Effects of chronic treatment with commonly used antiepileptic drugs on passive avoidance learning in prepubertal rats

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Antiepileptic drugs (AEDs), which are widely used to control and prevent epileptic seizures in children with epilepsy, have potential cognitive side effects. There have been several reports respecting different effects of the first and second generation ADEs on learning and memory. Therefore, we investigated the effects of valproate, carbamazepine, levetiracetam, oxcarbazepine, lamotrigine and topiramate, administered chronically by gavage for 21 days, on learning and memory retention of male and female prepubertal rats. Sixty male and forty-nine female prepubertal Sprague Dawley rats, 21 days old, were used in this study. Cognitive function was tested at 42 days by a step-through passive avoidance task. The results indicated that in both male and female young rats ADEs did not alter passive avoidance latency when compared with the control groups. There is no difference between the effects of the first (valproate and carbamazepine) and second generation ADEs (levetiracetam, oxcarbazepine, lamotrigine and topiramate) regarding learning and memory retention. However, valproate and levetiracetam displayed sexual dimorphism in passive avoidance tast performances. These data suggest that chronic use of both first and second generation ADEs to treat young rats practically could not cause any serious negative effects on cognitive performance.

J. Exp. Clin. Med., 2013; 30:57-61


Cognitive performance; epilepsy; memory; step-through test

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DOI: http://dx.doi.org/10.5835/jecm.omu.30.01.013


Aldenkamp, A.P., De Krom, M., Reijs, R., 2003. Newer antiepileptic drugs and cognitive issues. Epilepsia. 44, 21-29.

Cansu, A., Giray, S.G., Serdaroglu, A., Erdogan, D., Coskun, Z.K., Korucuoglu, U., Biri, A.A., 2008. Effects of chronic treatment with valproate and oxcarbazepine on ovarian folliculogenesis in rats. Epilepsia. 49, 1192-1201.

Carpay, J.A., Aldenkamp, A.P., Van Donselaar, C.A., 2005. Complaints associated with the use of antiepileptic drugs: Results from a community- based study. Seizure. 14, 198-206.

Coppola, G., Verrotti, A., Resicato, G., Ferrarelli, S., Auricchio, G., Operto, F.F., Pascotto, A., 2008. Topiramate in children and adolescents with epilepsy and mental retardation: A prospective study on behavior and cognitive effects. Epilepsy Behav. 12, 253-256.

Dalla, C., Edgecomb, C., Whetstone, A.S., Shors, T.J., 2008. Females do not express learned helplessness like males do. Neuropsychopharmacol- ogy. 33, 1559-1569.

Donati, F., Gobbi, G., Campistol, J., Rapatz, G., Daehler, M., Sturm, Y., Aldenkamp, A.P., Oxcarbazepine Cognitive Study Group., 2007. The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures. Seizure. 16, 670- 679.

Frisch, C., Kudin, A.P., Elger, C.E., Kunz, W.S., Helmstaedter, C., 2007. Amelioration of water maze performance deficits by topiramate applied during pilocarpine-induced status epilepticus is negatively dose-dependent. Epilepsy Res. 73, 173-180.

Harte, L.C., Dow-Edwards, D., 2010. Sexually dimorphic alterations in locomotion and reversal learning after adolescent tetrahydrocannabinol exposure in the rat. Neurotoxicol. Teratol. 32, 515-524.

Hauser, W.A., 1994. The prevalence and incidence of convulsive disorders in children. Epilepsia. 35, 1-6.

Helmstaedter, C., Witt, J.A., 2010. Cognitive outcome of antiepileptic treatment with levetiracetam versus carbamazepine monotherapy: A non- interventional surveillance trial. Epilepsy Behav. 18, 74-80.

Kanit, L., Koylu, E.O., Yararbas, G., Furedy, J.J., Pogun, S., 2003. The effect of nitric oxide synthase inhibition on cognitive ability and strategies employed for place learning in the water maze: Sex differences. Brain Res. Bull. 62, 151-159.

Kuzniecky, R.I., Mortati, K., 2005. Practical strategies for switching to newer antiepileptic drugs. Rev. Neurol. Dis. 2, 186-198.

Lagae, L., 2006. Cognitive side effects of anti-epileptic drugs. The relevance in childhood epilepsy. Seizure. 15, 235-241.

Lamberty, Y., Margineanu, D.G., Klitgaard, H., 2000. Absence of negative impact of levetiracetam on cognitive function and memory in normal and amygdala-kindled rats. Epilepsy Behav. 1, 333-342.

Lim, J., Miller, M.G., 1997. Role of testis exposure levels in the insensitivity of prepubertal rats to carbendazim-induced testicular toxicity. Fundam Appl Toxicol. 37, 158-167.

Lossius, M.I., Hessen, E., Mowinckel, P., Stavem, K., Erikssen, J., Gulbrandsen, P., Gjerstad, L., 2008. Consequences of antiepileptic drug with- drawal: A randomized, double-blind study (Akershus Study). Epilepsia. 49, 455-463.

Lynch, M.W., Rutecki, P.A., Sutula, T.P., 1996. The effects of seizures on the brain. Curr. Opin. Neurol. 9, 97-102.

Martin, R., Kuzniecky, R., Ho, S., Hetherington, H., Pan, J., Sinclair, K., Gilliam, F., Faught, E., 1999. Cognitive effects of topiramate, gabap- entin, and lamotrigine in healthy young adults. Neurology. 52, 321-327.

McLean, M.J., Macdonald, R.L., 1986. Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high fre- quency repetitive firing of action potentials of mouse central neurons in cell culture. J. Pharmacol Exp. Ther. 237, 1001-1011.

Meador, K.J., Loring, D.W., Ray, P.G., Murro, A.M., King, D.W., Perrine, K.R., Vazquez, B.R., Kiolbasa, T., 2001. Differential cognitive and behavioral effects of carbamazepine and lamotrigine. Neurology. 56, 1177-1182.

Meador, K.J., Loring, D.W., Vahle, V.J., Ray, P.G., Werz, M.A., Fessler, A.J., Ogrocki, P., Schoenberg, M.R., Miller, J.M., Kustra, R.P., 2005. Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers. Neurology. 64, 2108-2114.

Mula, M., Trimble, M.R., 2009. Antiepileptic drug-induced cognitive adverse effects: Potential mechanisms and contributing factors. CNS Drugs. 23, 121-137.

Nowakowska, E., Kus, K., Czubak, A., Jedrzejewska, J., 2009. Memory improving and antidepressant effects of topiramate in rats. Arzneimit- telforschung 59, 487-492.

Otoom, S., Batieneh, H., Hassan, Z., Daoud, A., 2004. Effects of long-term use Topiramate on fertility and growth parameter in adult male rats. Neuro. Endocrinol Lett. 25, 351-355.

Perez-Alvarez, F., Timoneda-Gallart, C., Baus-Rosell, J., 2006. Topiramate and epilepsy in the light of Das-Naglieri Cognitive Assessment System. Rev. Neurol. 42, 3-7.

Rücker, B., Pereira, G.S., Fürstenau, C.R., Izquierdo, I., Bonan, C.D., Sarkis, J.J., 2004. Inhibitory avoidance task reveals differences in ecto- nucleotidase activities between male and female rats. Neurochem. Res. 29, 2231-2237.

Seo, J.G., Lee, D.I., Hwang, Y.H., Lee, H.W., Jung, D.K., Suh, C.K., Kwon, S.H., Park, S.P., 2007. Comparison of cognitive effects of lam- otrigine and oxcarbazepine in epilepsy patients. J. Clin. Neurol. 3, 31-37.

Sirén, A., Kylliäinen, A., Tenhunen, M., 2007. Beneficial effects of antiepileptic medication on absence seizures and cognitive functioning in children. Epilepsy Behav. 11, 85-91.

Straussberg, R., Kivity, S., Weitz, R., Harel, L., Gadoth, N., 1998. Reversible cortical atrophy and cognitive decline induced by valproic acid. Eur. J. Paediatr. Neurol. 2, 213-218.

Svalheim, S., Taubİll, E., Surdova, K., Ormel, L., Dahl, E., Aleksandersen, M., McNeilly, A., Gjerstad, L., Ropstad, E., 2008. Long-term leve- tiracetam treatment affects reproductive endocrine function in female Wistar rats. Seizure. 17, 203-209.

Umka, J., Mustafa, S., ElBeltagy, M., Thorpe, A., Latif, L., Bennett, G., Wigmore, P.M., 2010. Valproic acid reduces spatial working memory and cell proliferation in the hippocampus. Neurosci. 166, 15-22.

Yildirim, M., Marangoz, C., 2004. Effects of nitric oxide on passive avoidance learning in rats. Int. J. Neurosci. 114, 597-606.

Yochum, C.L., Dowling, P., Reuhl, K.R., 2008. VPA induced apoptosis and behavioral deficits in neonatal mice. Brain Res. 1203, 126-132.

Zhou, J.L., Zhao, Q., Holmes, G.L., 2007. Effect of levetiracetam on visual-spatial memory following status epilepticus. Epilepsy Res. 73, 65- 74.