Abstracts

Induction of a seizure results in a tremendous increase in the expression of immediate early genes (IEG[apos]s) such as c-fos mRNA. Seizure-induced c-fos mRNA expression has been attributed to the increased activity of excitatory amino acids such as glutamate. This increased glutaminergic activity and increased IEG expression produced by a seizure has been shown to result in apoptosis and necrosis. It is unclear if antiepileptic drugs affect the neurodegenerative process of a seizure. We appraoched this question by measuring c-fos mRNA expression following flurothyl-induced seizures in rats that were administered saline, valproic acid (VP) or lamotrigine (LAM).
Saline, VP (250 mg/kg, ip) and LAM (10 mg/kg, ip) were administered twice a day for three days. On the fourth day, 1 hour after the first injection of either saline, VP or LAM, flurothyl seizure testing was performed in 6 animals from each group. The latency to the first myoclonic jerk and clonic-tonic seizure was recorded for each animal. These animals were sacrificed 1 hour after seizure-induction; brains removed and frozen on dry-ice. The remaining 4 animals for each group were sacrificed 2 hours after injection of saline, VP or LAM (no seizure animals). Twenty micron serial coronal sections were taken through the hippocampus and locus coeruleus (LC). In situ hybridization with an oligonucleotide probe complementary to c-fos mRNA was performed. c-Fos mRNA expression was measured in the cortex, hippocampus (CA1, CA3 and dentate gyrus), amygdala, septum, caudate and LC.
VP and LAM had a significant anticonvulsant effect against flurothyl-induced seizures. Seizure phenotype in VP amd LAM treated animals was similar to the seizure phenotype of saline treated animals. However, c-fos mRNA expression in seizure VP treated animals was significantly less than seizure saline treated animals in the cortex, hippocampus, septum, amygdala and LC. The c-fos mRNA expression in seizure VP treated animals was not significantly different than no seizure VP treated animals in the hippocampus, septum, amygdala and LC. Seizure LAM treated animals had similar c-fos mRNA expression as seizure saline treated animals in the cortex, hippocampus and LC. Expression of c-fos mRNA in seizure LAM treated animals was significantly greater then seizure saline treated animals in the amygdala, septum and caudate.
These data indicate that VP was able to prevent the induction of c-fos mRNA expression by a seizure in all regions of the CNS; for most regions (except the cortex) the c-fos expression was identical to animals given VP with no seizure. LAM had no effect on c-fos mRNA expression in most regions as compared to seizure saline treated animals, but was increased in others. If increased c-fos expression is involved in the process of apoptosis or necrosis, then VP may prevent the degeneration of neruons induced by a seizure.
[Supported by: PERC and VAMC, Seattle, WA]