11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

Rafal M. Kaminski, Michael A Rogawski

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Steroid 11β-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABA A receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is a potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED 50, 191 mg/kg), but is markedly more potent at 6 h (ED 50, 30 mg/kg). Similarly, etomidate is also protective at 30 min and 6 h (ED 50 values, 4.5 and 1.7 mg/kg). Finasteride, an inhibitor of neurosteroid synthesis, attenuated the anticonvulsant effects of both CYP11B1 inhibitors at 6 h, but not 30 min following their injection. Plasma THDOC levels measured by liquid chromatography-mass spectrometry were markedly increased 6 h after injection of both CYP11B1 inhibitors and this increase was attenuated by finasteride pretreatment. We conclude that inhibition of CYP11B1 causes delayed seizure protection due to slow build-up of neurosteroids. Early seizure protection is independent of neurosteroids.

Original languageEnglish (US)
Pages (from-to)133-137
Number of pages5
JournalNeuropharmacology
Volume61
Issue number1-2
DOIs
StatePublished - Jul 2011

Keywords

  • Allotetrahydrodeoxycorticosterone
  • Etomidate
  • Finasteride
  • Metyrapone
  • Neurosteroid
  • Steroid 11β-hydroxylase (CYP11B1) inhibitor

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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