The anticonvulsant properties of antisense c- fos oligodeoxynucleotides in kainic acid-induced seizures

Abstract

Evidence has accumulated that the immediate early gene c- fos has important physiological and pharmacological properties in the central nervous system. The role of c- fos in seizures and, in particular, kainic acid-induced seizures, is unclear. It is unknown if c- fos stimulation after kainic acid is a consequence of neuronal activation, or an intrinsic critical component of the metabolic pathways leading to seizure. To elucidate this problem we have pretreated male Wistar rats with antisense c- fos and nonsense c- fos oligodeoxynucleotides 12 h prior to kainic acid 10 mg/kg intraperitoneal. Antisense c- fos inhibited the number of wet dog shakes and the appearance of limbic motor seizures, effects not seen with nonsense or vehicle. The anticonvulsant effects were associated with reduction of both Fos and NGFI-A immunoreactivity and neuroprotection in the hippocampus, thalamus and primary olfactory cortex-amygdaloid region. Four days after antisense c- fos limbic motor seizures were not inhibited, and there was no decrease in Fos or NGFI-A immunoreactivity and no neuroprotection, indicating that the anticonvulsant effects were not secondary to a toxic effect. Sense oligonucleotides had no anticonvulsant effects when given 12 h prior to kainic acid and did not influence immunoreactivity or neuronal survival. In conclusion, these findings suggest a role for c- fos in the generation of kainic acid-induced limbic seizures and neuronal death.