The acute anticonvulsant effects of deoxycorticosterone in developing rats: role of metabolites and mineralocorticoid-receptor responses.
OBJECTIVE
The mechanisms that mediate the acute anticonvulsant effects of deoxycorticosterone (DOC) were investigated in young rats.


METHODS
Fifteen-day-old rats were pretreated with a variety of compounds, including (a) agonists of the receptors that bind DOC (mineralocorticoid receptors); (b) the DOC 5alpha- and 5alpha-3alpha-reduced metabolites, plus agonists that bind the receptors of the 5alpha-reduced metabolite of DOC (progesterone receptors); and (c) DOC itself in the presence and absence of metabolism and receptor blockers. Fifteen minutes later, pentylenetetrazol (PTZ) was administered, and maximal pentylenetetrazol (MMT) seizure responses were scored.


RESULTS
Agonists of mineralocorticoid receptors increased the latency to forelimb flexion in PTZ seizures and sometimes suppressed the seizures completely. At low, nonconvulsant doses, spironolactone (a mineralocorticoid-receptor antagonist) blocked the anticonvulsant effects of a nonsedating, but not a sedating, dose of DOC. These data suggest the possible direct involvement of mineralocorticoid receptors in the anticonvulsant effects of DOC. At low, nonconvulsant doses, finasteride (which blocks the metabolism of DOC) partially blocked the protective effects of DOC, suggesting the contribution of metabolites to the anticonvulsant actions of DOC. Dihydrodeoxycorticosterone (DHDOC)-the first metabolite of DOC, an agonist at progesterone receptors, and an allosteric modulator of the gamma-aminobutyric acid (GABA)(A) receptor-and tetrahydrodeoxycorticosterone, a secondary metabolite of DOC and an allosteric modulator of the GABA(A) receptor, both blocked MMT seizures.


CONCLUSIONS
These findings suggest that both DOC and its metabolites may contribute to the anticonvulsant effects seen in young rats, perhaps acting via interactions with several different receptors.
Edwards
Heather E
HE
University of Toronto Epilepsy Research Program and the Department of Pharmacology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada.
Vimal
Sutha
S
Burnham
W McIntyre
WM
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D010433:Pentylenetetrazole; D051381:Rats; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000187:drug effects*; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D013148:Spironolactone / Q000378:metabolism / Q000494:pharmacology
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D018079:Receptors, GABA; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D013148:Spironolactone; D003900:Desoxycorticosterone; C009413:tetrahydrodeoxycorticosterone; D018120:Finasteride; D010433:Pentylenetetrazole