Neuroprotective properties of topiramate in the lithium-pilocarpine model of epilepsy.
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.
Institut National de la Santé et de la Recherche Médicale U398, Faculty of Medicine, Strasbourg, France.
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Rigoulot
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Koning
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Ferrandon
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Nehlig
D000818:Animals; D001784:Blood Gas Analysis; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D004569:Electroencephalography / Q000187:drug effects; D005632:Fructose / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D008094:Lithium; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000077236:Topiramate
D018696:Neuroprotective Agents; D010862:Pilocarpine; D000077236:Topiramate; D005632:Fructose; D008094:Lithium