Neuroactive steroids for the treatment of status epilepticus

Michael A Rogawski, Carlos M. Loya, Kiran Reddy, Dorota Zolkowska, Christoph Lossin

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Benzodiazepines are the current first-line standard-of-care treatment for status epilepticus but fail to terminate seizures in about one third of cases. Synaptic GABAA receptors, which mediate phasic inhibition in central circuits, are the molecular target of benzodiazepines. As status epilepticus progresses, these receptors are internalized and become functionally inactivated, conferring benzodiazepine resistance, which is believed to be a major cause of treatment failure. GABAA receptor positive allosteric modulator neuroactive steroids, such as allopregnanolone, also potentiate synaptic GABAA receptors, but in addition they enhance extrasynaptic GABAA receptors that mediate tonic inhibition. Extrasynaptic GABAA receptors are not internalized, and desensitization of these receptors does not occur during continuous seizures in status epilepticus models. Here we review the broad-spectrum antiseizure activity of allopregnanolone in animal seizure models and the evidence for its activity in models of status epilepticus. We also demonstrate that allopregnanolone inhibits ongoing behavioral and electrographic seizures in a model of status epilepticus, even when there is benzodiazepine resistance. Parenteral allopregnanolone may provide an improved treatment for refractory status epilepticus.

Original languageEnglish (US)
Pages (from-to)93-98
Number of pages6
JournalEpilepsia
Volume54
Issue numberSUPPL. 6
DOIs
StatePublished - 2013

Keywords

  • Allopregnanolone
  • Allosteric modulator
  • Extrasynaptic GABAA receptor
  • Neurosteroid
  • Refractory status epilepticus
  • Seizure

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Medicine(all)

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  • Cite this

    Rogawski, M. A., Loya, C. M., Reddy, K., Zolkowska, D., & Lossin, C. (2013). Neuroactive steroids for the treatment of status epilepticus. Epilepsia, 54(SUPPL. 6), 93-98. https://doi.org/10.1111/epi.12289