Neurosteroids and infantile spasms: The deoxycorticosterone hypothesis

Michael A Rogawski, Doodipala S. Reddy

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Deoxycorticosterone (DOC) is a mineralocorticoid precursor that has anticonvulsant properties in animals and possibly also in humans. Studies indicate that the anticonvulsant activity of DOC requires its enzymatic conversion to 5a,3a-tetrahydrodeoxycorticosterone (THDOC), a neurosteroid that lacks classical hormonal properties but acts as a powerful positive allosteric modulator of GABAA receptors. DOC can be considered a stress hormone because its synthesis is under the control of ACTH. Therefore, stress-induced fluctuations in seizure susceptibility could in part result from alterations in DOC availability. Also, the therapeutic activity of ACTH in infantile spasms could partially relate to its stimulatory effects on the synthesis of DOC, which then undergoes biotransformation to neurosteroids. The recent demonstration that the synthetic neurosteroid analog ganaxolone reduces spasm frequency in children with intractable infantile spasms suggests that neurosteroid-related anticonvulsants may offer a potential new nonhormonal approach for the treatment of infantile spasms and other developmental epilepsies. In addition, it further confirms the utility of pharmacological enhancement of GABA-mediated inhibition in the control of infantile spasms.

Original languageEnglish (US)
Pages (from-to)199-219
Number of pages21
JournalInternational Review of Neurobiology
Volume49
StatePublished - 2002
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)
  • Neuropsychology and Physiological Psychology
  • Biochemistry
  • Endocrinology

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