Anticonvulsant activity of the testosterone-derived neurosteroid 3alpha-androstanediol.
3alpha-Androstanediol is synthesized from testosterone in peripheral tissues and in the brain, but the clinical importance of this neurosteroid remains unclear. This study evaluated the effects of 3alpha-androstanediol on seizure susceptibility in mouse models of epilepsy. 3alpha-Androstanediol protected mice against seizures induced by GABAA receptor antagonists pentylenetetrazol, picrotoxin, and beta-carboline ester in a dose-dependent fashion. However, 3alpha-androstanediol was inactive against seizures induced by glutamate receptor agonists kainic acid, NMDA and 4-aminopyridine. Pretreatment with the androgen receptor antagonist flutamide had no effect on seizure protection by 3alpha-androstanediol. These results suggest that 3alpha-androstanediol has powerful anticonvulsant activity that occurs largely through non-genomic mechanisms. Testosterone-derived 3alpha-androstanediol might be an endogenous protective neurosteroid in the brain.
Reddy
Doodipala S
DS
Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, 4700 Hillsborough Street, Raleigh, NC 27606, USA. samba_reddy@ncsu.edu
D000726:Androgen Antagonists / Q000494:pharmacology; D015113:Androstane-3,17-diol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants; D002243:Carbolines; D003292:Convulsants; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists; D005485:Flutamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011944:Receptors, Androgen / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013739:Testosterone / Q000378:metabolism*
D000726:Androgen Antagonists; D015113:Androstane-3,17-diol; D000927:Anticonvulsants; D002243:Carbolines; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D005485:Flutamide; D010433:Pentylenetetrazole; D010852:Picrotoxin; D011944:Receptors, Androgen; D011963:Receptors, GABA-A; D013739:Testosterone; C028895:androstane-3,17-diol glucuronide