Effect of hydroalcoholic extract of ginger on the liver of epileptic female rats treated with lamotrigine

Document Type : Original Research Article


Department of Biology, Faculty of Science, Urmia University, Urmia, I. R. Iran


Objective: Lamotrigine is an antiepileptic drug, widely used in the treatment of epilepsy; long-term use of this drug can cause hepatotoxicity. Zingiber officinale Roscoe (ginger) possesses antioxidant properties. In present research, the effect ofhydroalcoholic extract of ginger (HEG) on the liver of lamotrigine-treated epileptic rats was investigated
Material and Methods: Forty-eight female Wistar rats were selected and allocated to 8 groups of 6 each.  Group 1: Negative controls were treated with normal saline. Group 2: Positive controls were treated with lamotrigine (LTG) (10 mg/kg) daily by gavages for 4 consecutive weeks. Epilepsy was induced in treatment groups by i.p. injection of pentylenetetrazol (PTZ) (40 mg/kg). Group 3: Epileptic group received normal saline (10 ml/kg). Group 4: Epileptic group was treated with LTG (10 mg/kg). Groups 5 and 6: Epileptic groups received HEG (50 and 100 mg/kg). Groups 7 and 8: Epileptic groups received LTG and HEG (50 and 100 mg/kg). At the end of 28 days, blood samples were drawn and their livers were processed for light microscopy.
Results: The mean values of TG, CHOL, AST, and ALT activity significantly rose (p<0.01) in groups 2, 3, and 4, while in rats treated with HEG (groups 5, 6, 7, and 8), the levels of liver enzymes significantly decreased (p<0.05) compared with epileptic group treated with lamotrigine (group 4). Histopathological changes of liver samples were comparable with respective control.
Conclusion: These results suggest that hydroalcoholic extract of ginger improves liver function in lamotrigine-induced hepatotoxicity.


Main Subjects

Aebi H. 1984. Methods of Enzymatic Analysis.Catalase. In: Bergmayer HU eds. London: Academic press, pp. 671-684.
Aeschbach R, Loliger J, Scott BC, Murcia A, Butler B, Halliwell B, Aruoma OI. 1994. Antioxidant actions of thymol, carbacrol, 6-gingerol, zingerone and hydroxytyrosol. Food Chem Toxicol, 32: 31-36.
Akhani SP, Vishwakarma SL, Goyal RK. 2004. Anti-diabetic activity of Z. officinale in Streptozotocin-induced type I diabetic rats. J Pharm Pharmacol, 56: 101-105.
Alnaqeeb MA, Thomson M, Al-qattan KK, Kamel AF, Mustafa T, Ali M. 2003. Biochemical and histopathological toxicity of an aqueous extract of ginger in female rats. Kuwait J Sci Eng, 30: 35-48.
Amin A, Hamza AA. 2006. Effects of Rosell and ginger on cisplatin- induced reproductive toxicity inrats. Asian J Androl, 8: 607-612.
Anosike CA, Obidoa O, Ezeanyika LUS, Nwuba MM. 2009. Anti -inflammatory and anti-ulcerogenic activity of the ethanol extract of ginger (Zingiber officinale). Afr J Biochem Res, 3: 379-384.
Barber AA, Bernheim F. 1967. Lipid peroxidation its measurement occurrence and significance in animal tissues. Adv Gerontol, 2: 355-403.
Becker A, Grecksch G, Schröder H. 1995. N_-nitro-l-arginine methyl ester interferes with pentylenetetrazol-induced kindling and has no effect on changes in glutamate binding. Brain Res, 688: 230-232.
Becker A, Krug M, Schroder H. 1997. Strain differences in pentylenetetrazolekindling development and subsequent potentiation effects. Brain Res, 763: 87- 92.
Betts T, Goodwin G, Withers RM, Yuen AW. 1991. Human safety of lamotrigine. Epilepsia, 32: 17-21.
Bhandari U, Grover JK. 1998. Effect of ethanolic extract of ginger on hyperglycemic rats. Int J Diabet, 6: 95-96.
Bhandari U, Shamsher A, Pillai KK. 2003. Antihepatotoxic activity of Ginger Ethanol Extract in Rats.Pharm Biol, 41: 66-71.
Bhandari U, Kanojia R, Pillai KK. 2005. Effect of ethanolic extract of Zingiber officinale on dyslipidaemia in diabetic rats. J Ethnopharmacol, 97: 227-230.
Chang WS, Chang YH, Lu FJ, Chiang HC. 1994. Inhibitory effects of phenolics on xanthine oxidase. Anticancer Res, 14: 501-506.
Das UN. 2002. A radical approach to cancer. Med SciMonit, 8: RA79-82.
Fayad M, Choueiri R, Mikati M. 2000. Potential hepatotoxicity of lamotrigine.PediatrNeurol, 22: 49-52
Fisher- Rasmussen W, Kjaer SK, Dahl C, Asping U. 1991. Ginger treatment of hyperemesis gravidarm. Eur J Obstet Gynecol Reprod  Biol, 38: 19-24.
Fuhrman B, Roseblate M, Hayek T, Coleman  R, Aviram M. 2000. Ginger Extract Consumption Reduces Plasma Cholesterol, Inhibits LDL Oxidation and Attenuates Development of Atherosclerosis in Atherosclerotic, Apolipoprotein E-Deficient Mice. J Nutr, 130: 1124-1131.
Gram TE, Gillette JR. 1971. Biotransformation of drugs. In: Bacq., Z.M (Ed.), Fundamentals of Biochemical Pharmacology. New York: Pergamen Press; p.571-609.
Gujaral S, Bhumra H, Swaroop M. 1978. Effect of ginger oleoresin on serum and hepatic cholesterol levels in cholesterol-fed rats. Nutr Rep Int, 17: 183-187.
Halliwell B,Gutteridge J. 1999. Free Radicals in Biology and Medicine. Oxford: Oxford Univ.
Islam  MS, Choi H. 2008. Comparative effects of dietary ginger (Zingiber officinale) and garlic (Allium sativum) investigated in a type 2 diabetes model of rats. J Med Food, 11: 152-159.
Kamtchouing P, Fndio GY, Dimo T, Jatsa HB. 2002. Evaluation of androgenic activity of Zingiber officinale and Pentadiplandrabrazzeana in male rats. Asian J Androl, 4: 299- 301.
Kehrer JP.1993. Free radical as mediator of tissue injury and disease. Crit Rev Toxicol, 23: 21-48.
Leach M, Harden CM, Millar AA. 1986. Pharmacologicl studies of lamotrigine, a novel potential antiepileptic drug, II: Neurochemical studies on the mechanisms of action. Epilepsia, 27: 490-497.
Ledwozyw A, Michalak J, Stepian A , Kadziolka A. 1986. The relationship between plasma TG, cholesterol, total lipid peroxidation product during human atherosclerosis. Clin Chim Acta, 155: 272-284.
Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD. 1997.Safety of long-term lamotrigine in epilepsy. Epilepsia, 38: 881-6.
Maertens P, Dyken P, Graf W, Pippenger C, Chronister R, Shah  A. 1995. Free radicals, anticonvulsants and the neuronal ceroidlipofuscinoses. Am J Med Genet,7: 225-228.
Magda KE, Germine MH, Rasha MAE. 2011. The Synergistic Hepatoprotective Effect of Curcumina and Ginger Against Carbon Tetrachloride Induced- Liver Fibrosis in Rats. Aust J Basic Appl Sci, 5: 1962-1971.
Mascolo N, Jain  R, Tain  SC, Capasso  FJ. 1989. Ethnopharmacologic investigation of ginger (Zingiber officinale). J Ethnopharmacol, 27: 129-140
Mason CR, Cooper RM. 1972. A permanent change in convulsive threshold in normal and brain-damaged rats with repeated small doses of pentylenetetrazol. Epilepsia, 13: 663-674.
Mecarelli O, Pulitano P, Mingoia M, Ferretti G, Rossi M, Berloco PB, Muda AO. 2005. Acute hepatitis associated with lamotrigine and managed with the molecular adsorbents recirculating system (MARS). Epilepsia, 46: 1687-1689.
Messenheimer JA. 1995. Lamotrigine. Epilepsia, 36: S87-S94.
Meshkibaf  MH, Subhash MN, Rama  Rao  BSS, Narayanan  CP, Kailashnath KM. 1995. Comparative effect of single and poly therapy on liver enzymes in epileptic patients under long term treatment. NIMHANS J, 13: 141-146.
Mi-Ok S, Jeon-Ok M. 2010. Effect of dietary supplementation of grape skin and seeds on liver fibrosis induced by dimethyl-nitrosamine in rats. Nutr Res Pract, 4: 369-374
Nurtjahja T, Ammit A, Roufogalis B,  Tran V, Duke C. 2003. Effective anti-platelet and COX-1 enzyme inhibitor from pungent constituents of ginger. Trombo Res, 111: 259-265.
Overstreet K, Costanza C, Behling C, Hassanin T, Masliah E.  2002. Fatal progressive hepatic necrosis associated with lamotrigine treatment: A case report and literature review. Dig Dis Sci, 47: 1921-1925.
Rauca C, Zerbe R, Jantze H. 1999. Formation of free hydroxyl radicals after pentylenetetrazole-induced seizures and kindling. Brain Res, 847: 347-351
Rocha L, Briones M, Ackermann RF, Anton B, Maidment NT, Evans CJ, Engel J. 1996. Pentylenetetrazole-induced kindling: early involvement of excitatory and inhibitory systems. Epilepsy Res, 26: 105-113.
Ryter SW,Kim HP, Hoetzel A, Park JW,  Nakahira K, Wang X,choi AM. 2007. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal, 9: 49-89.
Sauve G, Bresson-Hadni S, Prost P, Le Calvez S, Becker MC, Galmiche J, Carbillet JP, Miguet JP. 2000. Acute hepatitis after lamotrigine administration. Dig Dis Sci, 45: 1874-1877
Schröder H, Becker A, Lössner B. 1993. Glutamate binding to brain membranes is increased in pentylenetetrazol kindled rats. J Neurochem, 60: 1007-1011.
Sechi G, Rosati G, Deiana GA, Petruzzi V, Deriu F, Correddu P, De-Riu PL.  1997. Co-variation of free amino acids in brain interstitial fluid during pentylenetetrazole-induced status epilepticus. Brain Res, 746: 230-236.
Sejima H, Ito M, Kishi K, Tsuda H, Shiraishi H. 1997. Regional excitatory and inhibitory amino acid concentrations in pentylenetetrazole kindling and kindled rat brain. Brain Dev, 19: 171-175.
Sekiwa Y, Kubota K, Kobayashi A. 2000. Isolation of novel glucosides related to gingerdiol from ginger and their antioxidative activities. J Agric Food Chem, 48: 373-377.
Sharma JN, Srivastava  KC, Gan EK. 1994. Suppressive effects of eugenol and ginger oil on arthriticrats. Pharmacol, 49: 314-318.
Sharma I, Gusain D, Dixit VP. 1996. Hypolipidemic and antiatherosclerotic effects of Zingiber officinalein cholesterol-fed rabbits. Phto Res, 10: 517-518.
Siddaraju MN, Dharmesh SM. 2007. Inhibition of gastric H+, k+, ATPase and Helicobacter pylori growth by phenolic antioxidants of Zingiber officinale. Mol Nutr Food Res, 51: 324-332.
Sudha K, Rao AV, Rao A. 2001.Oxidative stress and anti-oxidants in epilepsy. ClinChim Acta, 303:19-24.
Takeoka GR, Dao LT. 2003.Antioxidant constituent of almond [Prunusdulcis (Mill.) D.A.Webb.] hulls. J Agric Food Chem, 51: 496-501.
Wang B, Liu C, Tseng C, Wu C, Yu Z.  2004. Hepatoprotective and antioxidant effects of Bupleurumkaoi Liu (Chao et Chuang) extract and its fractions fractionated using supercritical CO2 on CCl4-induced liver damage. Food Chem Toxicol, 42: 609-617.
Weydert  C, Waugh T, Ritchie J, Iyer K, Smith J,  Spitz DR. 2006. Overexpression of manganese or copper-zinc superoxide dismutase inhibits breast cancer growth. Free Rad Biol med, 41: 226-237.
Yemitan OK, Izegbu MC. 2006. Protective effects of Zingiber officinale (Zingiberaceae) against carbon tetrachloride and acetaminophen-induced hepatotoxicity in rats. Phytother Res, 20: 997-1002.
Zancan KC, Marques MO, Petenate AJ, Meireles MA. 2002. Extraction of ginger (Zingiber officinale Roscoe) oleoresin with CO2 and cosolvents:A study of the antioxidant action of the extracts. J Supercrit Flu, 24: 57-76.
Zhou H, Deng Y, Xie Q. 2006. The modulatory effects of the volatile oil of ginger on the cellular immune response in vitro and in vivo in mice. J Ethnopharmacol, 105: 301-305.