Antiseizure effects of 5*-androstane-3*,7beta-diol may be independent of actions at estrogen receptor beta.
Testosterone (T), the principal androgen secreted by the testes, can have antiseizure effects; however, the mechanism(s) underlying this action is not well understood. T is metabolized to dihydrotestosterone (DHT) by the enzyme 5*-reductase. DHT is then converted to 5*-androstane-3*,17beta-diol (3*-diol) by the enzyme 3*-hydroxysteroid dehydrogenase. T and DHT bind with high affinity to intracellular androgen receptors; however, 3*-diol does not. The mnemonic effects of 3*-diol are mediated in part through the beta isoform of estrogen receptors (ERbeta) in the hippocampus. As such, we investigated whether 3*-diol has antiseizure effects in mice that require action at ERbeta. 3*-Diol (2 mg/kg subcutaneously) was administered to wild-type C57/B6 mice and heterozygous and homozygous ERbeta knockout (betaERKO) mice 1 hour prior to administration of pentylenetetrazol (PTZ; 85 mg/kg intraperitoneally). Mice administered 3*-diol had significantly longer latencies to clonic seizure and death and lower seizure scores than did mice administered vehicle. This pattern of effects was observed in wild-type or betaERKO mice. Thus, for these mice, the antiseizure effects of 3*-diol for the chemoconvulsant PTZ occur independent of actions at ERbeta.
Ryan
Allicia
A
Department of Psychology, University at Albany-SUNY, Albany, NY 12222, USA.
Frye
Cheryl A
CA
D015113:Androstane-3,17-diol / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*
D000927:Anticonvulsants; D047629:Estrogen Receptor beta; D015113:Androstane-3,17-diol; D010433:Pentylenetetrazole