Abstracts

Progestins mediate ictal activity . Variations in progestins[rsquo] across the estrous cycle of rodents and menstrual cycle of women are associated with differences in seizure susceptibility (Herzog et al., 1997; Pesce et al., 2000). Progesterone (P) replacement has anti-seizure effects in ovariectomized rodents (Craig, 1966; Frye [amp] Scalise, 2000; Spiegel [amp] Wycis, 1945). As well, some women with temporal lobe epilepsy have seizure susceptibility managed with P therapy (Herzog, 1995; 1999).
Progestins[rsquo] can have diverse actions. The mechanisms and brain areas by which progestins mediate ictal activity are not well understood. Progestin receptors (PRs), the traditional target of progestins[rsquo] actions (Etgen, 1984), have been localized to the hippocampus. As well, non-PR targets of progestins[apos] actions, such as GABA[sub]A[/sub] receptors and NMDA receptors, have also been localized to the hippocampus. However, there has been very little investigation of the role of PRs in the hippocampus in mediating progestins[rsquo] anti-seizure effects.
[underline]Hypothesis:[/underline] We hypothesized that if P[apos]s actions in the hippocampus to mediate seizure activity occur via intracellular PRs, then systemic and intra-hippocampal P administration should similarly reduce ictal activity and antagonism of intracellular PRs in the hippocampus should attenuate these anti-seizure effects.
Rats in the experimental conditions described below were administered pentylenetetrazol (75 mg/kg IP) and monitored for 10 min for ictal activity. The latency to, and incidence of, tonic clonic seizures were recorded.
[underline]Experiment 1:[/underline] Ictal activity of proestrous rats was compared to that of diestrous or ovx rats. Proestrous rats had significantly fewer tonic clonic seizures than did diestrous or ovx rats.
[underline]Experiment 2:[/underline] Effects of administration of SC P (500 [mu]g), E (10[mu]g)+P, or vehicle to ovx rats on ictal activity were compared to that of proestrous rats. Rats administered P or E+P had ictal activity that was similar to that of proestrous rats. Both groups had significantly fewer tonic clonic seizures than did ovx rats administered vehicle.
[underline]Experiment 3:[/underline] Intra-hippocampal and SC P (500 [mu]g) administration was compared for effects on ictal activity. Administration of intra-hippocampal P was as effective at reducing the number of tonic clonic seizures, compared to vehicle administration, as was SC administration of P.
[underline]Experiment 4:[/underline] Effects of blocking intracellular PRs in the hippocampus on ictal activity of P (500 [mu]g)-primed rats was examined. Administration of intra-hippocampal RU38486 (10 [mu]g) to P-primed rats increased tonic clonic seizures compared to P-primed rats administered vehicle to the hippocampus.
Together, these data suggest that progestins[rsquo] have actions in the hippocampus to mediate ictal activity and that RU486, a PR and glucocorticoid receptor antagonist, to the hippocampus, can attenuate these effects.
[Supported by: The National Science Foundation (98-96263) and The Epilepsy Foundation of America.]