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Article
Role of Neurosteroids in the Anticonvulsant Activity of Midazolam
British Journal of Pharmacology (2012)
  • Ashish Dhir, University of California - Davis
  • Michael A Rogawski, University of California - Davis
Abstract
BACKGROUND AND PURPOSE Midazolam is a short-acting benzodiazepine that is widely used as an intravenous 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. EXPERIMENTAL APPROACH Mice were pretreated with neurosteroid synthesis inhibitors and potentiators followed by midazolam or clonazepam, a weak TSPO ligand. Anticonvulsant activity was assessed with the intravenous pentylenetetrazol (PTZ) threshold test. KEY RESULTS Midazolam (500–5000 μg/kg, i.p.) caused a dose-dependent increase in seizure threshold. Pretreatment with the neurosteroid synthesis inhibitors finasteride, a 5α-reductase inhibitor, and 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195), a functional TSPO antagonist, 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) was reduced by finasteride but not by PK 11195, indicating a possible contribution of neurosteroids unrelated to TSPO. CONCLUSIONS AND IMPLICATIONS Enhanced endogenous neurosteroid synthesis, likely mediated by an interaction with TSPO, contributes 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.
Keywords
  • midazolam,
  • clonazepam,
  • peripheral benzodiazepine receptor,
  • neurosteroid,
  • finasteride,
  • PK 11195,
  • metyrapone,
  • pentylenetetrazol
Publication Date
April, 2012
Publisher Statement
Available at: http://dx.doi.org/10.1111/j.1476-5381.2011.01733.x
Citation Information
Ashish Dhir and Michael A Rogawski. "Role of Neurosteroids in the Anticonvulsant Activity of Midazolam" British Journal of Pharmacology Vol. 165 Iss. 8 (2012)
Available at: http://works.bepress.com/michael_rogawski/42/