Evaluation of L-arginine Effects on Refractory Seizures in Epileptic Patients

Document Type : Original Article


1 Professor of Neurology, Neurology Research Center, Kerman University of Medical Sciences, Kerman, Iran

2 Professor of Pharmacology, Kerman University of Medical Sciences, Kerman, Iran

3 Medical Student, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran


Background:epilepsy is one of the common neurological disorders and approximately
0.5-1% of populations suffers from it. Unfortunately, despite of treatment by antiepileptic drugs, between 20-30% of patients cannot be controlled completely. There are a lot of supplementary therapies for this group of patients and in this study, L-arginine was used as an additional therapy in refractory epileptic patients.
Methods: Two groups of epileptic patients (n=21) were selected randomly. Group 1 received lactose as a placebo, and group 2 received L-arginine (twofold of daily need) as a drug for three months. We used a standard questionnaire for evaluating the effect of L-arginine on the quality of life before and after the study.
Results: we did not find significant change in the quality of life of patients after using L-arginine, but the epileptic attacks decreased in L-arginine group significantly.
Conclusion: L-arginine therapy is safe and can decrease the rate of seizure attacks in refractory epileptic patients, and can be an alternative of ketogenic diets.


Scott RA, Lhatoo SD, Sander JW. The treatment of epilepsy in developing countries: where do we go from here?Bull World Health Organ 2001; 79(4): 344-51.
Banerjee PN, Filippi D,  Hauser WA. The descriptive epidemiology of epilepsy-a reviewEpilepsy Res 2009; 85(1): 31–45. DOI: 10.1016/j.eplepsyres.2009.03.003.
Sayehmiri K, Tavan H, Sayehmiri F, Mohamadi I, Carson KV. Prevalence of Epilepsy in Iran: A Meta-Analysis and Systematic Review. Iran J Child Neurol 2014; 8(4):9–17
Ebrahimi H, Shafa M, Hakimzadeh Asl S, Prevalence of Active Epilepsy in Kerman, Iran: a House Based Survey. Acta Neurol Taiwan 2012; 21(3): 115-24.
K. Radhakrishnan and M. B. Rao, in Epilepsy in India, B. S.Singhal and D. Nag, Eds 2000; pp. 343–362.
Devinsky O. Patients with Refractory Seizures. N Engl J Med 1999; 340(20): 1565-70. DOI: 10.1056/NEJM199905203402008
Patrick Kwan, Alexis Arzimanoglou, Anne T. Berg, Martin J. Brodie, W. Allen Hauser, Gary Mathern, Solomon L. Moshé, Emilio Perucca,Jacqueline French. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia Volume51, Issue6, June 2010, Pages 1069-1077
Surges R, Sander JW. Sudden unexpected death in epilepsy: mechanisms, prevalence, and prevention. Curr Opin Neurol 2012; 25(2): 201-7. DOI: 10.1097/WCO.0b013e3283506714.
Ebrahimi H, Arabpour E, Shafeie K, Khanjani N. Evaluation of seizures in pregnant women in Kerman – Iran. World Family Medicine 2017; 15(8): 52-58. DOI 10.5742/MEWFM.2017.93056.
Parra J, Kalitzin SN, Lopes da Silva FH. Photosensitivity and visually induced seizures. Curr Opin Neurol 2005; 18(2):155‐159. DOI: 10.1097/01.wco.0000162857.52520.68.
Peuscher R, Dijsselhof ME, Abeling NG, Van Rijn M, Van Spronsen FJ, Bosch AM. The Ketogenic Diet Is Well Tolerated and Can Be Effective in Patients with ArgininosuccinateLyase Deficiency and Refractory Epilepsy. JIMD Rep 2012; 5: 127-130. DOI: 10.1007/8904_2011_115.
Nei M, Ngo LY, Sirven JI, Sperling MR. Ketogenic diet in adolescents and adults with epilepsy. Seizure 2014; 23(6): 439-42. DOI: 10.1016/j.seizure.2014.02.015.
Xiao Y, Li X. Polyunsaturated fatty acids modify mouse hippocampal neuronal excitability during excitotoxic or convulsant stimulation. Brain Res 1999; 846(1): 112-21. DOI: 10.1016/s0006-8993(99)01997-6.
Kossoff EH, Krauss GL, McGrogan JR, Freeman JM. Efficacy of the Atkins diet as therapy for intractable epilepsy Neurology 2003; 61(12):1789-91. DOI: 10.1212/01.wnl.0000098889.35155.72.
Ebrahimi HA, Asadi M, Effect of charged amino acids on convulsion due to penthylentetrazol in male adult rat. Iranian journal of neurology 2005; 4(12): 13-7.
Ebrahimi HA, Ebrahimi S. Evaluation of the Effects of Charged Amino Acids on Uncontrolled Seizures. Neurol Res Int 2015; 2015: 124507. DOI: 10.1155/2015/124507.
Mercimek-Mahmutoglu S,  Cordeiro D, Cruz V, Hyland K. Struys EA, Kyriakopoulou L, etal. Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: l-arginine supplementation alternative to lysine-restricted diet.
Eur J Paediatr Neurol 2014; 18(6): 741-6. DOI: 10.1016/j.ejpn.2014.07.001. 17. Wu G, Morris Jr SM. Arginine Metabolism: Nitric Oxide and Beyond. Biochem J 1998; 336 (Pt 1) (Pt 1): 1-17. DOI: 10.1042/bj3360001.
Flynn NE, Meininger CJ, Haynes TE, Wu G. Themetabolic basis of arginine nutrition and pharmacotherapy.Biomed Pharmacother 2002; 56990:427-38. DOI: https://doi.org/10.1016/S0753-3322(02)00273-1.
Bahremand A, Ziai P, Khodadad TK, Payandemehr B, Rahimian R, Ghasemi A, et al. Agmatine enhances the anticonvulsant effect of lithium chloride on pentylenetetrazole-induced seizures in mice: Involvement of L-arginine/nitric oxide pathway. Epilepsy Behav 2010; 18(3): 186-92. DOI: 10.1016/j.yebeh.2010.04.014.
Yuzyuk T, Thomas A, Viau K, Liu A, De Biase I, Botto LD. Effect of dietary lysine restriction and arginine supplementation in two patients with pyridoxine-dependent epilepsy. Mol Genet Metab 2016; 118(3): 167-72. DOI: 10.1016/j.ymgme.2016.04.015.
Paul V. The effect of N-nitro-L-arginine methyl ester posttreatment on the anticonvulsant effect of phenobarbitone and diazepam on picrotoxin-induced convulsions in rats. Pharmacol Biochem Behav 2003; 74(4): 789-94. DOI: https://doi.org/10.1016/S0091-3057(03)00028-5.
Sinha S, Siddiqui KA. Definition of intractable epilepsy. Neurosciences (Riyadh). 2011; 16(1):3-9.
 Latorre G.a · Besa P.a · Parodi C.G.b · Ferrer V.b · Azocar L.c · Quirola M.b · Villarroel L.d · Miquel J.F.c · Agosin E.e · Chianale J.c Prevalence of Lactose Intolerance in Chile: A Double-Blind Placebo Study. Digestion 2014, Vol.90, No. 1
 Saadi A,  Patenaude B, Mateen FJ. Quality of life in epilepsy -31 inventory (QOLIE-31) scores: A global comparison. Epilepsy Behav 2016; 65:13-17. DOI: 10.1016/j.yebeh.2016.09.032.
Barbul A. Arginine: biochemistry, physiology, and therapeutic implications. JPEN J Parenter Enteral Nutr 1986; 10(2): 227-38. DOI: 10.1177/0148607186010002227.
de Boer J, Meurs H, Coers W, Koopal M, Bottone AE, Visser AC, Timens W, Zaagsma J. Deficiency of nitric oxide in allergen-induced.airwayhyperreactivity to contractile agonists after the early asthmatic reaction: an ex vivo study. Br J Pharmacol 1996; 119(6): 1109–16. DOI: 10.1111/j.1476-5381.1996.tb16011.x.
Ricciardolo FL, Di Maria GU, Mistretta A, Sapienza MA, Geppetti P. Impairment of bronchoprotection by nitric oxide in severe asthma. Lancet 1997; 350(9087): 1297–8. DOI: 10.1016/s0140-6736(05)62474-9.
Moncada S, Higgs A. The l-arginine-nitric oxide pathway. N Engl J Med 1993; 329(27): 2002–12.DOI: 10.1056/NEJM199312303292706
 Rose WC, Haines WJ, Warner DT. The amino acid requirements of man. V. The role of lysine, arginine, and tryptophan. J Biol Chem 1954; 206(1): 421-30.
Mertz ET, Beeson WM, Jackson HD. Classification of essential amino acids for the weanling pig. Arch Biochem Biophys 1952; 38: 121-8. DOI: 10.1016/0003-9861(52)90015-5.
Heird WC, Nicholson JF, Driscoll Jr JM, Schullinger JN, Winters RW. Hyperammonemia resulting from intravenous alimentation using a mixture of synthetic L-amino acids: a preliminary report. J Pediatr 1972; 81(1): 162-5. DOI: 10.1016/s0022-3476(72)80396-2.
G.Wu and S. M. Morris Jr., “Arginine metabolism: nitric oxide and beyond,” Biochemical Journal, vol. 336, no. 1, pp. 1–17, 1998.
Morris Jr SM. Arginine synthesis, metabolism, and transport: regulators of nitric oxide synthesis. In: Laskin JD, Laskin DL, editors. Cellular and Molecular Biology of Nitric Oxide. New York, NY, USA: Marcel Dekker; 1999. P. 57-85.
Wiesinger H. Arginine metabolism and the synthesis of nitric oxide in the nervous system. Prog Neurobiol 2001; 64(4):365-91. DOI: https://doi.org/10.1016/S0301-0082(00)00056-3.
Bagetta G, Iannone M,  Scorsa A M, Nisticò G. Tacrine-induced seizures and brain damage in LiCl-treated rats can be prevented by Nω-nitro-L-arginine methyl ester. Eur J Pharmacol 1992; 213(2): 301-4. DOI: 10.1016/0014-2999(92)90695-z.
Coughlin CR,  van Karnebeek CD,  Al-Hertanic W,  Shuen AY, Jaggumantri S,  Jack RM, et al. Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome. Mol Genet Metab 2015; 116(1-2): 35-43. DOI: 10.1016/j.ymgme.2015.05.011.
Beamer E, Otahal J, Sills GJ, Thippeswamy T. N w-Propyl-l-arginine (L-NPA) reduces status epilepticus and early epileptogenic events in a mouse model of epilepsy: behavioral, EEG and immunohistochemical analyses. Eur J Neurosci 2012; 36(9): 3194-203. DOI: 10.1111/j.1460-9568.2012.08234.x.
Roksana B Zak 1, Clayton L Camic, Ethan C Hill, Molly M Monaghan, Attila J Kovacs, Glenn A Wright. Acute Effects of an Arginine-Based Supplement on Neuromuscular, Ventilatory, and Metabolic Fatigue Thresholds During Cycle Ergometry. Appl Physiol Nutr Metab 2015; 40(4):379-85.
 Clayton L Camic 1, Terry J Housh, Jorge M Zuniga, Russell C Hendrix, Michelle Mielke, Glen O Johnson, Richard J Schmidt. Effects of Arginine-Based Supplements on the Physical Working Capacity at the Fatigue Threshold. J Strength Cond Res 2010; 24(5):1306-12.