5. Novel anticonvulsant effects of supraphysiological doses of progesterone in hippocampal-kindled mice

Abstract

Background Progesterone is a known anticonvulsant. Progesterone’s anticonvulsant effects are generally attributed to its secondary metabolite, 5α,3α-tetrahydroprogesterone (THP, also known as allopregnanolone), and THP’s enhancement of GABAA receptor activity. Accumulating evidence, however, suggests that progesterone itself may have anticonvulsant effects independent of the GABAA receptor. Using the enzyme inhibitor finasteride, we explored THP/GABAA-independent anticonvulsive actions of progesterone, in both a mouse model of hippocampal kindling in vivo and in mouse entorhinal slices in vitro. Methods Kindled mice were treated with intra-peritoneal injections of progesterone (10, 35, 100 and 160 mg/kg) with or without finasteride pretreatment (50 or 100 mg/kg), THP (1, 3.5, 10 and 30 mg/kg), midazolam (2 mg/kg) and carbamazepine (50 mg/kg). Entorhinal cortical slices were prepared from naive young mice, and repetitive epileptiform potentials were induced by 4-aminopyridine (100 μM), picrotoxin (100 μM) and finasteride (1 μM). Results Progesterone and THP were anticonvulsant, as expected. Pretreatment with finasteride, changed, did not abolish the anticonvulsant effects of progesterone. Progesterone doses of 100 and 160 mg/kg suppressed both hippocampal and cortical afterdischarges. In finasteride-pretreated mice, progesterone at 100 and 160 mg/kg decreased cortical but not hippocampal afterdischarges. With or without finasteride pre-treatment, motor seizure stages were significantly reduced by 100 and 160 mg/kg of progesterone. In brain slices, progesterone at 1 μM inhibited entorhinal epileptiform potentials in the presence of picrotoxin and finasteride. Conclusions Supraphysiological doses of progesterone have anticonvulsant effects, via an unknown mechanism, that are independent of both THP and the GABAA receptor. These results are novel. Further investigation of potential mechanisms is necessary to improve our understanding of neuroendocrinological aspects of seizures and epilepsy.