Allopregnanolone, the active metabolite of progesterone protects against neuronal damage in picrotoxin-induced seizure model in mice.
Progesterone exerts anti-seizure effect against several chemoconvulsants. However, there is no published report on the interaction between progesterone and picrotoxin (PTX). The present study evaluated the effects of progesterone and its active metabolite, allopregnanolone against PTX-induced seizures, brain lipid peroxidation and DNA fragmentation in male mice. Finasteride, a 5alpha-reductase inhibitor and indomethacin, an inhibitor of 3infinity-hydroxysteroid dehydrogenase were assessed against progesterone's effects on PTX-induced seizures, brain lipid peroxidation and DNA fragmentation. PTX produced clonic-tonic seizures in mice with CD50 and CD97 of 2.4 and 4.0mg/kg, i.p. respectively. Progesterone significantly countered PTX-induced seizures, with ED50 of 78.30mg/kg and ED97 of 200mg/kg. Progesterone antagonized PTX-induced DNA fragmentation. Finasteride (200mg/kg) and indomethacin (1mg/kg) reversed the anti-seizure and anti-DNA fragmentation effects of progesterone. Allopregnanolone, also protected against PTX-induced seizures and DNA fragmentation. There was no significant change in the brain lipid peroxidation parameters in any of the treatment groups. It may be concluded that progesterone protects against PTX-induced seizures and DNA fragmentation through its active metabolites allopregnanolone and 5alpha-pregnan-3,20-dione. However, it appears from the present study that, the neuroprotection with progesterone is primarily on account of allopregnalone. The therapeutic potential of allopregnanolone deserves to be evaluated clinically.
Departments of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
Surjit
S
Singh
Debasish
D
Hota
Ajay
A
Prakash
Krishan L
KL
Khanduja
Sunil K
SK
Arora
Amitava
A
Chakrabarti
D000818:Animals; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004587:Electrophoresis, Agar Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D010852:Picrotoxin / Q000633:toxicity*; D011280:Pregnanolone / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D003292:Convulsants; D004791:Enzyme Inhibitors; D018120:Finasteride; D007213:Indomethacin; D010852:Picrotoxin; D011280:Pregnanolone