Role of neurosteroids in the anticonvulsant activity of midazolam.
OBJECTIVE
Midazolam is a short-acting benzodiazepine that is widely used as an i.v. sedative and anticonvulsant. Besides interacting with the benzodiazepine site associated with GABA(A) receptors, some benzodiazepines act as agonists of translocator protein (18 kDa) (TSPO) to enhance the synthesis of steroids, including neurosteroids with positive modulatory actions on GABA(A) receptors. We sought to determine if neurosteroidogenesis induced by midazolam contributes to its anticonvulsant action.


METHODS
Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the i.v. pentylenetetrazol (PTZ) threshold test.


RESULTS
Midazolam (500-5000 µg·kg(-1) , i.p.) caused a dose-dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5α-reductase inhibitor, and a functional TSPO antagonist PK 11195, reduced the anticonvulsant action of midazolam. The anticonvulsant action of midazolam was enhanced by the neurosteroidogenic drug metyrapone, an 11β-hydroxylase inhibitor. In contrast, the anticonvulsant action of clonazepam (100 µg·kg(-1) ) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO.


CONCLUSIONS
Enhanced endogenous neurosteroid synthesis, possibly mediated by an interaction with TSPO, contributed to the anticonvulsant action of midazolam. Enhanced neurosteroidogenesis may also be a factor in the actions of other benzodiazepines, even those that only weakly interact with TSPO.
Department of Neurology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Ashish
A
Dhir
Michael A
MA
Rogawski
D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002998:Clonazepam / Q000627:therapeutic use; D003292:Convulsants; D004195:Disease Models, Animal; D018120:Finasteride / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008874:Midazolam / Q000627:therapeutic use*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010433:Pentylenetetrazole; D018079:Receptors, GABA / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
D058891:5-alpha Reductase Inhibitors; D000927:Anticonvulsants; C463819:Bzrp protein, mouse; D003292:Convulsants; D018756:GABA Antagonists; D007546:Isoquinolines; D018377:Neurotransmitter Agents; D018079:Receptors, GABA; D018120:Finasteride; D002998:Clonazepam; D008874:Midazolam; D010433:Pentylenetetrazole; C037850:PK 11195