Progestins in the hippocampus of female rats have antiseizure effects in a pentylenetetrazole seizure model

Purpose: Progestins call have profound effects on seizure processes. However. the effects and mechanisms of progestins to modulate seizures have not been systematically investigated. The present studies were designed to characterize the effects of progestins to modulate pentylenetetrazole (PTZ)-induced seizures in female rats. Methods: In Experiment 1. ictal activity and plasma and hippocampal progesterone (P) and 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) levels of proestrous rats were compared with those of diestrous and ovariectomized (ovx) rats. Experiments 2 and 3 examined effects of ovx and replacement with vehicle. P, or 3alpha,5alpha-THP, systemically (Experiment 2) or to the hippocampus (Experiment 3) on seizures and plasma and hippocampal P and 3alpha,5alpha-THP concentrations. Results: Proestrous rats had reduced ictal actiivty and increased levels of P and 3alpha,5alpha-THP in plasma and hippocampus compared with diestrous or ovx rats (Experiment 1). Rats administered systemic P or 3alpha,5alpha-THP had significantly reduced ictal activity and increased plasma and hippocampal P and 3alpha,5alpha-THP levels compared with vehicle-administered rats (Experiment 2). Administration of P or 3alpha,5alpha-THP to the hippocampus of ovx rats significantly reduced seizure activity and increased hippocampal, but not plasma, levels of P and 3alpha,5alpha-THP compared with vehicle administration (Experiment 3). Conclusions: Together, these data suggest that P can have antiseizure effects, and these effects may be due in part to actions of its metabolite, 3alpha,5alpha-THP, in the hippocampus.