Abstracts

A number of studies suggest that progesterone and its metabolite 5[alpha]-pregnane-3[alpha]-ol-20-one (3[alpha],5[alpha]-THP) act as endogenous anticonvulsants. 3[alpha],5[alpha]-THP is a positive modulator of GABA(A) receptors and reduced endogenous levels of 3[alpha],5[alpha]-THP increase seizure susceptibility. Studies from various laboratories suggest that early-life seizures increase susceptibility to development of seizures in later life. In the current study we induced prolonged status-epilepticus (SE) at postnatal day 10 (P10) and measured levels of progesterone and 3[alpha],5[alpha]-THP in plasma and hippocampus immediately after SE and in adulthood., Sprague-Dawley rat pups at P9 were injected intraperitoneally with 3mEq/kg lithium followed 14-18 hrs later by 60mg/kg pilocarpine. Control rats were treated identically to that of seizure rats but were injected with 0.9% saline on P10. Trunk blood and brains were collected 6 hours after the onset of SE or in adulthood for measurement of progesterone and 3[alpha],5[alpha]-THP in plasma and hippocampus by radioimmunoassay., 3[alpha],5[alpha]-THP levels in hippocampus increased significantly (p[lt]0.0002) in rats that were sacrificed 6 hours after SE induction. Plasma and hippocampal levels of progesterone and plasma 3[alpha],5[alpha]-THP were not different in SE as compared to control rats. Rats that had experienced SE at P10 and were sacrificed in adulthood had lower levels of 3[alpha],5[alpha]-THP in plasma as compared to control rats (p[lt]0.013). Levels of 3[alpha],5[alpha]-THP in hippocampus and progesterone levels in plasma and brain were not significantly different between seizure and control rats., These results suggest that 3[alpha],5[alpha]-THP levels increase locally in association with P10 SE, possibly as an adaptive mechanism to inhibit seizures. Long-term decreases in circulating levels of 3[alpha],5[alpha]-THP in adult rats that had experienced SE in early-life may contribute to increased seizure susceptibility in these rats., (Supported by NIH NS38595 to ABK and MH-067698 to CAF.)