Abstract
Plant polyphenols are dietary components that exert a variety of biochemical and pharmacological effects. Recently, considerable interest has been focused on polyphenols because of their antioxidant, anti-inflammatory, and antiproliferative activities. Oxidative stress is thought to be a key event in the pathogenesis of cerebral ischemia. Overproduction of reactive oxygen species during ischemia/reperfusion could cause an imbalance between oxidative and antioxidative processes. Reactive oxygen species can damage lipids, proteins, and nucleic acids, thereby inducing apoptosis or necrosis. There is increasing evidence supporting the hypothesis that plant polyphenols can provide protection against neurodegenerative changes associated with cerebral ischemia. This article reviews the neuroprotective effects of plant extracts and their constituents that have been used in animal models of cerebral ischemia. The use of polyphenols as therapeutic agents in stroke has been suggested.
Similar content being viewed by others
References
Bronner L.L., Kanter D.S., and Manson J.E. (1995) Primary prevention of stroke. N. Engl. J. Med. 333, 1392–1400.
De Freitas G.R. and Bogousslavsky J. (2001) Primary stroke prevention. Eur. J. Neurol. 8, 1–15.
Traystman R.J. (2003) Animal models of focal and global cerebral ischemia. Ilar. J. 44, 85–95.
Dirnagl U., Iadecola C., and Moskowitz M.A. (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397.
Chan P.H. (1996) Role of oxidants in ischemic brain damage. Stroke 27, 1124–1129.
Hara H., Sukamoto T., and Kogure K. (1993) Mechanism and pathogenesis of ischemiainduced neuronal damage. Prog. Neurobiol. 40, 645–670.
Chan P.H. (1994) Oxygen radicals in focal cerebral ischemia. Brain Pathol. 4, 59–65.
Kuroda S. and Siesjo B.K. (1997) Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clin. Neurosci. 4, 199–212.
Crews F.T., Steck J.C., Chandler L.J., et al. (1998) Ethanol, stroke, brain damage, and excitotoxicity. Pharmacol. Biochem. Behav. 59, 981–991.
Nakamura T., Minamisawa H., Katayama Y., et al. (1999) Increased intracellular Ca2+concentration in the hippocampal CA1 area during global ischemia and reperfusion in the rat: a possible cause of delayed neuronal death. Neuroscience 88, 57–67.
Chan P.H. (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J. Cereb. Blood Flow Metab. 21, 2–14.
Gilgun-Sherki Y., Rosenbaum Z., Melamed E., et al. (2002) Antioxidant therapy in acute central nervous system injury: current state. Pharmacol. Rev. 54, 271–284.
Bravo L. (1998) Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr. Rev. 56, 317–333.
Rice-Evans C.A., Miller N.J., Bolwell P.G., et al. (1995) The relative antioxidant activities of plantderived polyphenolic flavonoids. Free Radical Res. 22, 375–383.
Rice-Evans C.A., Miller J., and Paganga G. (1997) Antioxidant properties of phenolic compounds. Trends Plant Sci. 2, 152–159.
Sun A.Y. and Chen Y.M. (1998) Oxidative stress and neurodegenerative disorders. J. Biomed. Sci. 5, 401–414.
Renaud S. and de Lorgeril M. (1992) Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339, 1523–1526.
Acheson R.M. and Williams D.R. (1983) Does consumption of fruit and vegetables protect against stroke? Lancet 1, 1191–1193.
Vollset S.E. and Bjelke E. (1983) Does consumption of fruit and vegetables protect against stroke? Lancet 2, 742.
Joshipura K.J., Ascherio A., Manson J.E., et al. (1999) Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA 282, 1233–1239.
Youdim K.A. and Joseph J.A. (2001) A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: a multiplicity of effects. Free Radical Biol. Med. 30, 583–594.
Bastianetto S. and Quirion R. (2002) Natural extracts as possible protective agents of brain aging. Neurobiol. Aging 23, 891–897.
Sun A.Y., Simonyi A., and Sun G.Y. (2002) The “French Paradox” and beyond: neuroprotective effects of polyphenols. Free Radical Biol. Med. 32, 314–318.
Ross J.A. and Kasum C.M. (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr. 22, 19–34.
Manach C., Scalbert A., Morand C., et al. (2004) Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr. 79, 727–747.
Korkina L.G. and Afanas’ev I.B. (1997) Antioxidant and chelating properties of flavonoids. Adv. Pharmacol. 38, 151–163.
Nijveldt R.J., van Nood E., van Hoorn D.E., et al. (2001) Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr. 74, 418–425.
Esposito E., Rotilio D., Di Matteo V., et al. (2002) A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes. Neurobiol. Aging 23, 719–735.
Achike F.I. and Kwan C.Y. (2003) Nitric oxide, human diseases and the herbal products that affect the nitric oxide signalling pathway. Clin. Exp. Pharmacol. Physiol. 30, 605–615.
Williams R.J., Spencer J.P., and Rice-Evans C. (2004) Flavonoids: antioxidants or signalling molecules? Free Radical Biol. Med. 36, 838–849.
Skibola C.F. and Smith M.T. (2000) Potential health impacts of excessive flavonoid intake. Free Radical Biol. Med. 29, 375–383.
Walle T. (2004) Absorption and metabolism of flavonoids. Free Radical Biol. Med. 36, 829–837.
Graham H.N. (1992) Green tea composition, consumption, and polyphenol chemistry. Prev. Med. 21, 334–350.
Dufresne C.J. and Farnworth E.R. (2001) A review of latest research findings on the health promotion properties of tea. J. Nutr. Biochem. 12, 404–421.
Higdon J.V. and Frei B. (2003) Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit. Rev. Food Sci. Nutr. 43, 89–143.
Mandel S., Weinreb O., Amit T., et al. (2004) Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases. J. Neurochem. 88, 1555–1569.
Sato Y., Nakatsuka H., Watanabe T., et al. (1989) Possible contribution of green tea drinking habits to the prevention of stroke. Tohoku J. Exp. Med. 157, 337–343.
Arts I.C., Hollman P.C., Feskens E.J., et al. (2001) Catechin intake might explain the inverse relation between tea consumption and ischemic heart disease: the Zutphen Elderly Study. Am. J. Clin. Nutr. 74, 227–232.
Matsuoka Y., Hasegawa H., Okuda S., et al. (1995) Ameliorative effects of tea catechins on active oxygen-related nerve cell injuries. J. Pharmacol. Exp. Ther. 274, 602–608.
Inanami O., Watanabe Y., Syuto B., et al. (1998) Oral administration of (-)catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil. Free Radical Res. 29, 359–365.
Lee S., Suh S. and Kim S. (2000) Protective effects of the green tea polyphenol (-)-epigallocatechin gallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci. Lett. 287, 191–194.
Lee S.Y., Kim C.Y., Lee J.J., et al. (2003) Effects of delayed administration of (-)-epigallocatechin gallate, a green tea polyphenol on the changes in polyamine levels and neuronal damage after transient forebrain ischemia in gerbils. Brain Res. Bull. 61, 399–406.
Hong J.T., Ryu S.R., Kim H.J., et al. (2001) Protective effect of green tea extract on ischemia/reperfusion-induced brain injury in Mongolian gerbils. Brain Res. 888, 11–18.
Dajas F., Rivera F., Blasina F., et al. (2003) Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox. Res. 5, 425–432.
Soleas G.J., Diamandis E.P., and Goldberg D.M. (1997) Wine as a biological fluid: history, production, and role in disease prevention. J. Clin. Lab. Anal. 11, 287–313.
Wolter F. and Stein J. (2002) Biological activities of resveratrol and its analogs. Drugs Future 27, 949–959.
Pervaiz S. (2003) Resveratrol: from grapevines to mammalian biology. FASEB J. 17, 1975–1985.
Huang S.S., Tsai M.C., Chih C.L., et al. (2001) Resveratrol reduction of infarct size in Long-Evans rats subjected to focal cerebral ischemia. Life Sci. 69, 1057–1065.
Sinha K., Chaudhary G., and Gupta Y.K. (2002) Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci. 71, 655–665.
Inoue H., Jiang X.F., Katayama T., et al. (2003) Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferatoractivated receptor alpha in mice. Neurosci. Lett. 352, 203–206.
Wang Q., Xu J., Rottinghaus G.E., et al. (2002) Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res. 958, 439–447.
Wang Q., Simonyi A., MacDonald R.S., et al. (2004) Dietary supplementation of grape extract protects against ischemia-induced neural injury. J. Neurochem. 88(Suppl. 1), 41.
Shutenko Z., Henry Y., Pinard E., et al. (1999) Influence of the antioxidant quercetin in vivo on the level of nitric oxide determined by electron paramagnetic resonance in rat brain during global ischemia and reperfusion. Biochem. Pharmacol. 57, 199–208.
Bagchi D., Garg A., Krohn R.L., et al. (1998) Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice. Gen. Pharmacol. 30, 771–776.
Defeudis F.V. (2002) Bilobalide and neuroprotection. Pharmacol. Res. 46, 565–568.
Diamond B.J., Shiflett S.C., Feiwel N., et al. (2000) Ginkgo biloba extract: mechanisms and clinical indications. Arch. Phys. Med. Rehabil. 81, 668–678.
Biber A. (2003) Pharmacokinetics of Ginkgo biloba extracts. Pharmacopsychiatry. 36 (Suppl. 1), S32-S37.
Ahlemeyer B. and Krieglstein J. (2003) Neuroprotective effects of Ginkgo biloba extract. Cell. Mol. Life Sci. 60, 1779–1792.
Spinnewyn B. (1992) Ginkgo biloba extract (EGb 761) protects against delayed neuronal death in gerbil, in Effects of Ginkgo Biloba (EGB 761) on the Central Nervous System, Christen Y., Costentin J., and Lacour M., eds., Elsevier, Paris, pp, 113–118.
Calapai G., Crupi A., Firenzuoli F., et al. (2000) Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis. Life Sci. 67, 2673–2683.
Pierre S., Jamme I., Droy-Lefaix M.T., et al. (1999) Ginkgo biloba extract (EGb 761) protects Na,K-ATPase activity during cerebral ischemia in mice. Neuroreport 10, 47–51.
Clark W.M., Rinker L.G., Lessov N.S., et al. (2001) Efficacy of antioxidant therapies in trasient focal ischemia in mice. Stroke 32, 1000–1004.
Unal I., Gursoy-Ozdemir Y., Bolay H., et al. (2001) Chronic daily administration of selegiline and EGb 761 increases brain’s resistance to ischemia in mice. Brain Res. 917, 174–181.
Lee E.J., Chen H.Y., Wu T.S., et al. (2002) Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats. J. Neurosci. Res. 68, 636–645.
Ahlemeyer B. and Krieglstein J. (2003) Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer’s disease. Pharmacopsychiatry. 36 (Suppl. 1), S8-S14.
Chandrasekaran K., Mehrabian Z., Spinnewyn B., et al. (2001) Neuroprotective effects of bilobalide, a component of the Ginkgo biloba extract (EGb 761), in gerbil global brain ischemia. Brain Res. 922, 282–292.
Ahlemeyer B., Junker V., Huhne R., et al. (2001) Neuroprotective effects of NV-31, a bilobalidederived compound: evidence for an antioxidative mechanism. Brain Res. 890, 338–342.
Cooper T.H., Clark G., and Guzinski J. (1994) Teas, spices and herbs. Food Phytochem. 1, 231–236.
Ammon H.P. and Wahl M.A. (1991) Pharmacology of Curcuma longa. Planta Med. 57, 1–7.
Garcea G., Jones D.J., Singh R., et al. (2004) Detection of curcumin and its metabolithepatic d hepatic tissue and portal blood of patients following oral administration. Br. J. Cancer 90, 1011–1015.
Sreejayan and Rao M.N. (1997) Nitric oxide scavenging by curcuminoids. J. Pharm. Pharmacol. 49, 105–107.
Khopde S.M., Priyadarsini K.I., Venkatesan P., et al. (1999) Free radical scavenging ability and antioxidant efficiency of curcumin and its substituted analogue. Biophys. Chem. 80, 85–91.
Priyadarsini K.I., Maity D.K., Naik G.H., et al. (2003) Role of phenolic O-H and methylene hydrogen on the free radical reactions and antioxidant activity of curcumin. Free Radical Biol. Med. 35, 475–484.
Singh S. and Aggarwal B.B. (1995) Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane). J. Biol. Chem. 270, 24,995–25,000.
Arbiser J.L., Klauber N., Rohan R., et al. (1998) Curcumin is an in vivo inhibitor of angiogenesis. Mol. Med. 4, 376–383.
Howes M.J. and Houghton P.J. (2003) Plants used in Chinese and Indian traditional medicine for improvement of memory and cognitive function. Pharmacol. Biochem. Behav. 75, 513–527.
Ghoneim A.I., Abdel-Naim A.B., Khalifa A.E., et al. (2002) Protective effects of curcumin against ischaemia/reperfusion insult in rat forebrain. Pharmacol. Res. 46, 273–279.
Thiyagarajan M. and Sharma S.S. (2004) Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci. 74, 969–985.
Wang Q Jenson M., Simonyi A., et al. (2004) Curcumin protects against delayed neuronal death-induced by global ischemia/reperfusion in gerbils. J. Neurochem. 88 (Suppl. 1), 39.
Chen Y.C., Shen S.C., Chen L.G., et al. (2001) Wogonin, baicalin, and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expressions induced by nitric oxide synthase inhibitors and lipopolysaccharide. Biochem. Pharmacol. 61, 1417–1427.
Chi Y.S., Cheon B.S., and Kim H.P. (2001) Effect of wogonin, a plant flavone from Scutellaria radix, on the suppression of cyclooxygenase-2 and the induction of inducible nitric oxide synthase in lipopolysaccharide-treated RAW 264.7 cells. Biochem. Pharmacol. 61, 1195–1203.
Lee H., Kim Y.O., Kim H., et al. (2003) Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia. FASEB J. 17, 1943–1944.
Trieu V.N., Dong Y., Zheng Y., et al. (1999) In vivo antioxidant activity of genistein in a murine model of singlet oxygen-induced cerebral stroke. Radiat. Res. 152, 508–516.
Kindy M.S. (1993) Inhibition of tyrosine phosphorylation prevents delayed neuronal death following cerebral ischemia. J. Cereb. Blood Flow Metab. 13, 372–377.
Lee B., Choi Y., Kim H., et al. (2003) Protective effects of methanol extract of Acori graminei rhizoma and Uncariae Ramulus et Uncus on ischemia-induced neuronal death and cognitive impairments in the rat. Life Sci. 74, 435–450.
Sweeney M.I., Kalt W., MacKinnon S.L., et al. (2002) Feeding rats diets enriched in lowbush blueberries for six weeks decreases ischemia-induced brain damage. Nutr. Neurosci. 5, 427–431.
Pu F., Mishima K., Egashira N., et al. (2004) Protective effect of buckwheat polyphenols against long-lasting impairment of spatial memory associated with hippocampal neuronal damage in rats subjected to repeated cerebral ischemia. J. Pharmacol. Sci. 94, 393–402.
Backhauss C. and Krieglstein J. (1992) Extract of kava (Piper methysticum) and its methysticin constituents protect brain tissue against ischemic damage in rodents. Eur. J. Pharmacol. 215, 265–269.
Wen T.C., Yoshimura H., Matsuda S., et al. (1996) Ginseng root prevents learning disability and neuronal loss in gerbils with 5-minute fore-brain ischemia. Acta Neuropathol. (Berl.) 91, 15–22.
Lim J.H., Wen T.C., Matsuda S., et al. (1997) Protection of ischemic hippocampal neurons by ginsenoside Rb1, a main ingredient of ginseng root. Neurosci. Res. 28, 191–200.
Shen L. and Zhang J. (2003) Ginsenoside Rg1 increases ischemia-induced cell proliferation and survival in the dentate gyrus of adult gerbils. Neurosci. Lett. 344, 1–4.
Wang Z., Du Q Wang F., et al. (2004) Microarray analysis of gene expression on herbal glycoside recipes improving deficient ability of spatial learning memory in ischemic mice. J. Neurochem. 88, 1406–1415.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Simonyi, A., Wang, Q., Miller, R.L. et al. Polyphenols in cerebral ischemia. Mol Neurobiol 31, 135–147 (2005). https://doi.org/10.1385/MN:31:1-3:135
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/MN:31:1-3:135