Effect of acute administration of docosahexaenoic acid in mice resistant to antiepileptic drugs in 6Hz model of epilepsy


1 Department of Basic Sciences, Faculty of veterinary Medicine, University of Tehran, Tehran, Iran

2 Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran


BACHGROUND: Epilepsy is a chronic neurological disorder. Despite discovery of effective antiepileptic drugs (AEDs), more than 30% of patients are still resistant to AEDs. OBJECTIVES: Evaluation the effect of acute administration of Docosahexaenoic acid (DHA) in mice resistant to antiepileptic drugs in 6Hz model of epilepsy. METHODS: at first we evaluted intracerebroventricularly (i.c.v) injection and oral consumption of DHA alone and intrapritoneal (i.p.) injection of drugs in separate groups. In test groups LTG 25mg/kg or PHT 25mg/kg were injected i.p. 105 min after injection of PHT, 45 min after injection of LTG, DHA (1mM) was injected i.c.v. In control groups drugs solvent or DHA solvent was injected DHA. 15 min after injection of DHA or DHA solvent, in all groups 6 Hz stimulation was exerted and occurrence of limbic seizures was registered. In oral test groups PHT 25mg/kg or LTG 25mg/kg were injected i.p. 60 min after injection of PHT and simultaneous injection of LTG, DHA (0.1 ml) was gavaged. 60 minutes after injection of DHA 6 Hz stimulation was exerted. RESULTS: Acute administration of DHA alone via i.c.v injection or oral gavage had no protective effect on inhibiting seizures. Administration of DHA with LTG or PHT also couldn’t inhibit drug resistance. 6-Hz seizures when administered chronically. However, chronically administered DHA inhibited limbic seizures resistant to LTG and PHT. CONCLUSIONS: Acute administration of DHA couldn’t inhibits resistance to LTG and phenytoin in 6-Hz model of epilepsy. Also consumption of single dose of DHA with anticonvulsant drugs don’t have any effect on prevention of drug resistance in epileptic patients.


Barton, M.E., Klein, B.D., Wolf, H.H., White, H.S. (2001) Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 47: 217-227. ##
Bromfield, E., Dworetzky, B., Hurwitz, S., Eluri, Z., Lane, L., Replansky, S., Mostofsky, D. (2008) A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilepsy Behav. 12: 187-190. ##
Curatolo, N., Lecointe, C., Bordet, R., Vallée, L., Galabert, C., Gressens, P., Auvin, S. (2011) Oral administration of docosahexaenoic acid/eicosapentaeinoic acids is not anticonvulsant in rats: implications for translational research. Pediatr Res. 70: 584-588. ##
Dahlin, M., Hjelte, L., Nilsson, S., Åmark, P. (2007) Plasma phospholipid fatty acids are influenced by a ketogenic diet enriched with n-3 fatty acids in children with epilepsy. Epilepsy Res. 73: 199-207. ##
Das, U.N., Madhavi, N. (2011) Effect of polyunsaturated fatty acids on drug-sensitive and resistant tumor cells in vitro. Lipids Health Dis. 10: 159. ##
Gavzan, H., Sayyah, M., Sardari, S., Babapour, V. (2015) Synergistic effect of docosahexaenoic acid on anticonvulsant activity of valproic acid and lamotrigine in animal seizure models. N-S Arch Pharmacol. 388: 1029-1038. ##
Gelsomino, G., Corsetto, P.A., Campia, I., Montorfano, G., Kopecka, J., Castella, B., Gazzano, E., Ghigo, D., Rizzo, A.M., Riganti, C. (2013) Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition. Mol Can. 12: 137. ##
Haley, T., McCormick, W. (1957) Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse. Bri J Pharmacol. 12: 12-15. ##
Krüger, A. (2006) The Role of Fatty Acids in Drug Resistant Epilepsy. Blackwell Sciences Ltd. london, UK. ##
Löscher, W. (2011) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure 20: 359-368. ##
Löscher, W., Klitgaard, H., Twyman, R.E., Schmidt, D.(2013) New avenues for anti-epileptic drug discovery and development. Nature reviews. Drug Disc. 12: 757. ##
Łuszczki, J.J., Wlaz, A., Marzeda, E., Durmowicz, D., Florek-Łuszczki, M. (2013) Additive interaction of levetiracetam with lamotrigine in the mouse 6 Hz psychomotor seizure model-an isobolographic analysis. Curr. Issues Pharm Med Sci. 26: 82. ##
Potschka, H. (2012) Animal models of drug-resistant epilepsy. Epileptic Disord. 14: 226-234. ##
Scorza, F.A., Cavalheiro, E.A., Arida, R.M., Terra, V.C., Scorza, C.A., Ribeiro, M.O., Cysneiros, R.M. (2009) Positive impact of omega-3 fatty acid supplementation in a dog with drug-resistant epilepsy: a case study. Epilepsy Behav. 15: 527-528. ##
Shandra, A., Shandra, P., Kaschenko, O., Matagne, A., Stöhr, T. (2013) Synergism of lacosamide with established antiepileptic drugs in the 6-Hz seizure model in mice. Epilepsia. 54: 1167-1175. ##
Taha, A.Y., Ciobanu, F.A., Saxena, A., Burnham, W.M. (2009) Assessing the link between omega-3 fatty acids, cardiac arrest, and sudden unexpected death in epilepsy. Epilepsy Behav. 14: 27-31. ##
Taha, A.Y., Filo, E., Ma, D.W., McIntyre Burnham, W. (2009) Dose-dependent anticonvulsant effects of linoleic and α-linolenic polyunsaturated fatty acids on pentylenetetrazol induced seizures in rats. Epilepsia. 50: 72-82. ##
Taha, A.Y., Jeffrey, M.A., Taha, N.M., Bala, S., Burnham, W. (2010) Acute administration of docosahexaenoic acid increases resistance to pentylenetetrazol-induced seizures in rats. Epilepsy  Behav. 17: 336-343. ##
Tao, S., Yang, X., Chen, Y., Wang, X., Xiao, Z., Wang, H., Wu, Q., Wang, X. (2012) Up-regulated methyl CpG binding protein-2 in intractable temporal lobe epilepsy patients and a rat model. Neurochem Res. 37: 1886-1897. ##
Vamecq, J., Vallée, L., Lesage, F., Gressens, P., Stables, J.P. (2005) Antiepileptic popular ketogenic diet: emerging twists in an ancient story. Prog Neurobiol. 75: 1-28. ##
Voskuyl, R.A., Vreugdenhil, M., Kang, J.X., Leaf, A. (1998) Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model. Eur Jo Pharmacol. 341: 145-152. ##
Willis, S., Samala, R., Rosenberger, T.A., Borges, K. (2009) Eicosapentaenoic and docosahexaenoic acids are not anticonvulsant or neuroprotective in acute mouse seizure models. Epilepsia. 50: 138-142. ##
Xu, X.-p., Erichsen, D., Börjesson, S.I., Dahlin, M., Åmark, P., Elinder, F. (2008) Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: a putative mechanism of antiseizure action. Epilepsy Res. 80: 57-66. ##
Yuen, A.W., Sander, J.W., Fluegel, D., Patsalos, P.N., Bell, G.S., Johnson, T., Koepp, M.J. (2005) Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy behav. 7: 253-258. ##