Role of neurosteroids in the anticonvulsant activity of midazolam

Ashish Dhir, Michael A Rogawski

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

BACKGROUND AND PURPOSE: 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 Areceptors. 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 i.v. pentylenetetrazol (PTZ) threshold test. KEY 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. CONCLUSION AND IMPLICATIONS: 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.

Original languageEnglish (US)
Pages (from-to)2684-2691
Number of pages8
JournalBritish Journal of Pharmacology
Volume165
Issue number8
DOIs
StatePublished - Apr 2012

Keywords

  • Clonazepam
  • Finasteride
  • Metyrapone
  • Midazolam
  • Neurosteroid
  • Pentylenetetrazol
  • Peripheral benzodiazepine receptor
  • PK 11195

ASJC Scopus subject areas

  • Pharmacology

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