The effects of gallic acid on pain and memory following transient global ischemia/reperfusion in Wistar rats

Document Type: Original Research Article


1 Physiology Research Center and Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I. R. Iran

2 Physiology Research Center, Medicinal Plants Research Center and Department of Physiology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I. R. Iran

3 Physiology Research Center and Department of Pharmacology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I. R. Iran


Objective: It is generally agreed that most of the phenomena observed during brain ischemia and reperfusion can be explained by the damage to membrane structure. Oxidative stress is resulted in an imbalance between high consumption of oxygen and low levels of endogenous antioxidants. It is known that gallic acid (GA) is a strong antioxidant. The present study was carried out to evaluate the effect of GA on ischemia/reperfusion (I/R)-induced brain injury in rats.
 Materials and Methods: Wistar adult male rats weighing 200–250 g were divided into six groups as sham operated (Sh), ischemia/reperfusion (I/R) received normal saline (I+Veh), I/R groups treated with gallic acid (I+GA, 50, 100, or 200 mg/kg, orally, respectively), or with 100 mg /kg phenytoin (I+Phen). The global cerebral I/R injury was induced by occluding bilateral common carotid arteries (BCCA) for 20 min, followed by 5 days reperfusion in adult male rats.
Results: It was found that administration of 100 mg/kg GA for 5 days before and 5 days after I/R induction reversed gait performance, sensorimotor disorders (p<0.01), and hypoalgesia (p<0.001) while dose of 50 mg/kg increased passive avoidance memory significantly (p<0.05).
Conclusion: Our findings clearly demonstrate that GA has beneficial effects on behavioral impairments after brain injury induced by I/R. The results of this study show that GA pretreatment ameliorates cerebral ischemia/reperfusion injury and enhances the antioxidant defense against BCCA occlusion-induced I/R in rats, so it exhibits cerebroprotective property.


Cheeseman KH. 1993. Mechanisms and effects of lipid peroxidation. Mol Aspects Med, 14: 191-197.

Chen J, Jin K, Chen M, Pei W, Kawaguchi K, Greenberg DA, and Simon RP. 1997. Early detection of DNA strand breaks in the brain after transient focal ischemia: implications for the role of DNA damage in apoptosis and neuronal cell death. J Neurochem, 69: 232-245.

Chu YF, Sun J, Wu X, Liu RH. 2002. Antioxidant and antiproliferative activities of common vegetables. J Agric Food Chem, 50: 6910-6916.

Dubinsky JM, Kristal BS, Elizondo-Fournier M. 1995. An obligate role for oxygen in the early stages of glutamate-induced, delayed neuronal death. J Neurosci, 15: 7071-7078.

Freund TF, Buzsaki G, Leon A, Baimbridge KG, Somogyi P. 1990. Relationship of neuronal vulnerability and calcium binding protein immunoreactivity in ischemia. Exp Rrain Res, 83: 55-66.

Garcia JH, Wagner S, Liu KF, Hu XJ. 1995. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke, 26: 627-34.

Greenamyre JT, Olson JM, Penney JB, Young AB. 1985. Autoradiographic characterization of N-methyl-D-aspartate-, quisqualate- and kainate-sensitive glutamate binding sites. J Pharmacol Exp Ther, 233: 254-263.

Gustavsson M, Anderson MF, Mallard C, Hagberg H. 2005. Hypoxic preconditioning confers long-term reduction of brain injury and improvement of neurological ability in immature rats. Pediatr Res, 57: 305-309.

Hosseinzadeh H, Nassiri Asl M, Parvardeh S. 2005. The effects of carbenoxolone, a semisynthetic derivative of glycyrrhizinic acid, on peripheral and central ischemia-reperfusion injuries in the skeletal muscle and hippocampus of rats. Phytomedicine, 12: 632-7.

Imai F, Suzuki H, Oda J, Ninomiya T, Ono K, Sano H, Sawada M. 2007. Neuroprotective effect of exogenous microglia in global brain ischemia. J Cereb Blood Flow Metab, 27: 488-500.

Inoue M, Suzuki R, Koide T, Sakaguchi N, Ogihara Y, Yabu Y. 1994. Antioxidant, gallic acid, induces apoptosis in HL-60RG cells. Biochem Biophys Rese Commun, 204: 898-904.

Jokinen H, Kalska H, Mantyla R, Pohjasvaara T, Ylikoski R, Hietanen M, Salonen O, Kaste M, Erkinjuntti T. 2006. Cognitive profile of subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry, 77: 28-33.

Kaeidi A, Esmaeili-Mahani S, Abbasnejad M, Sheibani V, Rasoulian B, Hajializadeh Z,  Pasban-Aliabadi H. 2013. Satureja khuzestanica attenuates apoptosis in hyperglycemic PC12 cells and spinal cord of diabetic rats. J Nat Med, 67: 61-69.

Kalaria RN. 2000. The role of cerebral ischemia in Alzheimer's disease. Neurobiol Aging, 21: 321-330.

Kanbak G,  Canbek M, Oglakci A, Kartkaya K, Senturk H, Bayramoglu G, Bal C, Gol B, Ozmen A. 2012. Preventive role of gallic acid on alcohol dependent and cysteine protease-mediated pancreas injury. Mol Biol Rep, 39: 10249-10255.

Kaur M, Velmurugan B, Rajamanickam S, Agarwal R,  Agarwal C. 2009. Gallic acid, an active constituent of grape seed extract, exhibits anti-proliferative, pro-apoptotic and anti-tumorigenic effects against prostate carcinoma xenograft growth in nude mice. Pharm Res, 26: 2133-2140.

Kim SH ,  Jun CD,  Suk K,  Choi BJ, Lim H, Park S. 2006. Gallic acid inhibits histamine release and pro-inflammatory cytokine productionin mast cells.  Toxicol Sci, 91: 123-131.

Kleinschnitz C, Kraft P, Dreykluft A, Hagedorn I, Gobel K, Schuhmann M K, Langhauser F, Helluy X, Schwarz T, Bittner S, Mayer CT, Brede M, Varallyay C, Pham M, Bendszus M, Jakob P, Magnus T, Meuth SG, Iwakura Y, Zernecke A, Sparwasser T, Nieswandt B, Stoll G, Wiendl H. 2013. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood, 121: 679-691.

Koyama S, Cobb LJ, Mehta HH, Seeram NP, Heber D, Pantuck AJ, Cohen P. 2010. Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis. Growth Horm IGF Res, 20: 55-62.

Kuhr S and Engelhardt UH. 1991. Determination of flavanols, theogallin, gallic acid and caffeine in tea using HPLC. Zeitschrift für Lebensmitteluntersuchung und-Forschung, 192: 526-529.

Langdon KD, Granter-Button S, and Corbett D. 2008. Persistent behavioral impairments and neuroinflammation following global ischemia in the rat. Eur J Neurosci, 28: 2310-2318.

Leeuwenburgh C and Heinecke JW. 2001. Oxidative stress and antioxidants in exercise. Curr Med Chem, 8: 829-838.

Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F. 1985. Predicting outcome from hypoxic-ischemic coma. JAMA, 253: 1420-1426.

Li JX, Shah AP, Patel SK, Rice  KC, France CP. 2013. Modification of the behavioral effects of morphine in rats by serotonin (5-HT)(1A) and 5-HT (2A) receptor agonists: antinociception, drug discrimination, and locomotor activity. Psychopharmacology, 225: 791-801.

Li LX, Cheng YF, Lin HB, Wang C, Xu JP, Zhang HT. 2011. Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats. Metab Brain Dis, 26: 37-47.

Lipton SA and Rosenberg PA. 1994. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med ,330: 613-622.

Luo Z, Harada T,  London S,  Gajdusek C, Mayberg MR. 1995. Antioxidant and iron-chelating agents in cerebral vasospasm. Neurosurgery, 37: 1154-1158.

Mahut H, Zola-Morgan S, Moss M. 1982. Hippocampal resections impair associative learning and recognition memory in the monkey. J Neurosci, 2: 1214-1220.

Mansoorali KP, Prakash T, Kotresha D, Prabhu K, Rama Rao N. 2012. Cerebroprotective effect of Eclipta alba against global model of cerebral ischemia induced oxidative stress in rats. Phytomedicine, 19: 1108-1116.

Mansouri MT,    Farbood Y,  Jafar Sameri M,  Sarkaki A,  Naghizadeh B,  Rafeirad M. 2012. Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats. Food Chemistry, 138: 1028-1033.

Margaill I, Plotkine M, Lerouet D. 2005. Antioxidant strategies in the treatment of stroke. Free Radic Biol Med, 39: 429-443.

Murray L and Stein A. 1989. The effects of postnatal depression on the infant. Baillieres Clin Obstet Gynaecol, 3: 921-933.

Niemetz R and Gross GG. 2005. Enzymology of gallotannin and ellagitannin biosynthesis. Phytochem, 66: 2001-2011.

Niho N, Shibutani M,  Tamura T,  Toyoda K,  Uneyama C, Takahashi N,    Hirose M. 2001. Subchronic toxicity study of gallic acid by oral administration in F344 rats. Food Chem Toxicol, 39: 1063-1070.

Pande G and Akoh CC. 2009. Antioxidant capacity and lipid characterization of six Georgia-grown pomegranate cultivars. J Agric Food Chem, 57: 9427-9436.

Pilsakova L, Riecansky I, Jagla F. 2010. The physiological actions of isoflavone phytoestrogens. Physiol Res, 59: 651-664.

Pulsinelli WA, Brierley JB, Plum F. 1982. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol, 11: 491-498.

Qian ZJ, Jung WK, Kim SK. 2008. Free radical scavenging activity of a novel antioxidative peptide purified from hydrolysate of bullfrog skin, Rana catesbeiana Shaw. Bioresour Technol, 99: 1690-1698.

Quartu M, Serra MP, Boi M, Pillolla G, Melis T, Poddighe L, Del Fiacco M, Falconieri D, Carta G, Murru E, Cordeddu L, Piras A, Collu M, Banni S. 2012. Effect of acute administration of Pistacia lentiscus L. essential oil on rat cerebral cortex following transient bilateral common carotid artery occlusion. Lipids Health Dis, 11: 8-16.

Reiter RJ. 1995. Oxidative processes and antioxidative defense mechanisms in the aging brain. FASEB J, 9: 526-533.

Renis M, Calabrese V, Russo A, Calderone A, Barcellona M L, Rizza V.  1996. Nuclear DNA strand breaks during ethanol-induced oxidative stress in rat brain. FEBS Lett, 390: 153-156.

Sarkaki A, Rafieirad M, Hossini SE, Farbood Y, Mansouri SMT,  Motamedi F. 2012. Cognitive deficiency induced by cerebral hypoperfusion/ischemia improves by exercise and grape seed extract. Health Med, 6: 1097-1104.

Shahrzad S, Aoyagi K, Winter A, Koyama A, Bitsch I. 2001. Pharmacokinetics of gallic acid and its relative bioavailability from tea in healthy humans. J Nutr, 131: 1207-1210.

Shahrzad S and Bitsch I. 1996. Determination of some pharmacologically active phenolic acids in juices by high-performance liquid chromatography. J Chromatogr, 741: 223-231.

Sharifi ZN, Abolhassani F, Zarrindast MR, Movassaghi S, Rahimian N, Hassanzadeh G. 2012. Effects of FK506 on Hippocampal CA1 Cells Following Transient Global Ischemia/Reperfusion in Wistar Rat. Stroke Res Treat, 2012: 417-425.

Shukitt-Hale B, Carey A, Simon L, Mark DA, Joseph JA. 2006. Effects of Concord grape juice on cognitive and motor deficits in aging. Nutrition, 22: 295-302.

Simon RP, Swan JH, Griffiths T, Meldrum BS. 1984. Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science, 226: 850-852.

Singleton VL. 1981. Naturally occurring food toxicants: phenolic substances of plant origin common in foods. Adv Food Res, 27: 149-242.

Smith ML, Auer RN, Siesjo BK. 1984. The density and distribution of ischemic brain injury in the rat following 2-10 min of forebrain ischemia. Acta Neuropathol, 64: 319-332.

Sopala M and Danysz W. 2001.Chronic cerebral hypoperfusion in the rat enhances age-related deficits in spatial memory. J Neural Transm, 108: 1445-1456.

Sun AY, Simonyi A, Sun GY. 2002. The French Paradox and beyond: neuroprotective effects of polyphenols. Free Radic Biol Med, 32: 314-318.

Taati M, Moghadasi M, Dezfoulian O, Asadian P, Kheradmand A, Abbasi M, Zendehdel M. 2012. The effect of ghrelin pretreatment on epididymal sperm quality and tissue antioxidant enzyme activities after testicular ischemia/reperfusion in rats. J Physiol Biochem, 68: 91-97.

Tamburella A, Micale V, Mazzola C, Salomone S, Drago F. 2012. The selective norepinephrine reuptake inhibitor atomoxetine counteracts behavioral impairments in trimethyltin-intoxicated rats. Eur J Pharmacol, 683: 148-154.

Tran HN, Bae SY, Song BH, Lee BH, Bae YS, Kim YH, Lansky EP, Newman RA. 2010. Pomegranate (Punica granatum) seed linolenic acid isomers: concentration-dependent modulation of estrogen receptor activity. Endocr Res, 35: 1-16.

Urso ML and Clarkson PM. 2003. Oxidative stress, exercise, and antioxidant supplementation. Toxicology, 189: 41-54.

Valizadeh Z, Eidi A, Sarkaki A, Farbood Y, Motrtazavi P. 2012. Dementia type of Alzheimer’s disease due to beta-amyloid wad improved by gallic acid in rats. Health Med, 6: 3648-3657.

Vannucci RC and Vannucci SJ. 1997. A model of perinatal hypoxic-ischemic brain damage. Ann N Y Acad Sci, 835: 234-249.

Wallace JE, Krauter EE, Campbell BA. 1980. Motor and reflexive behavior in the aging rat. J Gerontol, 35: 364-370.

Wickens AP. 2001. Ageing and the free radical theory. Respir Physiol, 128: 379-391.

Wigstrom H, Gustafsson B, Huang YY. 1986. Mode of action of excitatory amino acid receptor antagonists on hippocampal long-lasting potentiation. Neuroscience, 17: 1105-1115.

Wolfe K, Wu X, Liu RH. 2003. Antioxidant activity of apple peels. J Agric Food Chem, 51: 609-614.

Yigitkanli K, Pekcec A, Karatas H, Pallast S, Mandeville, N. Joshi, N. Smirnova, I. Gazaryan E, Ratan RR, Witztum JL, Montaner J, Holman TR, Lo EH, van Leyen K. 2013. Inhibition of 12/15-lipoxygenase as therapeutic strategy to treat stroke. Ann Neurol, 73: 129-135.

Ylikoski R, and Hanninen T. 2003. Assessment of executive function in clinical trials. Int Psychogeriatr, 15: 219-224.

Yoo KY, Li H, Hwang IK, Choi JH, Lee CH, Kwon DY, Ryu SY, Kim YS, Kang IJ, Shin HC, Won MH. 2010. Zizyphus attenuates ischemic damage in the gerbil hippocampus via its antioxidant effect. J Med Food, 13: 557-563.

Zarow C, Vinters HV, Ellis WG, Weiner MW, Mungas D, White L, Chui HC. 2005. Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia. Ann neurol, 57: 896-903.

Zhao Q, Murakami Y, Tohda M, Obi R, Shimada Y, Matsumoto K. 2007. Chotosan, a kampo formula, ameliorates chronic cerebral hypoperfusion-induced deficits in object recognition behaviors and central cholinergic systems in mice. J  Pharmacol Sci, 103: 360-373.

Zola-Morgan S and Squire LR. 1986. Memory impairment in monkeys following lesions limited to the hippocampus. Behav Neurosci, 100: 155-160.

Zong L, Inoue M, Nose M, Kojima K, Sakaguchi N, Isuzugawa K, Takeda T, Ogihara Y. 1999. Metabolic fate of gallic acid orally administered to rats. Biol Pharm Bull, 22: 326-29.