Abstracts

RATIONALE: Estrogen administration in physiological doses has anticonvulsant and neuroprotective effects on hilar and CA3 neurons in the kainic acid model of status epilepticus. Protective effects are mediated by intracellular estrogen receptors leading to gene activation, which results in modulation of protein synthesis. Our present study examined the possibility that the anticonvulsant and neuroprotective effects may in part be mediated by estrogen-induced increase in GABA(B) neurotransmission and neuropeptide Y (NPY) involvement in the hilar hippocampal region.
METHODS: Rats were ovariectomized one week before hormone replacement. Oil vehicle or b-estradiol (2 kg/day s.c.) were injected 48 and 24 hours prior to saline or kainic acid (16 mg/kg i.p.). Rats were behaviorally monitored for 5 hours and then injected with pentobarbital (50 mg/kg i.p.) irrespective of seizure severity. The rats received two additional doses of b-estradiol or oil (immediately and 24 hours after the seizures). All rats were sacrificed 48 hours after the injection of either KA or saline. Thus, there were four groups: oil + KA seizures, oil + saline (no seizures), estrogen + KA seizures, estrogen + saline (no seizures). Horizontal hippocampal slices were prepared for in vitro electrophysiology. Evoked population spikes were recorded in the granule cell layer of the dentate gyrus after mixed perforant path stimulation with paired pulses (interstimulation interval 10-1000 ms).
RESULTS: There was a loss of paired pulse inhibition in ovariectomized rats after KA seizures and alos in the ovariectomized rats without seizures. This loss was partially (in rats after KA seizures) or fully (in rats without seizures) restored after b-estradiol treatment. Experiments using GABA(B) receptor antagonist CGP 35348 demonstrated that most of the loss of inhibition is due to altered GABA(B) neurotransmission. Additional experiments using NPY antibody (1:1000) incubation in slices from estrogen-treated rats demonstrated a breakdown of paired pulse inhibition suggesting that estrogen-induced NPY increase may be also partially responsible for the paired pulse inhibition recovery.
CONCLUSIONS: Our findings indicate that the anticonvulsant and neuroprotective effects of estrogen on seizure-induced hippocampal damage may involve an interaction with GABA(B) neurotransmission and NPY neuromodulation.
Support: Supported by NS 20253 and NS 30387.