NEURO-PROTECTIVE EFFECTS OF GINKGO BILOBA LEAVES EXTRACT ON CEREBRAL ISCHEMIA-REPERFUSION INJURY INDUCED EXPERIMENTALLY IN OVARIECTOMIZED RATS
Keywords:
Ginkgo biloba, Cerebral, Ischemia-Reperfusion injury, Ovariectomy, RatsAbstract
Objective: This study investigated the possible neuroprotective effects of Ginkgo biloba on cerebral ischemia-reperfusion (I/R) injury in ovariectomized rats.
Methods: Rats were randomly allocated into 5 groups as follows: Sham-operated group, Ovariectomized group (OVX), Cerebral I/R injury ovariectomized group (OVX+I/R) and two treated groups given Ginkgo biloba leaves extract in two doses [(OVX+I/R)+Gin50 and (OVX+I/R)+Gin100] for one month starting one month after ovariectomization. Two months after ovariectomization, cerebral I/R injury was induced. 24 h later, blood and brain samples were collected.
Results: Ginkgo biloba (50 and100 mg/kg) significantly decreased concentrations of TNF-α, MDA and NO, increased GSH concentration in serum and brain tissue and improved the histopathological pictures of treated rats when compared to ovariectomized cerebral I/R injury group. The effect of Ginkgo biloba high dose was better than the low dose.
Conclusion: Thus the study suggests Ginkgo biloba as a potent supplement for protection against cerebral I/R injury in estrogen deficient females, after full clinical evaluation. The proposed mechanisms include neuroprotective, anti-inflammatory and anti-oxidant actions.
Downloads
References
McCullough LD, Hurn PD. Estrogen and ischemic neuroprotection: an integrated view. Trends Endocrinol Metab 2003;14:228-35.
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243-9.
Brown CM, Mulcahey TA, Filipek NC, Wise PM. Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors alpha and beta. Endocrinology 2010;151:4916-25.
Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244-54.
Salem ML. Estrogen, a double-edged sword: modulation of TH1-and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets: Inflammation Allergy 2004;3:97-104.
Abu-Taha M, Rius C, Hermenegildo C, Noguera I, Cerda-Nicolas JM, Issekutz AC, et al. Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan. J Immunol 2009;183:1393-402.
Salvioli S, Capri M, Valensin S, Tieri P, Monti D, Ottaviani E, et al. Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology. Curr Pharm Des 2006;12:3161-71.
Vegeto E, Benedusi V, Maggi A. Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Front Neuroendocrinol 2008;29:507-19.
Suzuki S, Brown CM, Wise PM. Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 2009;30:201-11.
de Rivero Vaccari JP, Patel HH, Brand FJ, Perez-Pinzon MA, Bramlett HM, Raval AP. Estrogen receptor beta signaling alters cellular inflammasomes activity after global cerebral ischemia in reproductively senescence female rats. J Neurochem 2016;136:492-6.
Grodstein F, Stampfer MJ, Colditz GA, Willett WC, Manson JE, Joffe M, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769-75.
Liao SL, Chen WY, Kuo JS, Chen CJ. Association of serum estrogen level and ischemic neuroprotection in female rats. Neurosci Lett 2001;297:159-62.
Straub RH. The complex role of estrogens in inflammation. Endocr Rev 2007;28:521-74.
Waters EM, Yildirim M, Janssen WG, Lou WY, McEwen BS, Morrison JH, et al. Estrogen and aging affect the synaptic distribution of estrogen receptor beta immunoreactivity in the CA1 region of female rat hippocampus. Brain Res 2011;1379:86-97.
Schaller B, Graf R. Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab 2004;24:351-71.
Aronowski J, Strong R, Grotta JC. Reperfusion injury: demonstration of brain damage produced by reperfusion after transient focal ischemia in rats. J Cereb Blood Flow Metab 1997;17:1048-56.
Kuroda S, Siesjo BK. Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clin Neurosci 1997;4:199-212.
Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J. Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology 2007;49:93-102.
Huh H, Staba EJ. The botany and chemistry of Ginkgo biloba L. J Herbs Spices Med Plants 1992;1:91-124.
Puttalingamma V. Ginkgo biloba living fossilâ€, wonderful medicinal plant-A review. Int J Adv Res 2015;3:506-11.
Le Bars PL. The magnitude of effect and special approach to ginkgo biloba extract EGb 761 in cognitive disorders. Pharmacopsychiatry 2003;36 Suppl 1:S44-9.
Smith PF, Maclennan K, Darlington CL. The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF). J Ethnopharmacol 1996;50:131-9.
Shi C, Zhao L, Zhu B, Li Q, Yew DT, Yao Z, et al. Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against beta-amyloid peptide-induced toxicity in SH-SY5Y cells. Chem Biol Interact 2009;181:115-23.
Smith JV, Luo Y. Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761. J Alzheimers Dis 2003;5:287-300.
Luo Y. Ginkgo biloba neuroprotection: therapeutic implications in Alzheimer's disease. J Alzheimers Dis 2001;3:401-7.
Holstein N. Ginkgo special extract EGb 761 in tinnitus therapy. An overview of results of completed clinical trials. Fortschr Med Orig 2001;118:157-64.
Shi C, Liu J, Wu F, Yew DT. Ginkgo biloba extract in Alzheimer's disease: from action mechanisms to medical practice. Int J Mol Sci 2010;11:107-23.
Dua JS, Prasad DN, Tripathi AC, Gupta R. Role of traditional medicine in neuropsychopharmacology. Asian J Pharm Clin Res 2009;2:72-6.
Smith JV, Luo Y. Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol 2004;64:465-72.
Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci 2003;60:1779-92.
Sasaki K, Hatta S, Wada K, Ueda N, Yoshimura T, Endo T, et al. Effects of an extract of Ginkgo biloba leaves and its constituents on carcinogen-metabolizing enzyme activities and glutathione levels in mouse liver. Life Sci 2002;70:1657-67.
Braquet P, Hosford D. Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents. J Ethnopharmacol 1991;32:135-9.
Chan PC, Xia Q, Fu PP. Ginkgo biloba leave extract: biological, medicinal, and toxicological effects. J Environ Sci Health Part C: Environ Carcinog Ecotoxicol Rev 2007;25:211-44.
Shi C, Xiao S, Liu J, Guo K, Wu F, Yew DT, et al. Ginkgo biloba extract EGb761 protects against aging-associated mitochondrial dysfunction in platelets and hippocampi of SAMP8 mice. Platelets 2010;21:373-9.
Shi C, Fang L, Yew DT, Yao Z, Xu J. Ginkgo biloba extract EGb761 protects against mitochondrial dysfunction in platelets and hippocampi in ovariectomized rats. Platelets 2010;21:53-9.
Berrocal M, Marcos D, Sepulveda MR, Perez M, Avila J, Mata AM. Altered Ca2+dependence of synaptosomal plasma membrane Ca2+-ATPase in the human brain affected by Alzheimer's disease. FASEB J 2009;23:1826-34.
Institute of Laboratory Animal Resources. Committee on Care Use of Laboratory Animals; 2010.
National Institutes of Health. Division of research resources guide for the care and use of laboratory animals. National Academies; NIH Publication No. 85-23, U. S. Department of Health, Education and Welfare; 1985.
Turner RT, Maran A, Lotinun S, Hefferan T, Evans GL, Zhang M, et al. Animal models for osteoporosis. Rev Endocr Metab Disord 2001;2:117-27.
Lee EJ, Chen HY, Wu TS, Chen TY, Ayoub IA, Maynard KI. Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats. J Neurosci Res 2002;68:636-45.
Chandrasekaran K, Mehrabian Z, Spinnewyn B, Chinopoulos C, Drieu K, Fiskum G. Neuroprotective effects of bilobalide, a component of Ginkgo biloba extract (EGb 761) in global brain ischemia and in excitotoxicity-induced neuronal death. Pharmacopsychiatry 2003;36 Suppl 1:S89-94.
Renolleau S, Aggoun-Zouaoui D, Ben-Ari Y, Charriaut-Marlangue C. A model of transient unilateral focal ischemia with reperfusion in the P7 neonatal rat: morphological changes indicative of apoptosis. Stroke 1998;29:1454-61.
Kuluz JW, Prado RJ, Dietrich WD, Schleien CL, Watson BD. The effect of nitric oxide synthase inhibition on infarct volume after reversible focal cerebral ischemia in conscious rats. Stroke 1993;24:2023-9.
Ruiz-Larrea MB, Leal AM, Liza M, Lacort M, de Groot H. Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids 1994;59:383-8.
Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 2001;5:62-71.
Brouckaert P, Libert C, Everaerdt B, Takahashi N, Cauwels A, Fiers W. Tumor necrosis factor, its receptors and the connection with interleukin 1 and interleukin 6. Immunobiology 1993;187:317-29.
Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959;82:70-7.
Bulaj G, Kortemme T, Goldenberg DP. Ionization-reactivity relationships for cysteine thiols in polypeptides. Biochemistry 1998;37:8965-72.
Bancroft J, Stevens A, Turner D. Theory and practice of histological techniques: Churchill Livingstone New York. the text; 1996. p. 766.
Garcia-Segura LM, Azcoitia I, Don Carlos LL. Neuroprotection by estradiol. Prog Neurobiol 2001;63:29-60.
Ozacmak VH, Sayan B. The Effects of 17[beta] Estradiol, 17[alpha] Estradiol and progesterone on oxidative stress biomarkers in ovariectomized female rat brain subjected to global cerebral ischemia. Physiol Res 2009;58:909-12.
Arslan A, Orkun S, Aydin G, Keles I, Tosun A, Arslan M, et al. Effects of ovariectomy and ascorbic acid supplement on oxidative stress parameters and bone mineral density in rats. Libyan J Med 2011;6:10.
Aly HF, Metwally FM, Ahmed HH. Neuroprotective effects of dehydroepiandrosterone (DHEA) in rat model of Alzheimer's disease. Acta Biochim Pol 2011;58:513-20.
Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 1982;11:491-8.
Fellman V, Raivio KO. Reperfusion injury as the mechanism of brain damage after perinatal asphyxia. Pediatr Res 1997;41:599-606.
Traystman RJ, Kirsch JR, Koehler RC. Oxygen radical mechanisms of brain injury following ischemia and reperfusion. J Appl Physiol 1991;71:1185-95.
Anderson MF, Nilsson M, Eriksson PS, Sims NR. Glutathione monoethyl ester provides neuroprotection in a rat model of stroke. Neurosci Lett 2004;354:163-5.
White BC, Sullivan JM, DeGracia DJ, O'Neil BJ, Neumar RW, Grossman LI, et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 2000;179(Suppl 1-2):1-33.
Morikawa E, Huang Z, Moskowitz MA. L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR. Am J Physiol 1992;263:H1632-5.
Yamamoto S, Golanov EV, Berger SB, Reis DJ. Inhibition of nitric oxide synthesis increases focal ischemic infarction in rat. J Cereb Blood Flow Metab 1992;12:717-26.
Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, et al. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic caenorhabditis elegans. J Neurosci 2006; 26:13102-13.
Jin Z, Liang J, Wang J, Kolattukudy PE. MCP-induced protein 1 mediates the minocycline-induced neuroprotection against cerebral ischemia/reperfusion injury in vitro and in vivo. J Neuroinflammation 2015;12:39.
Silva B, Sousa L, Miranda A, Vasconcelos A, Reis H, Barcelos L, et al. Memory deficit associated with increased brain proinflammatory cytokine levels and neurodegeneration in acute ischemic stroke. Arq Neuropsiquiatr 2015;73:655-9.
Wei T, Ni Y, Hou J, Chen C, Zhao B, Xin W. Hydrogen peroxide-induced oxidative damage and apoptosis in cerebellar granule cells: protection by Ginkgo biloba extract. Pharmacol Res 2000;41:427-33.
Bridi R, Crossetti FP, Steffen VM, Henriques AT. The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytother Res 2001;15:449-51.
Maclennan KM, Darlington CL, Smith PF. The CNS effects of Ginkgo biloba extracts and ginkgolide B. Prog Neurobiol 2002;67:235-57.