Amelioration of water maze performance deficits by topiramate applied during pilocarpine-induced status epilepticus is negatively dose-dependent

Summary

Temporal lobe epilepsy is characterized by a progressive loss of memory capacities, due to sclerosis and functional impairment of mesiotemporal brain areas. We have shown recently that topiramate (TPM) dose-dependently protects hippocampal CA1 and CA3 neurons during initial status epilepticus in the rat pilocarpine model of temporal lobe epilepsy by inhibition of mitochondrial transition pore opening. In the present study, in order to evaluate possible positive effects of the treatment on learning and memory, we investigated water maze performance of rats receiving different dosages of TPM (20 and 100 mg/kg) after 40 min and 4 mg/kg diazepam after 160 min of pilocarpine-induced status epilepticus in relation to performance of animals receiving 4 mg/kg diazepam after 40 min of SE, and to performance of sham-treated control animals. Unexpectedly, 20 but not 100 mg/kg TPM significantly extenuated short-term memory deficits. While neuroprotective effects of TPM were observed in hippocampal CA subfields of animals treated with 100 mg/kg TPM, cell loss in rats treated with 20 mg/kg TPM was indistinguishable from animals receiving diazepam only. The present results indicate a negative dose-dependency of memory-saving effects of TPM applied during status epilepticus apparently dissociated from hippocampal neuroprotection.

Introduction

In the pharmacological treatment of partial epilepsies, topiramate (TPM) was shown to be effective as add-on therapy (Reife et al., 2000, Fritz et al., 2005, Kalviainen et al., 2005) as well as a first line antiepileptic drug (Arroyo et al., 2005). It has a broad spectrum of antiepileptic actions related to its anticonvulsive effects, as current attenuation at voltage-gated sodium-channels (Zona et al., 1997), potentiation of GABA activities (White et al., 1997), or modulation of calcium channels (Zhang et al., 2000). Besides its efficacy with regard to seizures, TPM can induce cognitive impairments which are reversible with discontinuation (Kockelmann et al., 2003, Mula et al., 2003).

Pilocarpine-induced status epilepticus (SE) in the rat is a well-established model of temporal lobe epilepsy reproducing main characteristics of the disease (see Holmes et al., 2002, Löscher, 2002). After SE, rats exhibit a “silent” seizure-free phase characterized by development of extensive damage in hippocampal structures crucially involved in spatial memory (see Silva et al., 1998, Pothuizen et al., 2004), followed by occurrence of spontaneous seizures over the entire life span. Persisting cognitive deficits, observable several days after induction of SE (Rice et al., 1998, Detour et al., 2005, Niessen et al., 2005), are sensitive to pharmacological and environmental interventions during and after SE (Stewart and Persinger, 2001, Faverjon et al., 2002, Pitkanen and Kubova, 2004).

TPM was effective in SE suppression in patients (Blumkin et al., 2005) and in animal models (Fisher et al., 2004). It was shown that TPM, applied during pilocarpine-induced SE in the rat, dose-dependently increased status survival rate and saved hippocampal CA1 and CA3 neurons by protection of hippocampal mitochondria against external calcium challenge (Rigoulot et al., 2003, Kudin et al., 2004). Recently, beneficial effects of TPM application after experimental induction of seizures on cognitive functions were described: chronic administration after pilocarpine-induced SE in weanling rats or after fluoroethyl-induced multiple seizures during P0–P4 led to a reduction of impairments in subsequent water maze performance, while no effects on SE-induced hippocampal cell loss were observed (Cha et al., 2002). The same TPM treatment regimen applied after fluoroethyl-induced seizures during P10–P14 also diminishes water maze deficits, while seizure induction at this age had no effect on neuronal density in CA areas (Zhao et al., 2005). These results indicate that appearance and degree of neuroprotective effects and inhibition of dysfunctional reactive neuronal outgrowth by TPM depend on the modus of seizure induction, application time, and application schedule. Furthermore, behavioral impairment after SE is related to the age of animals and is more pronounced in adult rats (Kubova et al., 2004, Liu et al., 1994). Until now, there are no studies investigating memory effects of TPM applied during SE. Therefore, we investigated effects of TPM application during pilocarpine-induced SE on water maze performance in young adult rats.