Effect of topiramate following recurrent and prolonged seizures during early development

Abstract

Topiramate, an antiepileptic drug with a number of mechanisms of action including inhibition of glutamate activity at the AMPA and KA receptors, was assessed as a neuroprotective agent following seizures. We administered topiramate, 80 mg/kg, or saline for 4 weeks following a series of 25 neonatal seizures or status epilepticus (SE) induced by lithium–pilocarpine in postnatal day 20 rats. Age-matched control rats without a history of seizures were administered topiramate or saline. Following completion of the topiramate injections, animals were tested in the water maze for spatial learning and the brains examined for cell loss and sprouting of mossy fibers. While there was a trend for improved visual–spatial performance in the water maze following topiramate therapy in rats with neonatal seizures, no differences were found in the histological examination of the hippocampus. Neonatal rats exposed to 4 weeks of topiramate did not differ from non-treated controls in water maze performance or histological examination. In weanling rats subjected to SE, topiramate provided a moderate degree of neuroprotection, with topiramate-treated rats performing better in the water maze than rats receiving saline. However, no differences in cell loss or mossy fiber sprouting were found in the histological examination of the brains. These findings demonstrate that chronic treatment with topiramate following SE improves cognitive function. In addition, long-term administration of high-dose topiramate in the normal developing rat brain does not appear to impair cognitive performance.

Introduction

Status epilepticus (SE; Eriksson and Koivikko, 1997, van Esch et al., 1996) and recurrent seizures (Bourgeois et al., 1983, Farwell et al., 1985, Funakoshi et al., 1988, Rodin et al., 1986) can be associated with cognitive impairment in children. Animal data has paralleled these clinical findings; both recurrent seizures (Holmes et al., 1998, Holmes et al., 1999) and SE (Kubová et al., 2000, Kubová et al., 2001) have been demonstrated to be harmful to the developing brain (reviewed in Holmes et al., 2002, Holmes and Ben-Ari, 2001). Therapies are urgently needed that can alter the cascade of seizure-induced changes that subsequently impair the developing brain.

Topiramate, a sulfate-substituted monosaccharide, is a novel compound that has a broad spectrum of antiepileptic activity (Shank et al., 1994). The mechanisms that likely account for the anticonvulsant activity of TPM include a negative modulatory effect on the α-amino-3-hydroxy-5-methyl-4-isoxazol propionic acid (AMPA)/kainate (KA) subtype of glutamate receptors, a positive modulatory effect on γ-aminobutyric acid (GABA_A) receptors, a use- and time-dependent blockade of voltage-activated Na⁺ channels, a negative modulatory effect on a neuronal L-type high-voltage-activated Ca²⁺ channel (L-type HVACC), and an inhibitory effect on carbonic anhydrase isozymes (Perucca, 1997, Rosenfeld, 1997, Schneiderman, 1998, Shank et al., 1994, White et al., 1997).

While this drug has features that make it attractive as a potential neuroprotective agent, there are concerns about its long-term use on cognitive function. Clinical studies have demonstrated adverse effects on cognitive function including impaired concentration and memory, slowed thinking, and word finding difficulties (Aldenkamp et al., 2000, Gerber et al., 2000, Martin et al., 1999, Tatum et al., 2001, Thompson et al., 2000). Furthermore, studies have demonstrated that drugs altering excitatory neurotransmission, specifically through NMDA blockage, may result in apoptosis (Ikonomidou et al., 1999, Pohl et al., 1999). While topiramate has no direct effect on the NMDA receptor, it is not yet clear whether chronic blocking of AMPA and KA receptors is detrimental to the developing brain.

We hypothesized that administration of topiramate after recurrent seizures and SE in immature rats may suppress neuronal excitability, modulate network reorganization, and improve cognitive function following seizures. A secondary goal of the study was to determine whether long-term treatment with topiramate, a non-NMDA blocker of excitatory neurotransmission, impairs subsequent cognition in the developing brain.