Folic acid supplementation alleviates behavioral manifestations of lindane-induced seizures
Keywords:lindane, folic acid, seizures, rat, intoxication
- Lindane poisoning evokes tonic and clonic seizures which are refractory to many antiepileptic drugs. Therefore, lindane is suitable for novel antiepileptic substance assessment and testing. Folic acid was shown to possess neuroprotective and anticonvulsive effect in certain experimental models.
- Our work reports for the first time that acute folic acid pretreatment alleviates the behavioral manifestations of lindane-induced seizures through prolonged seizure latency and decreased frequency of grade 4 seizures.
- Our data suggest that folic acid can be proposed as a potential adjuvant in lindane poisoning.
Abstract: Lindane is a scabicide and pesticide that can exert neurotoxic effects such as tonic and clonic seizures that are refractory to many antiepileptic drugs. Folic acid stands out as a potential substance worth testing for its neuroprotective and in certain experimental models anticonvulsive effects. The aim of the present study was to examine the potential therapeutic value of folic acid supplementation on the behavioral characteristics of lindane-induced seizures. Adult male Wistar rats were divided into the following groups: Controls: dimethyl sulfoxide-injected (C1), saline-treated (C2); lindane (4 mg/kg; 6 mg/kg; 8 mg/kg; L4;L6;L8, respectively); folic acid 15 mg/kg (F) and F administered 30 min prior to L4, L6, or L8 (L4F; L6F; L8F, respectively). Convulsive behavior was assessed by the incidence of seizures, seizure latency and seizure severity. Lindane administration has shown a tendency of proportional increase in seizure incidence, decrease in seizure latency and increase in seizure intensity. Pretreatment with folic acid significantly prolonged the latency period and decreased the frequency of grade 4 seizures in the L8F group when compared to the L8 group. We concluded that folic acid alleviates the behavioral manifestations of lindane-induced seizures and that it can be applied as a potential adjuvant in lindane-poisoned patients; however, further research is still needed.
Received: December 9, 2018; Revised: January 31, 2019; Accepted: February 1, 2019; Published online: April 1, 2019
How to cite this article: Djurić E, Hrnčić D, Šutulović N, Škrijelj D, Grubač Ž, Ćirković V, Rašić-Marković A, Stanojlović O. Folic acid supplementation alleviates behavioral manifestations of lindane-induced seizures. Arch Biol Sci. 2017;71(3):403-8.
Li Y. Global technical hexachlorocyclohexane usage and its contamination consequences in the environment: from 1948 to 1997. Sci Total Environ. 1999;232(3):121-58.
Hengge UR, Currie BJ, Jäger G, Lupi O, Schwartz RA. Scabies: a ubiquitous neglected skin disease. Lancet Infect Dis. 2006;6(12):769-79.
Sahoo A, Samanta L, Chainy GB. Mediation of oxidative stress in HCH-induced neurotoxicity in rat. Arch Environ Contam Toxicol. 2000;39(1):7-12.
Sahaya K, Mahajan P, Mediratta PK, Ahmed RS, Sharma KK. Reversal of lindane-induced impairment of step-down passive avoidance and oxidative stress by neurosteroids in rats. Toxicology. 2007;239(1-2):116-26.
Anand M, Gupta GSD, Gopal K, Agrawal D, Khanna RN, Srimal RC. Influence of dietary protein deficiency on EEG neurotransmitters and neurobehaviour after chronic exposure to HCH. Toxicol Environ Chem. 1991;34(1):1-11.
Anand M, Meera P, Kumar R, Gupta GS, Tripathi O, Srimal RC. Possible role of calcium in the cardiovascular effects of prolonged administration of gamma-HCH (lindane) in rats. J Appl Toxico. 1995;15(4):245-8.
Anand M, Agrawal AK, Rehmani BN, Gupta GS, Rana MD, Seth PK. Role of GABA receptor complex in low dose lindane (HCH) induced neurotoxicity: neurobehavioural, neurochemical and electrophysiological studies. Drug Chem Toxicol. 1998;21(1):35-46.
Srivastava MK, Raizada RB. A limited three-generation reproduction study on hexachlorocyclohexane (HCH) in rats. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2000;38(2-3):195-201.
Mladenović D, Hrncić D, Vucević D, Radosavljević T, Loncar-Stevanović H, Petrović J, Susic V, Djuric D, Stanojlović O. Ethanol suppressed seizures in lindane-treated rats. Electroencephalographic and behavioral studies. J Physiol Pharmacol Off J Pol Physiol Soc. 2007;58(4):641-56.
Radosavljević T, Mladenović D, Vucević D, Petrović J, Hrncić D, Djuric D, Loncar-Stevanović H, Stanojlović O. Effect of acute lindane and alcohol intoxication on serum concentration of enzymes and fatty acids in rats. Food Chem Toxicol. 2008;46(5):1739-43.
Tusell JM, Vendrell M, Serratosa J, Trullas R. Lindane-induced convulsions in NMRI and OF1 mice: antagonism with (+)MK-801 and voltage-dependent calcium channel blockers. Brain Res. 1992;593(2):209-14.
Woolley DE, Griffith JA. Kinetics and thresholds of several indices of lindane-induced toxicity. Pharmacol Biochem Behav. 1989;33(4):787-92.
Tusell JM, Suñol C, Gelpí E, Rodríguez-Farré E. Relationship between lindane concentration in blood and brain and convulsant response in rats after oral or intraperitoneal administration. Arch Toxicol. 1987;60(6):432-7.
Vucević D, Hrncić D, Radosavljević T, Mladenović D, Rasić-Marković A, Loncar-Stevanović H,Djurić D, Macut D, Susić V, Stanojlović O. Correlation between electrocorticographic and motor phenomena in lindane-induced experimental epilepsy in rats. Can J Physiol Pharmacol. 2008;86(4):173-9.
Ortiz Martinez A, Martinez-Conde E. The neurotoxic effects of lindane at acute and subchronic dosages. Ecotoxicol Environ Saf. 1995;30(2):101-5.
Tochman AM, Kamiński R, Turski WA, Czuczwar SJ. Protection by conventional and new antiepileptic drugs against lindane-induced seizures and lethal effects in mice. Neurotox Res. 2000;2(1):63-70.
Djukic A. Folate-responsive neurologic diseases. Pediatr Neurol. 2007;37(6):387-97.
Folate – Health Professional Fact Sheet [Internet]. Office of Dietary Supplements: National Institutes of Health; [updated 2018 Oct 4; cited 2019 Mar 27].Available from: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
Caudill MA. Folate bioavailability: implications for establishing dietary recommendations and optimizing status. Am J Clin Nutr. 2010;91(5):1455S-1460S.
Hamid A, Wani NA, Kaur J. New perspectives on folate transport in relation to alcoholism-induced folate malabsorption--association with epigenome stability and cancer development. FEBS J. 2009;276(8):2175-91.
Brocardo PS, Budni J, Lobato KR, Santos ARS, Rodrigues ALS. Evidence for the involvement of the opioid system in the antidepressant-like effect of folic acid in the mouse forced swimming test. Behav Brain Res. 2009;200(1):122-7.
Girotto F, Scott L, Avchalumov Y, Harris J, Iannattone S, Drummond-Main C, Tobias R, Bello-Espinosa L, Rho JM, Davidsen J, Teskey GC, Colicos MA. High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring. Sci Rep. 2013;3:1465.
Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab. 2000;71(1-2):121-38.
Mattson MP, Kruman II, Duan W. Folic acid and homocysteine in age-related disease. Ageing Res Rev. 2002;1(1):95-111.
Sarna LK, Wu N, Wang P, Hwang S-Y, Siow YL, O K. Folic acid supplementation attenuates high fat diet induced hepatic oxidative stress via regulation of NADPH oxidase. Can J Physiol Pharmacol. 2012;90(2):155-65.
Matté C, Mackedanz V, Stefanello FM, Scherer EBS, Andreazza AC, Zanotto C, Moro AM, Garcia SC, Gonçalves CA, Erdtmann B, Salvador M, Wyse AT. Chronic hyperhomocysteinemia alters antioxidant defenses and increases DNA damage in brain and blood of rats: protective effect of folic acid. Neurochem Int. 2009;54(1):7-13.
Lin Y, Desbois A, Jiang S, Hou ST. Group B vitamins protect murine cerebellar granule cells from glutamate/NMDA toxicity. Neuroreport. 2004;15(14):2241-4.
Marković AR, Hrnčić D, Macut D, Stanojlović O, Djuric D. Anticonvulsive effect of folic acid in homocysteine thiolactone-induced seizures. Cell Mol Neurobiol. 2011;31(8):1221-8.
Reynolds EH. Benefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry. 2002;72(5):567-71.
Stanojlović O, Rasić-Marković A, Hrncić D, Susic V, Macut D, Radosavljević T, Djuric D. Two types of seizures in homocysteine thiolactone-treated adult rats, behavioral and electroencephalographic study. Cell Mol Neurobiol. 2009;(29):329-39.
Croom EL, Shafer TJ, Evans MV, Mundy WR, Eklund CR, Johnstone AFM, Mack CM, Pegram RA. Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: A case study of lindane-induced neurotoxicity. Toxicol Appl Pharmacol. 2015;283(1):9-19.
Nyitrai G, Kékesi KA, Szilágyi N, Papp A, Juhász G, Kardos J. Neurotoxicity of lindane and picrotoxin: neurochemical and electrophysiological correlates in the rat hippocampus in vivo. Neurochem Res. 2002;27(1-2):139-45.
Rivera S, Rosa R, Martínez E, Suñol C, Serrano MT, Vendrell M, Rodríguez-Farré E, Sanfeliu C. Behavioral and monoaminergic changes after lindane exposure in developing rats. Neurotoxicol Teratol. 1998;20(2):155-60.
Rosa R, Sanfeliu C, Suñol C, Pomés A, Rodríguez-Farré E, Schousboe A, Frandsen A. The mechanism for hexachlorocyclohexane-induced cytotoxicity and changes in intracellular Ca2+ homeostasis in cultured cerebellar granule neurons is different for the gamma- and delta-isomers. Toxicol Appl Pharmacol. 1997;142(1):31-9.
Kehl SJ, Mclennan H, Collingridge GL. Effects of folic and kainic acids on synaptic responses of hippocampal neurones. Neuroscience. 1984;11(1):111-24.
Apeland T, Mansoor MA, Pentieva K, McNulty H, Seljeflot I, Strandjord RE. The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs. Epilepsy Res. 2002;51(3):237-47.
Tjiattas L, Ortiz DO, Dhivant S, Mitton K, Rogers E, Shea TB. Folate deficiency and homocysteine induce toxicity in cultured dorsal root ganglion neurons via cytosolic calcium accumulation. Aging Cell 2004;3(2):71-6.
Morrell MJ. Folic Acid and Epilepsy. Epilepsy Curr. 2002;2(2):31-4.
Hrncić D, Rasić-Marković A, Susić V, Djurić D, Stanojlović O. Influence of NR2B-selective NMDA antagonist on lindane-induced seizures in rats. Pharmacology. 2009;84(4):234-9.
Sattayasai J, Ehrlich D. Folic acid protects chick retinal neurons against the neurotoxic action of excitatory amino acids. Exp Eye Res. 1987;44(4):523-35.
Mladenović D, Djuric D, Petronijević N, Radosavljević T, Radonjić N, Matić D, Hrncić D, Rasić-Marković A, Vucević D, Dekanski D, Stanojlović O. The correlation between lipid peroxidation in different brain regions and the severity of lindane-induced seizures in rats. Mol Cell Biochem. 2010;333(1-2):243-50.
Singh R, Kanwar SS, Sood PK, Nehru B. Beneficial effects of folic acid on enhancement of memory and antioxidant status in aged rat brain. Cell Mol Neurobiol. 2011;31(1):83-91.
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