Neuroprotective Herbs for Stroke

Natural Synergy

Traditional Chinese Medicine

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Hocheol Kim

Abstract In recent years, many attempts have been made to document research data from extracts of composite formulas, single herbs, or single compounds from traditional Eastern medicine (TEM) herbs, according to orthodox pharmacological actions. Basic and clinical research in TEM constitutes an abundant source of new drug discovery and development with the integration of TEM and Western pharmacology. This article reviews herbs that have been documented to have a neuropro-tective effect in in vitro and in vivo ischemic model systems and the neuroprotective compounds isolated from them. The neuroprotective mechanisms of herbs and single compounds relevant to the treatment of brain ischemia, including antioxidant, antiexcitotoxic, and anti-inflammatory effects were also discussed.

Keywords Cerebral ischemia • Herbs • Neuroprotection • Traditional medicine • Stroke

Abbreviations

4-VO

4-vessel occlusion

BCAo

Bilateral common carotid artery occlusion

CAT

Catalase

CCA

Common carotid artery

CNS

Central nervous system

COX-2

Cyclooxygenase-2

DPPH

2,2-diphenyl-1-picrylhydrazyl,

(-)-EGCG

(-)-epigallocatechin gallate

GABA

Gamma-aminobutyric acid

GCRP

Calcitonin gene-related peptide

GPX

Glutathione peroxidase

Department of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Korea e-mail: [email protected]

Department of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Korea e-mail: [email protected]

K.G. Ramawat (ed.), Herbal Drugs: Ethnomedicine to Modern Medicine, DOI 10.1007/978-3-540-79116-4_16, © Springer-Verlag Berlin Heidelberg 2009

GSH-Px

Glutathione peroxidase

GSH

Glutathione

IFN-y

Interferon 7

IL-1ß

Interleukin ß

iNOS

Inducible nitric oxcide synthase

KA

Kainic acid

LPS

Lipopolysaccharide

MDA

Malondialdehyde

NMDA

N-methyl-D-aspartate

NO

Nitric oxide

NR2B

NMDA receptor 2B

OGD

Deprivation of oxygen and glucose

PGE2

Prostaglandin E2

PGI2

Prostaglandin I2

PTK

Protein tyrosine kinase

rt-PA

Recombinant tissue-plasminogen activator

SD

Sprague-Dawley

SOD

Superoxide dismutase

TBARS

Thiobarbiturate reactive substances

TCM

Traditional Chinese medicine

TEM

Traditional Eastern medicine

tMCAo

Transient middle carotid artery occlusion

TNF-a

Tumor necrosis factor a

TXA2

Tromboxane A2

VCAM-1

Vascular cell adhesion molecule-1

VEGF

Vascular endothelial growth factor

VIP

Vasoactive intestinal peptide

16.1 Introduction

Stroke is the third leading cause of death in industrialized countries, followed by cancer and heart attack. It is a major cause of permanent disability for which there is currently no effective treatment. Most strokes (80%) are ischemic and the majority of ischemic strokes result from occlusion of a major cerebral artery by thrombus or embolism, which leads to loss of blood flow in a specific region. The remaining strokes are hemorrhagic, where a blood vessel bursts either in the brain or on its surface [1].

Two major approaches have been developed in ischemic stroke. The first is to establish reperfusion by dissolution of the clot using thrombolytic drugs. At present, rt-PA is the only thrombolytic drug approved for the treatment of acute ischemic stroke; rt-PA administration is restricted to within 3 h of stroke and its use increases the risk of hemorrhagic transformation [2].

The second approach is to develop neuroprotective agents that interfere with the biochemical cascade of events that leads to cell death in the penumbra area that surrounds the core. This protection would attenuate lots of the clinical problems of stroke, including motor disability and spatial hemiplegia. However, although more than 37 potential neuroprotective agents have been studied in more than 114 clinical trials [3], none of them is clinically efficacious and in use in the Western world [4].

In Far Eastern countries such as Korea, China, and Japan, stroke has been treated by traditional Eastern medicine (TEM) for thousands of years. TEM is also known as traditional Chinese medicine (TCM), traditional Korean medicine, Sino-Japanese medicine, oriental medicine, traditional herbal medicine, and traditional Asian medicine. In China, traditional medicine is prevalent; approximately one third of patients are treated with traditional medicine [5], and in Korea, 25% of stroke patients also visit traditional medicine doctors [6].

Extensive experience and abundant clinical data on stroke treatment have been accumulated on TEM. Basic and clinical research in TEM constitutes a potentially rich source of drug discovery and development with the integration of TEM and western pharmacology. In recent years, many attempts have been made to document research data about extracts of composite formulas, single herbs, or single compounds from TEM herbs according to orthodox pharmacological actions. Groups of TEM herbs have been identified as potential sources for compounds with predominant effects on the circulation, thrombogenesis, inflammatory processes, and neuroprotection.

This chapter reviews herbs and prescriptions that have been screened for neuroprotective effects in in vitro and in vivo ischemic model systems and the neu-roprotective compounds isolated from them. Neuroprotective mechanisms of prescriptions, herbs, and single compounds relevant to the treatment of brain ischemia, including antioxidant, antiexcitotoxic, and anti-inflammatory effects are also discussed.

16.2 Stroke Therapy in Traditional Medicine

Stroke is the first of the four major serious syndromes and the most acute disease in TEM. Stroke in TEM is called 'wind stroke' because it happens abruptly like the wind. The concept of stroke in TEM is quite different in many ways from that held by western medicine. The syndrome is characterized by the sudden appearance of hemiplegia, deviated eyes and mouth, and impeded speech that may or may not start with sudden loss of consciousness.

The theoretical systems of TEM are based on the doctrines of yin and yang, the five elements, viscera, and meridian systems. Gong and Sucher nicely reviewed the basic principles and classification of wind stroke in TEM [7]. Generally, the disease state is considered mainly as a destruction of the harmonious components of yin and yang. Wind stroke is considered to be caused either by weak internal strength (so-called 'qi') invaded by strong external 'bad wind' or by excessive internal 'fire', such as anger, fatigue, heavy drinking, or dietary problems. Both can violate the harmonious negative-positive balance of the self, which eventually leads to stroke.

The treatment of wind stroke in TEM is aimed at creating equilibrium between the relative strength of the patient's body resistance and the intensity of endogenous and exogenous pathogenic factors. Because wind stroke in TEM is caused by hy-peractivity of liver yang, obstruction of the heart orifices by phlegm, excessive heat, or blood stasis. The treatments in TEM include heat-clearing drugs, antirheumatics, drugs for dispersing exterior wind, drugs for promoting blood circulation, drugs for relieving phlegm, drugs for subduing interior wind, drugs for resuscitation, or tonics for deficiency syndromes, in accordance with the cause. Recently, these drugs have been demonstrated to have antioxidant, anti-inflammatory, and antiglutamate effects. Usually, drugs for clearing away heat, inducing resuscitation, expelling wind, activating blood and removing stasis are used in the early acute stage, and drugs for invigorating and treating deficiencies are used in the later stage.

In the book Tongeuibokam, one of the famous classics in TEM in Korea, 123 different prescriptions for stroke are recorded in the wind stroke section [8]. The herbs used in these prescriptions include, Saposhnikoviae Radix, Ligustichi Radix, Ginseng Radix, Angelicae Sinensis Radix, Paeoniae Radix, Arisaematis Rhizoma, Atylactylodis Rhizoma, Notopterygii Rhizoma seu Radix, Ephedrae Herba, and Scutellariae Radix, in decreasing frequency. Herbs listed in Table 16.1 are used to treat neurological symptoms of strokes.

16.3 Neuroprotective Herbs for Stroke

Cerebral ischemic injury is the result of an obstruction of blood flow in a major cerebral vessel, which will lead to a core of severely ischemic brain tissue that may not be salvaged. However, the ultimate size of the brain infarct also depends on the penumbra, a zone of tissue around the core of the infarct where blood flow is maintained above a neuronal disabling level or the critical 20 to 25% of normal blood flow. Decreased blood flow leads to severe impairment of cellular function by disruption of ATP-dependent processes [9].

Ischemia and subsequent reperfusion provide circumstances that produce oxygen radical production. Several studies have suggested a relationship between cerebral ischemia and oxidative stress in humans [10,11]. Therefore, antioxidants have been evaluated as neuroprotective agents in stroke [12]. Many herbs, especially those that contain flavonoids, are suggested to have antioxidant effects and possibly might be protective against brain injury caused by ischemia and reperfusion.

Many herbs have also been shown to have anti-inflammatory properties, and thus there is potential for novel anti-inflammatory agents to be identified from plant sources. For example, numerous flavonoid compounds have been associated with anti-inflammatory activity and may have the potential for use in the management of inflammatory disorders [13].

Glutamate toxicity and glucose deprivation is one mechanism of neuronal injury following ischemia. For a thousand years in TEM, some herbs have been used as tranquilizers for their central nervous system (CNS) inhibitory effects. Some of

Table 16.1 Herbs used in stroke therapy in TEM with their main component compounds

Medicine

Scientific name

Chinese Main components

Drugs for clearing away heat

Scutellariae Radix Coptidis Rhizoma

Gardeniae Fructus Rhei Radix et Rhizoma Bovi Calculus

Antirheumatics

Saposhnikoviae Radix Notopterygii Rhizoma seu Radix Angelicae pubescens Radix Gentianae Macrophyllae Radix Aconiti Radix Stephaniae Tetrandrae Radix

Drugs for promoting blood circulation

Ligustichi Radix Salviae Miltorrhizae Radix

Carthami Flos

Scutellaria baicalensis M-W

Copt is japónica K® C. chinensis

Gardenia jasminoides Hi

Rheum palmatum

Bos taurus +K

Saposhnikovia divaricata Kill

Notopterygium incisum SÉ55

Angelica pubescens 8)3 Gentiana macrophylla Aconitum cannichaeli

Sinomenium acutum HjB Stephania tetrandra

Ligusticum chuanxiong JH^ Salvia miltiorrhiza

Carthamus tinctorius UÍÉ

Baicalein, biacalin, wogonin, wogonoside Berberine, coptisine, worenine, palmatine, jatrorrhizine

Gardenoside, geniposide, shanzhiside, gardoside Rhein, aloe-emodin, sennoside A,B,C,D,E,F Cholic acid, deoxycholic acid, bilirubin, taurine

Bisabolene, imperatorin, hellopterin, ledebourielol a-thujene, a-pinene, ß-pinene, ß-ocimine, Othol, columbiamotin, xanthotoxin, angelol Gentianine, gentianidine, gentiopieroside Aconitine, hypaconitine, mesaconitine Hanfangchin A, fangchinoline

Chuanxiongzine, ligustilide Tanshinone I.IIA, cryptotanshinone, dihydrotanshinone Carthamin, saffloryellow A, B, safflomin A

Table 16.2 (continued)

Medicine

Scientific name

Chinese

Main components

Tonics for deficiency syndromes

Gingseng Radix

Panax ginseng

Ginsenoside-Rbl, Rc, Rgl, Re

Aconthopanacis Senticosi Radix

Acanthopanax senticosus

ÍJÜP

Eleutheroside A-E

Astragali Radix

Astragalus mumbranaceus

as

Astragaloside I, II,IV, soyasaponin I

Atylactylodis Rhizoma

Atractylodes japónica

e^t

Atractylol, atractylon, junipercamphor, atractylolide

Poria

Poria cocos

ß-pachyman, pachymic acid

Schizandriae Fructus

Schizandra chinensis

Schizandrin, deoxyschizandrin, schizandrol

Dioscoreae Rhizoma

Dioscorea batatas

OjS

Choline, allantoin, batasine, abscine

D. japónica

Rehmanniae Radix

Rehmannia glutinosa

Catalpol, digydrocatalpol, remannioside

Angelicae Sinensis Radix

Angelicae gigas

Ligustilide, N-butylidenece phthalide.

A. sinensis

Paeoniae Radix

Paeoniae lactiflora, P. veitchii

0*3 II

Paeoniflorine, paeonol

Drugs for releaving phlegm

Pinelliae Tuber Arisaematis Rhizoma Platycody Radix Pruni Mandshuricae Semen

Drugs for dispersing exterior wind

Ephedrae Herba Puerariae Radix Angelicae Dahuricae Radix Mentae Herba Cinnamomi Cortex Schizonepetae Herba Asari Radix Zingiberis Rhizoma Viticis Fructus

Pinellia tennata Arisaema ammese Platycodon grandiflorum Primus mandshurica

Ephedra sinica, Pueraria thunbergiana Angelica dahurica Mentha aivensis Cinnamomum cassia Schizonepeta tenuifolia Asarum sieboldii Zingiberis officinale Vitex rotundifolia

Sg St

Choline, 1-ephedrine, |3-sitosterol Saponin, alkaloids, benzoic acid, d-mannitol Platycodoside, platycodin D Amygdalin, prunase

Ephedrine, d-pseudoephedrine, 1-N-methylephedrine Daidzin, daidzein, puerarin 1-tetradecene, lauric acid, agidol. Menthol, menthacamphor

Cinnamon oil, cinnamic aldehyde, cinnamic acid Pulegone, d-menthone, isomenthone, d-limonene a-pinene, |3-pinene, safrole, asarone Zingiberol, borneol, 6-gingerol, 6-shogaol Rotundifuron, prerotundifuran, vitexilactone

Table 16.3 (continued)

Medicine

Scientific name

Chinese Main components

Drugs for subduing interior wind

Gastrodiae Rhizoma Uncariae Ramulus cum Uncis Bombyx Corpus Scorpion

Drugs for promoting qi circulation

Citri Percarpium Aurantii Fructus Saussurae Radix Linderae Radix Magnoliae Cortex

Drugs for resuscitation

Moschus

Acori Graminei Rhizoma

Gastrodia elata Uncaria.rhynchophylla Bombyx mori Buthus martensi

Citrus unshiu, C. reticulate Citus aurantium Saussurea lappa Lindera strychnifolia Magnolia obovata, M. officinalis

Moschus moschiferus Acorus gramineus ft®. SB:

JM Sit-

Gastrodin, gastrodioside, vanillyl alcohol Rhynchophylline, isorhynchophylline Ammonium sxalate, pyridine-2,6-dicarboxyl acid Buthatoxin, betaine

Limonene, a,ß-pinene, hesperidin Hesperidin, neohesperidin, naringin Aplotaxene, a,ß-costene Lindenenol, lindenene, lineroxide ß-eudesmol, magnolol, honokiol

Muscone, muscopyridine

ß-asarone, a-asarone, caryophyllene, a-humulene these herbs are known to have neuroprotective effects by the antagonism of excitatory amino acids, particularly glutamate, which is increased in the early postcerebral ischemia period and activates NMDA receptors.

Individual herbs are comprised of many compounds, and it is therefore difficult to investigate the exact neuroprotective mechanism of many herbs, even though some show high efficacy in in vitro and in vivo ischemia models. The effective mechanisms of herbs may include antioxidant, anti-inflammatory, and antiglutamate actions.

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