occludin in a focal cerebral ischemia mouse. In addition to the protective effect on the BBB, it reduced the infarct volume and improved the neurological function in ischemic stroke [60].

(8) Cistanche deserticola is used to invigorate ‘Yang’ in traditional Chinese medicine and is known to mainly act in the kidneys [37]. Total glycosides of C. deserticola reduced brain damage via promoting angiogenesis and decreasing oxidative stress in ischemic stroke. It also attenuated BBB disruption by increasing the expression of tight junction proteins such as ZO-1, claudin, and occludin [67].

Active components (Table 4, Table 5)

(1) Borneol is extracted from the chrysanthemum family and is used in traditional Chinese medicine to treat many brain diseases. D-borneol, L-borneol, and synthetic borneol (DL-borneol) are commonly used [39]. D-borneol, L-borneol, and synthetic borneol were found to reduce cerebral infarction and edema in the MCAO rat model. In addition, it was found that all three types have a preventive effect on BBB damage by increasing the expression of tight junction proteins, claudin-5 [21]. Other experiments showed that borneol preserves BBB integrity by increasing tight junction proteins ZO-1 and TIMP1 and reducing VEGF, MMP-2/9, and AQP4 [15,39,55]. Borneol has also been shown to have anti-inflammatory, anti-apoptosis, and angiogenic effects against ischemic stroke [21].

(2) Scutellarin and 3,5-dicaffeoylquinic acid are the active components of Erigeron breviscapus injection. E. breviscapus injection has been found to reduce the infarct size, improve neurobehaviorals, and protect the BBB via reducing MMP-9 and increasing tight junction proteins such as claudin-5 and ZO-1. In particular, 3,5-dicaffeoylquinic acid was found to be effective in reducing brain edema and significantly increasing claudin-5 [43].

(3) Panax notoginseng saponins are extracted from Panax notoginseng Radix. Furthermore, it is an effective component of Xuesaitong injection used to treat ischemic stroke. It inhibits ROS and prevents the destruction of the BBB by increasing the expression of ZO-1 and claudin-5 [26].

(4) Ginsenoside Rg1 and Ginsenoside Rb1 are major active ingredients of Panax ginseng and Panax notoginseng, which have been widely used in traditional Chinese medicine for a long time. Ginsenoside Rg1 and Ginsenoside Rb1 are known to decrease the infarct volume and BBB disruption and improve neurological deficits [1,41]. Ginsenoside Rg1 decreased AQP4 in the MCAO rat model [82], and Ginsenoside Rb1decreased MMP-9 and prevented the loss of tight junction proteins (occludin and ZO-1) in the MCAO mouse model [14]. In addition, Ginsenoside Rb1 also reported the anti-inflammatory, anti-apoptotic and antioxidant effects in ischemic stroke [73].

(5) Ligustrazine is the main active compound of Ligusticum wallichii Franchat (Chuan Xiong) and Ligusticum chuanxiong Hort. It is also known as 2,3,4,5-tetramethylpyrazine. Chuan Xiong is used in traditional Chinese medicine for cerebral ischemia and cardiovascular disease. Ligustrazine was found to reduce infarct volume, brain edema, neurological deficits, neuroinflammation, and BBB dysfunction in the ischemic brain. It was also found to preserve BBB permeability by increasing tight junction proteins, such as occludin and claudin-5, and reducing MMP-9 expression and activation [30, 62].

(6) Oridonin is a component extracted from a herb called Rabdosia rubescens. It reduced infarct volume, apoptosis, and neuroinflammation in the cerebral ischemia model. In addition, it was found that oridonin protected the BBB by increasing tight junction proteins (ZO-1, claudin-5, and occludin) in both in vivo and in vitro models (tMCAO mouse model and OGD and reperfusion bEND.3 model) [34].

(7) Baicalin is a natural flavonoid component extracted from the roots of Scutellaria baicalensis [12]. S. baicalensis is a widely used herb in traditional Chinese medicine under the name Huang-qin. Baicalin has been reported to have anti-oxidative, anti-thrombotic, anti-apoptosis, and anti-tumor effects on ischemic stroke [40]. Baicalin was found to prevent BBB damage and cerebral edema by reducing MMP-9 and enhancing tight junction protein expression in the ischemic rat [11, 64] and OGD BMEC models [83].

(8) Ruscogenin is an active ingredient found at the root of Ophiopogon japonicus (Thumb.) under the name Ker-Gawl which is a herb used in traditional Chinese medicine. Ruscogenin reduced the infarct volume, brain edema, and neurological deficit by inhibiting NLRP3 inflammasome activation and IL-Iβ and caspase-1 expression in the MCAO mouse model. In addition, it attenuated BBB dysfunction by increasing tight junction proteins such as ZO-1 and occludin in both in vivo and in vitro models [5].

Table 4. Chemical structure and source of the Traditional Korean medicine active components

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(9) Salidroside is a component extracted from a herb called Rhodiola rosea L., which has long been used in traditional Chinese medicine. It has been reported that Salidroside has anti-apoptosis, anti-inflammatory, anti-oxidant, and anti-tumor neuroprotective effects [23, 38]. In addition, Salidroside was found to reduce BBB permeability by decreasing the activation of MMP-9 and increasing claudin-5 and occludin expression in the MCAO rat model [85].

(10) Astragaloside IV is an extraction component of Astragalus radix (Huang Qi). In traditional Chinese medicine, A. radix is used for cerebrovascular diseases, cardiovascular diseases, diabetes, and cancers. Astragaloside IV reduced the infarct volume and brain edema and restored neurological deficits due to its anti-inflammatory, anti-apoptosis, and anti-oxidant effects in ischemic stroke [58, 79]. Astragaloside IV protected BBB permeability by increasing the expression of tight junction proteins (ZO-1 and occludin) [58]. In addition, Cycloastragenol, an active form of Astragaloside IV, reduced MMP-9 and increased the expression of ZO-1 and occludin [36]. In addition to in vivo models, Astragaloside IV and Hydroxysafflor Yellow A inhibited cell death and increased proliferation in vitro in the OGD BMEC model [7].

(11) Notoginseng leaf triterpenes are total saponins extracted from the leaves and stems of Panax notoginseng. P. notoginseng saponins are mainly extracted from the roots of P. notoginseng. Although there are many effective ingredients in the stems and leaves of P. notoginseng, it is not used well. However, it has been found that Notoginseng leaf triterpenes reduced the infarct volume and brain edema and improved neurological function by decreasing apoptosis in ischemic stroke. In addition, Notoginseng leaf triterpenes showed BBB protective effects by decreasing MMP-2/9 expression and inflammation in the MCAO rat model [74].

(12) Methylophiopogonanone A (MO-A) is an isoflavonoid extracted from Opiopogon japonicus. O. japonicus is widely used to treat myocardial ischemia, thrombosis, and hypoxia in traditional Chinese medicine. MO-A reduced infarct volume and brain edema and improved neurological deficit in MCAO rats. In addition, MO-A attenuated BBB permeability by decreasing MMP-9 and increasing tight junction proteins such as claudin-5 and claudin-3. In the in vitro model, MO-A was also found to prevent BBB damage by reducing ROS generation [42].

(13) Levo-tetrahydropalmatine (L-THP) is an active component extracted from the Corydalis genus. L-THP reduced the infarction volume, improved neurological deficits, and attenuated BBB permeability by decreasing the expression of MMP-2/9 and caveolin-1 and attenuating the loss of tight junction proteins (ZO-1, occludin, claudin-5) in the MCAO mouse model [51].

(14) Curculigoside A is an active component extracted from the roots of Curculigo orchioides. C. orchioides is used to restore physical strength in traditional Chinese medicine. As a result of the administration of Curculigoside A to MCAO rats, the infarct volume was significantly reduced, and cerebral damage was alleviated. In addition, Curculigoside A inhibited HMGB1 expression and NF-κB activation associated with inflammatory reactions, reducing BBB breakdown [29].

(15) Shikonin has been known to have anti-inflammatory effects. It reduced the infarct volume and edema and improved neurological deficits by suppressing the pre-inflammatory mediators such as TLR-4 and TNF-α in the tMCAO mice model. In addition, Shikonin maintained the integrity of the BBB by increasing the expression of tight junction Journal of Life Science 2022, Vol. 32. No. 7 5 proteins, claudin-5, and reducing MMP-9 expression [68].

Table 5. Traditional Korean medicine active components targeting the BBB in cerebral ischemia rodent models

SMGHBM_2022_v32n7_550_t0008.png 이미지

BBB: blood-brain barrier, BMEC: brain microvascular endothelial cell, HBMEC: human brain microvascular endothelial cell, NVU: neurovascular unit, MCAO: middle cerebral artery occlusion, pMCAO: permanent middle cerebral artery occlusion, tMCAO: transient middle cerebral artery occlusion, OGD: oxygen-glucose deprivation, EB: evans blue, ZO-1: zonula occludens-1, AQP4: aquaporin4, MMP-2/9: matrix metalloproteinase-2/9, TIMP1: tissue inhibitor of metalloproteinase 1, Alb: albumin, TEER: trans-epithelial electrical resistance, VEGF: vascular endothelial growth factor, iNOS: inducible nitric oxide synthase, FITC-dextran: fluorescein isothiocyanate-dextran, HRP: horseradish peroxidase, SF-absorbance: sodium fluorescein-absorbance, γ-GTP: γ-glutamyl transpeptidase.

(16) Green tea polyphenols are a major active component in green tea and widely used in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Green tea polyphenols showed the effect of attenuating the disruption of the BBB via increasing the expression of tight junction proteins ZO-1, occludin, and claudin-5 in the MCAO rat model [46].

(17) The lyophilized powder of Catalpol and Puerarin are two active components extracted from the traditional Chinese medicine herbs, Rehmannia glutinosa Libosch and Radix Puerariae. Catalpol and Puerarin were found to reduce the infarct volume and neurological deficiency by attenuating apoptosis, oxidative stress, and inflammation in both in vivo and in vitro cerebral ischemia models. In addition, they protected BBB integrity by increasing the expression of the claudin-5 in vitro model [75].

Conclusion and future perspectives

Ischemic stroke elicits BBB disruption that aggravates inflammation and generates neurotoxicity in the damaged site, resulting in neuron cell death. Therefore, new treatments targeting the protection and restoration of the BBB are needed to help protect tissue injury from increasing in the setting of ischemic stroke. Traditional Korean medicine has been recorded in the treatment of neurovascular disorders. This review has presented several traditional Korean medicines, including the herbal formula, decoction, herbs, and active components, which exert a neuroprotective effect on cerebral ischemia-induced BBB disruption. These traditional medicines were shown to have protective effects on the BBB in many cellular ischemia models such as OGD and hypoxia, various animal ischemia models of stroke such as MCAO and photothrombosis, and experiments in various animal species such as mice and rats. In addition, they showed brain-protective effects by protecting the BBB through regulation of tight junction proteins (ZO-1, occludin, and claudin-5) and MMP-9, reducing edema, neuroinflammation, and neuronal cell death. However, there are also several limitations to the existing studies that have focused on the neuroprotective effects of traditional Korean medicines on BBB dysfunction after ischemic stroke. Many traditional Korean medicines were found to exert a neuroprotective effect on ischemia-induced BBB disruption using rodent models, which differ greatly from human patients. Therefore, we hope that this review will stimulate the performance of clinical trials of Korean herbal medicine-derived drugs in patients with stroke.

Acknowledgment

This work was supported by a 2-Year Research Grant of Pusan National University.

The Conflict of Interest Statement

The authors declare that they have no conflicts of interest with the contents of this article.

참고문헌

  1. Ahmed, T., Raza, S. H., Maryam, A., Setzer, W. N., Braidy, N., Nabavi, S. F., de Oliveira, M. R. and Nabavi, S. M. 2016. Ginsenoside Rb1 as a neuroprotective agent: A review. Brain Res. Bull. 125, 30-43. https://doi.org/10.1016/j.brainresbull.2016.04.002
  2. Bai, X., Tan, T. Y., Li, Y. X., Li, Y., Chen, Y. F., Ma, R., Wang, S. Y., Li, Q. and Liu, Z. Q. 2020. The protective effect of cordyceps sinensis extract on cerebral ischemic injury via modulating the mitochondrial respiratory chain and inhibiting the mitochondrial apoptotic pathway. Biomed. Pharmacother. 124, 109834. https://doi.org/10.1016/j.biopha.2020.109834
  3. Ballabh, P., Braun, A. and Nedergaard, M. 2004. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol. Dis. 16, 1-13. https://doi.org/10.1016/j.nbd.2003.12.016
  4. Boehme, A. K., Esenwa, C. and Elkind, M. S. 2017. Stroke risk factors, genetics, and prevention. Circ. Res. 120, 472-495. https://doi.org/10.1161/CIRCRESAHA.116.308398
  5. Cao, G., Jiang, N., Hu, Y., Zhang, Y., Wang, G., Yin, M., Ma, X., Zhou, K., Qi, J., Yu, B. and Kou, J. 2016. Ruscogenin attenuates cerebral ischemia-induced Blood-Brain Barrier dysfunction by suppressing TXNIP/NLRP3 inflammasome activation and the MAPK pathway. Int. J. Mol. Sci. 17, 1418. https://doi.org/10.3390/ijms17091418
  6. Cao, G., Ye, X., Xu, Y., Yin, M., Chen, H., Kou, J. and Yu, B. 2016. YiQiFuMai powder injection ameliorates blood-brain barrier dysfunction and brain edema after focal cerebral ischemia-reperfusion injury in mice. Drug Des. Devel. Ther. 10, 315-325.
  7. Cao, J., Wang, K., Lei, L., Bai, L., Liang, R., Qiao, Y., Duan, J., Gao, K., Cao, S., Zhao, C. and Yang, Z. 2020. Astragaloside and/or Hydroxysafflor Yellow A attenuates Oxygen-Glucose deprivation-induced cultured brain microvessel endothelial cell death through downregulation of PHLPP-1. Evid. Based Complement. Alternat. Med. 2020, 3597527.
  8. Chang, L., Hu, L., Wei, C., Zhang, H. and Liu, S. 2020. Chinese medicine Tongxinluo capsule protects against blood-brain barrier disruption after ischemic stroke by inhibiting the low-density lipoprotein receptor-related protein 1 pathway in mice. J. Stroke Cerebrovasc. Dis. 29, 105071. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105071
  9. Chang, L. L., Li, C., Li, Z. L., Wei, Z. L., Jia, X. B., Pang, S. T., An, Y. Q., Gu, J. F. and Feng, L. 2020. Carthamus tinctorius L. Extract ameliorates cerebral ischemia-reperfusion injury in rats by regulating matrix metalloproteinases and apoptosis. Indian J. Pharmacol. 52, 108-116. https://doi.org/10.4103/ijp.IJP_400_18
  10. Chen, F. Q., Li, Q., Pan, C. S., Liu, Y. Y., Yan, L., Sun, K., Mao, X. W., Mu, H. N., Wang, M. X., Wang, C. S., Fan, J. Y., Cui, Y. C., Zhang, Y. P., Yang, J. Y., Bai, W. and Han, J. Y. 2016. Kudiezi Injection(®) alleviates blood-brain barrier disruption after ischemia-reperfusion in rats. Microcirculation 23, 426-437. https://doi.org/10.1111/micc.12288
  11. Chen, H., Guan, B., Chen, X., Chen, X., Li, C., Qiu, J., Yang, D., Liu, K. J., Qi, S. and Shen, J. 2018. Baicalin attenuates Blood-Brain Barrier disruption and hemorrhagic transformation and improves neurological outcome in ischemic stroke rats with delayed t-PA treatment: Involvement of ONOO(-)-MMP-9 pathway. Transl. Stroke Res. 9, 515-529. https://doi.org/10.1007/s12975-017-0598-3
  12. Chen, H., He, Y., Chen, S., Qi, S. and Shen, J. 2020. Therapeutic targets of oxidative/nitrosative stress and neuroinflammation in ischemic stroke: Applications for natural product efficacy with omics and systemic biology. Pharmacol. Res. 158, 104877. https://doi.org/10.1016/j.phrs.2020.104877
  13. Chen, H. J., Shen, Y. C., Shiao, Y. J., Liou, K. T., Hsu, W. H., Hsieh, P. H., Lee, C. Y., Chen, Y. R. and Lin, Y. L. 2015. Multiplex brain proteomic analysis revealed the molecular therapeutic effects of Buyang Huanwu Decoction on cerebral ischemic stroke mice. PLoS One 10, e0140823. https://doi.org/10.1371/journal.pone.0140823
  14. Chen, W., Guo, Y., Yang, W., Zheng, P., Zeng, J. and Tong, W. 2015. Protective effect of ginsenoside Rb1 on integrity of blood-brain barrier following cerebral ischemia. Exp. Brain. Res. 233, 2823-2831. https://doi.org/10.1007/s00221-015-4352-3
  15. Chen, Z. X., Xu, Q. Q., Shan, C. S., Shi, Y. H., Wang, Y., Chang, R. C. and Zheng, G. Q. 2019. Borneol for regulating the permeability of the Blood-Brain Barrier in experimental ischemic stroke: Preclinical evidence and possible mechanism. Oxid. Med. Cell. Longev. 2019, 2936737. https://doi.org/10.1155/2019/2936737
  16. Choi, M. J., Choi, B. T., Shin, H. K., Shin, B. C., Han, Y. K. and Baek, J. U. 2015. Establishment of a comprehensive list of candidate antiaging medicinal herb used in Korean Medicine by text mining of the classical Korean Medical literature, "Dongeuibogam," and preliminary evaluation of the antiaging effects of these herbs. Evid. Based Complement. Alternat. Med. 2015, 873185.
  17. Colombo, E. and Farina, C. 2016. Astrocytes: Key regulators of neuroinflammation. Trends Immunol. 37, 608-620. https://doi.org/10.1016/j.it.2016.06.006
  18. Cui, Z., Liu, S., Hou, L., Sun, Y., Chen, H., Mao, H., Zhao, Y. and Qiao, L. 2021. Effect of Tongfu Xingshen capsule on the endogenous neural stem cells of experimental rats with intracerebral hemorrhage. Mol. Med. Report. 24, 624. https://doi.org/10.3892/mmr.2021.12263
  19. Daneman, R. and Prat, A. 2015. The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 7, a020412. https://doi.org/10.1101/cshperspect.a020412
  20. Daneman, R., Zhou, L., Kebede, A. A. and Barres, B. A. 2010. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562-566. https://doi.org/10.1038/nature09513
  21. Dong, T., Chen, N., Ma, X., Wang, J., Wen, J., Xie, Q. and Ma, R. 2018. The protective roles of L-borneolum, D-borneolum and synthetic borneol in cerebral ischaemia via modulation of the neurovascular unit. Biomed. Pharmacother. 102, 874-883. https://doi.org/10.1016/j.biopha.2018.03.087
  22. Dou, B., Zhou, W., Li, S., Wang, L., Wu, X., Li, Y., Guan, H., Wang, C., Zhu, S., Ke, Z., Huang, C. and Wang, Z. 2018. Buyang Huanwu Decoction attenuates infiltration of Natural Killer cells and protects against ischemic brain injury. Cell. Physiol. Biochem. 50, 1286-1300. https://doi.org/10.1159/000494587
  23. Fan, F., Yang, L., Li, R., Zou, X., Li, N., Meng, X., Zhang, Y. and Wang, X. 2020. Salidroside as a potential neuroprotective agent for ischemic stroke: a review of sources, pharmacokinetics, mechanism and safety. Biomed. Pharmacother. 129, 110458. https://doi.org/10.1016/j.biopha.2020.110458
  24. Forster, A., Brown, L., Smith, J., House, A., Knapp, P., Wright, J. J. and Young, J. 2012. Information provision for stroke patients and their caregivers. Cochrane Database Syst. Rev. 11, Cd001919.
  25. He, F., Duan, X., Dai, R., Wang, W., Yang, C. and Lin, Q. 2016. Protective effects of ethyl acetate extraction from Gastrodia elata blume on blood-brain barrier in focal cerebral ischemia reperfusion. Afr. J. Tradit. Complement. Altern. Med. 13, 199-209. https://doi.org/10.21010/ajtcam.v13i2.24
  26. Hu, S., Wu, Y., Zhao, B., Hu, H., Zhu, B., Sun, Z., Li, P. and Du, S. 2018. Panax notoginseng Saponins protect cerebral microvascular endothelial cells against oxygenglucose deprivation/reperfusion-induced barrier dysfunction via activation of PI3K/Akt/Nrf2 antioxidant signaling pathway. Molecules 23, 2781. https://doi.org/10.3390/molecules23112781
  27. Hughes, R. E., Tadi, P. and Bollu, P. C. 2022. TPA Therapy, StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.: Treasure Island (FL).
  28. Ishida, H., Takemori, K., Dote, K. and Ito, H. 2006. Expression of glucose transporter-1 and aquaporin-4 in the cerebral cortex of stroke-prone spontaneously hypertensive rats in relation to the blood-brain barrier function. Am. J. Hypertens. 19, 33-39. https://doi.org/10.1016/j.amjhyper.2005.06.023
  29. Jiang, W., Fu, F., Tian, J., Zhu, H. and Hou, J. 2011. Curculigoside A attenuates experimental cerebral ischemia injury in vitro and vivo. Neuroscience 192, 572-579. https://doi.org/10.1016/j.neuroscience.2011.06.079
  30. Jin, Z., Liang, J. and Kolattukudy, P. E. 2021. Tetramethylpyrazine preserves the integrity of Blood-Brain Barrier associated with upregulation of MCPIP1 in a murine model of focal ischemic stroke. Front. Pharmacol. 12, 710358. https://doi.org/10.3389/fphar.2021.710358
  31. Kim, M. J., Lee, S. Y., Hwang, J. Y., Kim, H., Ha, K. T., Choi, B. T., Baek, J. U. and Shin, H. K. 2018. Pretreatment with Shuanghe-Tang Extract attenuates postischemic brain injury and edema in a mouse model of stroke: An analysis of medicinal herbs listed in Dongui Bogam. Oxid. Med. Cell. Longev. 2018, 2479602.
  32. Kim, M. J., Park, K. H., Lee, J. Y., Ha, K. T., Choi, B. T., Baek, J. U., Yun, Y. J., Lee, S. Y. and Shin, H. K. 2019. Weisheng-Tang ameliorates acute ishemic brain damage in mice by maintaining Blood-Brain Barrier integrity. Oxid. Med. Cell. Longev. 2019, 4379732.
  33. Koehn, F. E. and Carter, G. T. 2005. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 4, 206-220. https://doi.org/10.1038/nrd1657
  34. Li, L., Cheng, S. Q., Guo, W., Cai, Z. Y., Sun, Y. Q., Huang, X. X., Yang, J., Ji, J., Chen, Y. Y., Dong, Y. F., Cheng, H. and Sun, X. L. 2021. Oridonin prevents oxidative stress-induced endothelial injury via promoting Nrf-2 pathway in ischaemic stroke. J. Cell. Mol. Med. 25, 9753-9766. https://doi.org/10.1111/jcmm.16923
  35. Li, L., Wang, N., Jin, Q., Wu, Q., Liu, Y. and Wang, Y. 2017. Protection of Tong-Qiao-Huo-Xue Decoction against cerebral ischemic injury through reduction Blood-Brain Barrier permeability. Chem. Pharm. Bull (Tokyo). 65, 1004-1010. https://doi.org/10.1248/cpb.c17-00267
  36. Li, M., Li, S. C., Dou, B. K., Zou, Y. X., Han, H. Z., Liu, D. X., Ke, Z. J. and Wang, Z. F. 2020. Cycloastragenol upregulates SIRT1 expression, attenuates apoptosis and suppresses neuroinflammation after brain ischemia. Acta Pharmacol. Sin. 41, 1025-1032. https://doi.org/10.1038/s41401-020-0386-6
  37. Li, N., Wang, J., Ma, J., Gu, Z., Jiang, C., Yu, L. and Fu, X. 2015. Neuroprotective effects of Cistanches Herba therapy on patients with moderate Alzheimer's disease. Evid. Based Complement. Alternat. Med. 2015, 103985.
  38. Li, Y., Cai, M., Mao, G. X., Shu, Q. F., Liu, X. B. and Liu, X. L. 2021. Preclinical evidence and possible mechanisms of Rhodiola rosea L. and its components for ischemic stroke: A systematic review and meta-analysis. Front. Pharmacol. 12, 736198. https://doi.org/10.3389/fphar.2021.736198
  39. Li, Y., Ren, M., Wang, J., Ma, R., Chen, H., Xie, Q., Li, H., Li, J. and Wang, J. 2021. Progress in Borneol intervention for ischemic stroke: A systematic review. Front. Pharmacol. 12, 606682. https://doi.org/10.3389/fphar.2021.606682
  40. Liang, W., Huang, X. and Chen, W. 2017. The effects of Baicalin and Baicalein on cerebral ischemia: A review. Aging Dis. 8, 850-867. https://doi.org/10.14336/AD.2017.0829
  41. Lin, M., Sun, W., Gong, W., Ding, Y., Zhuang, Y. and Hou, Q. 2015. Ginsenoside Rg1 protects against transient focal cerebral ischemic injury and suppresses its systemic metabolic changes in cerabral injury rats. Acta Pharmacol. Sin. 5, 277-284. https://doi.org/10.1016/j.apsb.2015.02.001
  42. Lin, M., Sun, W., Gong, W., Zhou, Z., Ding, Y. and Hou, Q. 2015. Methylophiopogonanone A protects against cerebral ischemia/reperfusion injury and attenuates Blood-Brain Barrier disruption in vitro. PLoS One 10, e0124558. https://doi.org/10.1371/journal.pone.0124558
  43. Liu, G., Liang, Y., Xu, M., Sun, M., Sun, W., Zhou, Y., Huang, X., Song, W., Liang, Y. and Wang, Z. 2021. Protective mechanism of Erigeron breviscapus injection on blood-brain barrier injury induced by cerebral ischemia in rats. Sci. Rep. 11, 18451. https://doi.org/10.1038/s41598-021-97908-x
  44. Liu, S., Chang, L. and Wei, C. 2019. The sonic hedgehog pathway mediates Tongxinluo capsule-induced protection against blood-brain barrier disruption after ischaemic stroke in mice. Basic Clin. Pharmacol. Toxicol. 124, 660-669. https://doi.org/10.1111/bcpt.13186
  45. Liu, X., Jin, X., Chen, B., Liu, X., Liang, X., Fang, X., Wu, H., Fu, X., Zheng, H., Ding, X., Duan, N. and Zhang, Y. 2018. Effects of Kudiezi Injection on serum inflammatory biomarkers in patients with acute cerebral infarction. Dis. Markers. 2018, 7936736.
  46. Liu, X., Wang, Z., Wang, P., Yu, B., Liu, Y. and Xue, Y. 2013. Green tea polyphenols alleviate early BBB damage during experimental focal cerebral ischemia through regulating tight junctions and PKCalpha signaling. BMC Complement. Altern. Med. 13, 187. https://doi.org/10.1186/1472-6882-13-187
  47. Liu, Z. and Chopp, M. 2016. Astrocytes, therapeutic targets for neuroprotection and neurorestoration in ischemic stroke. Prog. Neurobiol. 144, 103-120. https://doi.org/10.1016/j.pneurobio.2015.09.008
  48. Lv, L., Liu, Y., Shi, H. F. and Dong, Q. 2009. Qingkailing injection attenuates apoptosis and neurologic deficits in a rat model of intracerebral hemorrhage. J. Ethnopharmacol. 125, 269-273. https://doi.org/10.1016/j.jep.2009.06.031
  49. Ma, C., Wang, X., Xu, T., Yu, X., Zhang, S., Liu, S., Gao, Y., Fan, S., Li, C., Zhai, C., Cheng, F. and Wang, Q. 2019. Qingkailing injection ameliorates cerebral ischemia-reperfusion injury and modulates the AMPK/NLRP3 inflammasome signalling pathway. BMC Complement. Altern. Med. 19, 320. https://doi.org/10.1186/s12906-019-2703-5
  50. Ma, C., Wang, X., Xu, T., Zhang, S., Liu, S., Zhai, C., Wang, Z., Mu, J., Li, C., Cheng, F. and Wang, Q. 2020. An integrative pharmacology-based analysis of refined Qingkailing Injection against cerebral ischemic stroke: A novel combination of Baicalin, Geniposide, Cholic Acid, and Hyodeoxycholic Acid. Front. Pharmacol. 11, 519. https://doi.org/10.3389/fphar.2020.00519
  51. Mao, X. W., Pan, C. S., Huang, P., Liu, Y. Y., Wang, C. S., Yan, L., Hu, B. H., Chang, X., He, K., Mu, H. N., Li, Q., Sun, K., Fan, J. Y. and Han, J. Y. 2015. Levo-tetrahydropalmatine attenuates mouse blood-brain barrier injury induced by focal cerebral ischemia and reperfusion: Involvement of Src kinase. Sci. Rep. 5, 11155. https://doi.org/10.1038/srep11155
  52. May, B. H., Lu, C., Bennett, L., Hugel, H. M. and Xue, C. C. 2012. Evaluating the traditional Chinese literature for herbal formulae and individual herbs used for age-related dementia and memory impairment. Biogerontology 13, 299-312. https://doi.org/10.1007/s10522-012-9375-6
  53. Michinaga, S. and Koyama, Y. 2015. Pathogenesis of brain edema and investigation into anti-edema drugs. Int. J. Mol. Sci. 16, 9949-9975. https://doi.org/10.3390/ijms16059949
  54. Nakagomi, T., Kubo, S., Nakano-Doi, A., Sakuma, R., Lu, S., Narita, A., Kawahara, M., Taguchi, A. and Matsuyama, T. 2015. Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells. Stem Cells 33, 1962-1974. https://doi.org/10.1002/stem.1977
  55. Ni, C., Zeng, N., Xu, F., Gou, L., Liu, J., Wang, J. and Xia, H. 2011. Effects of aromatic resuscitation drugs on blood brain barrier in cerebral ischemia-reperfusion injury model rats. Zhongguo Zhong Yao Za Zhi 36, 2562-2566.
  56. Nour, M., Scalzo, F. and Liebeskind, D. S. 2013. Ischemiareperfusion injury in stroke. J. Vasc. Interv. Neurol. 1, 185-199.
  57. Park, M. Y., Jung, Y. S., Park, J. H., Choi, Y. W., Lee, J., Kim, C. M., Baek, J. U., Choi, B. T. and Shin, H. K. 2015. PMC-12, a prescription of Traditional Korean Medicine, improves Amyloid β-Induced cognitive deficits through modulation of neuroinflammation. Evid. Based Complement. Alternat. Med. 2015, 768049.
  58. Qu, Y. Z., Li, M., Zhao, Y. L., Zhao, Z. W., Wei, X. Y., Liu, J. P., Gao, L. and Gao, G. D. 2009. Astragaloside IV attenuates cerebral ischemia-reperfusion-induced increase in permeability of the blood-brain barrier in rats. Eur. J. Pharmacol. 606, 137-141. https://doi.org/10.1016/j.ejphar.2009.01.022
  59. Rosell, A. and Lo, E. H. 2008. Multiphasic roles for matrix metalloproteinases after stroke. Curr. Opin. Pharmacol. 8, 82-89. https://doi.org/10.1016/j.coph.2007.12.001
  60. Seo, H. B., Kang, B. K., Kim, J. H., Choi, Y. W., Hong, J. W., Choi, B. T. and Shin, H. K. 2015. Partially purified components of Uncaria sinensis attenuate blood brain barrier disruption after ischemic brain injury in mice. BMC Complement. Altern. Med. 15, 157. https://doi.org/10.1186/s12906-015-0678-4
  61. Sun, Z. Y., Wang, F. J., Guo, H., Chen, L., Chai, L. J., Li, R. L., Hu, L. M., Wang, H. and Wang, S. X. 2019. Shuxuetong injection protects cerebral microvascular endothelial cells against oxygen-glucose deprivation reperfusion. Neural Regen. Res. 14, 783-793. https://doi.org/10.4103/1673-5374.249226
  62. Tan, F., Fu, W., Cheng, N., Meng, D. I. and Gu, Y. 2015. Ligustrazine reduces blood-brain barrier permeability in a rat model of focal cerebral ischemia and reperfusion. Exp. Ther. Med. 9, 1757-1762. https://doi.org/10.3892/etm.2015.2365
  63. Tsoi, B., Chen, X., Gao, C., Wang, S., Yuen, S. C., Yang, D. and Shen, J. 2019. Neuroprotective effects and hepatorenal toxicity of Angong Niuhuang Wan against ischemia-reperfusion brain injury in rats. Front. Pharmacol. 10, 593. https://doi.org/10.3389/fphar.2019.00593
  64. Tu, X. K., Yang, W. Z., Liang, R. S., Shi, S. S., Chen, J. P., Chen, C. M., Wang, C. H., Xie, H. S., Chen, Y. and Ouyang, L. Q. 2011. Effect of baicalin on matrix metalloproteinase-9 expression and blood-brain barrier permeability following focal cerebral ischemia in rats. Neurochem. Res. 36, 2022-2028. https://doi.org/10.1007/s11064-011-0526-y
  65. Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Delling, F. N., Djousse, L., Elkind, M. S. V., Ferguson, J. F., Fornage, M., Khan, S. S., Kissela, B. M., Knutson, K. L., Kwan, T. W., Lackland, D. T., Lewis, T. T., Lichtman, J. H., Longenecker, C. T., Loop, M. S., Lutsey, P. L., Martin, S. S., Matsushita, K., Moran, A. E., Mussolino, M. E., Perak, A. M., Rosamond, W. D., Roth, G. A., Sampson, U. K. A., Satou, G. M., Schroeder, E. B., Shah, S. H., Shay, C. M., Spartano, N. L., Stokes, A., Tirschwell, D. L., VanWagner, L. B. and Tsao, C. W. 2020. Heart disease and stroke statistics-2020 update: A report from the American Heart Association. Circulation 141, e139-e596.
  66. Wang, B., Lyu, Z., Chan, Y., Li, Q., Zhang, L., Liu, K., Li, Y. and Yu, Z. 2021. Tongxinluo exerts inhibitory effects on pyroptosis and amyloid-β peptide accumulation after cerebral ischemia/reperfusion in rats. Evid. Based Complement. Alternat. Med. 2021, 5788602.
  67. Wang, F., Li, R., Tu, P., Chen, J., Zeng, K. and Jiang, Y. 2020. Total glycosides of Cistanche deserticola promote neurological function recovery by inducing neurovascular regeneration via Nrf-2/Keap-1 pathway in MCAO/R rats. Front. Pharmacol. 11, 236. https://doi.org/10.3389/fphar.2020.00236
  68. Wang, L., Li, Z., Zhang, X., Wang, S., Zhu, C., Miao, J., Chen, L., Cui, L. and Qiao, H. 2014. Protective effect of shikonin in experimental ischemic stroke: attenuated TLR4, p-p38MAPK, NF-κB, TNF-α and MMP-9 expression, up-regulated claudin-5 expression, ameliorated BBB permeability. Neurochem. Res. 39, 97-106. https://doi.org/10.1007/s11064-013-1194-x
  69. Wang, S., Guo, H., Wang, X., Chai, L., Hu, L., Zhao, T., Zhao, B., Tan, X. and Jia, F. 2014. Pretreatment with Danhong injection protects the brain against ischemia-reperfusion injury. Neural Regen. Res. 9, 1453-1459. https://doi.org/10.4103/1673-5374.139462
  70. Wolburg, H. and Lippoldt, A. 2002. Tight junctions of the blood-brain barrier: development, composition and regulation. Vascul. Pharmacol. 38, 323-337. https://doi.org/10.1016/S1537-1891(02)00200-8
  71. Woodruff, T. M., Thundyil, J., Tang, S.-C., Sobey, C. G., Taylor, S. M. and Arumugam, T. V. 2011. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol. Neurodegener. 6, 11. https://doi.org/10.1186/1750-1326-6-11
  72. Wu, S. P., Wang, N. and Zhao, L. 2020. Network pharmacology reveals the mechanism of activity of Tongqiao Huoxue Decoction extract against middle cerebral artery occlusion-induced cerebral ischemia-reperfusion injury. Front. Pharmacol. 11, 572624.
  73. Xie, W., Wang, X., Xiao, T., Cao, Y., Wu, Y., Yang, D. and Zhang, S. 2021. Protective effects and network analysis of Ginsenoside Rb1 against cerebral ischemia injury: A pharmacological review. Front. Pharmacol. 12, 604811. https://doi.org/10.3389/fphar.2021.604811
  74. Xie, W., Zhu, T., Dong, X., Nan, F., Meng, X., Zhou, P., Sun, G. and Sun, X. 2019. HMGB1-triggered inflammation inhibition of notoginseng leaf triterpenes against cerebral ischemia and reperfusion injury via MAPK and NF-κB signaling pathways. Biomolecules 9, 512. https://doi.org/10.3390/biom9100512
  75. Xue, Q., Liu, Y., He, R., Yang, S., Tong, J., Li, X., Chen, Y. and Xu, X. 2016. Lyophilized powder of Catalpol and Puerarin protects neurovascular unit from stroke. Int. J. Biol. Sci. 12, 367-380. https://doi.org/10.7150/ijbs.14059
  76. Yang, D., Li, S. Y., Yeung, C. M., Chang, R. C., So, K. F., Wong, D. and Lo, A. C. 2012. Lycium barbarum extracts protect the brain from blood-brain barrier disruption and cerebral edema in experimental stroke. PLoS One 7, e33596. https://doi.org/10.1371/journal.pone.0033596
  77. Yang, P., Tian, Y. M., Deng, W. X., Cai, X., Liu, W. H., Li, L. and Huang, H. Y. 2019. Sijunzi decoction may decrease apoptosis via stabilization of the extracellular matrix following cerebral ischaemia-reperfusion in rats. Exp. Ther. Med. 18, 2805-2812.
  78. Yang, W., Zhang, L., Chen, S., Yao, Q., Chen, H., Zhou, J., Chen, W., He, L. and Zhang, Y. 2020. Longshengzhi Capsules improve ischemic stroke outcomes and reperfusion injury via the promotion of anti-inflammatory and neuroprotective effects in MCAO/R rats. Evid. Based Complement. Alternat. Med. 2020, 9654175.
  79. Yin, Y. Y., Li, W. P., Gong, H. L., Zhu, F. F., Li, W. Z. and Wu, G. C. 2010. Protective effect of astragaloside on focal cerebral ischemia/reperfusion injury in rats. Am. J. Chin. Med. 38, 517-527. https://doi.org/10.1142/S0192415X10008020
  80. Zeng, M., Zhou, H., He, Y., Du, H., Yin, J., Hou, Y., Zhu, J., Zhang, Y., Shao, C., Yang, J. and Wan, H. 2021. Danhong injection enhances the therapeutic effect of mannitol on hemispheric ischemic stroke by ameliorating bloodbrain barrier disruption. Biomed. Pharmacother. 142, 112048. https://doi.org/10.1016/j.biopha.2021.112048
  81. Zhang, S., Wang, X., Cheng, F., Ma, C., Fan, S., Xu, W., Jin, N., Liu, S., Lv, K. and Wang, Q. 2020. Network pharmacology-based approach to revealing biological mechanisms of qingkailing injection against ischemicstroke: focusing on blood-brain barrier. Evid. Based Complement. Alternat. Med. 2020, 2914579.
  82. Zhou, Y., Li, H. Q., Lu, L., Fu, D. L., Liu, A. J., Li, J. H. and Zheng, G. Q. 2014. Ginsenoside Rg1 provides neuroprotection against blood brain barrier disruption and neurological injury in a rat model of cerebral ischemia/reperfusion through downregulation of aquaporin 4 expression. Phytomedicine 21, 998-1003. https://doi.org/10.1016/j.phymed.2013.12.005
  83. Zhu, H., Wang, Z., Xing, Y., Gao, Y., Ma, T., Lou, L., Lou, J., Gao, Y., Wang, S. and Wang, Y. 2012. Baicalin reduces the permeability of the blood-brain barrier during hypoxia in vitro by increasing the expression of tight junction proteins in brain microvascular endothelial cells. J. Ethnopharmacol. 141, 714-720. https://doi.org/10.1016/j.jep.2011.08.063
  84. Zivin, J. A. 2009. Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA). Ann. Neurol. 66, 6-10. https://doi.org/10.1002/ana.21750
  85. Zuo, W., Yan, F., Zhang, B., Hu, X. and Mei, D. 2018. Salidroside improves brain ischemic injury by activating PI3K/Akt pathway and reduces complications induced by delayed tPA treatment. Eur. J. Pharmacol. 830, 128-138. https://doi.org/10.1016/j.ejphar.2018.04.001