Abstract
The lithium-pilocarpine model reproduces the main characteristics of human temporal lobe epilepsy. After status epilepticus (SE), rats exhibit a latent seizure-free phase characterized by development of extensive damage in limbic areas and occurrence of spontaneous recurrent seizures. Neuroprotective and antiepileptogenic effects of topiramate were investigated in this model. SE was induced in adult male rats by LiCl (3 mEq/kg) followed 20 h later by pilocarpine (25 mg/kg). Topiramate (10, 30, or 60 mg/kg) was injected at 1 and 10 h of SE. Injections were repeated twice a day for six additional days. Another group received two injections of diazepam on the day of SE and of vehicle for 6 days. Neuronal damage was assessed at 14 days after SE by cell counting on thionin-stained sections. Occurrence of spontaneous recurrent seizures (SRS) was videorecorded for 10 h per day in other groups of rats. In diazepam-treated rats, the number of neurons was dramatically reduced after SE in all subregions of hippocampus and layers II–IV of ventral cortices. At all doses, topiramate induced a 24 to 30% neuroprotection in layer CA1 of hippocampus (p < 0.05). In CA3b, the 30-mg/kg dose prevented neuronal death. All rats subjected to SE became epileptic. The latency (14–17 days) to and frequency of SRS were similar in topiramate- and diazepam-treated rats. The high mortality in the 30 mg/kg topiramate group (84%) was possibly the result of interaction between lithium and topiramate. In conclusion, topiramate displayed neuroprotective properties only in CA1 and CA3 that were not sufficient to prevent epileptogenesis.
Footnotes
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This work was supported by INSERM U 398 (Institut National de la Santé et de la Recherche Médicale), the Fondation pour la Recherche Médicale, and by a grant from Johnson and Johnson Pharmaceutical Research and Development, LLC (Raritan, NJ).
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Present address: INSERM U405, Faculty of Medicine, 67085 Strasbourg, France.
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ABBREVIATIONS: TLE, temporal lobe epilepsy; SE, status epilepticus; HS, hippocampal sclerosis; Lipilo, lithium-pilocarpine; SRS, spontaneous recurrent seizures; TPM, topiramate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.
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DOI: 10.1124/jpet.103.057091.
- Received July 17, 2003.
- Accepted October 14, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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