Neurotherapeutics

, Volume 6, Issue 2, pp 392–401

Neurosteroid replacement therapy for catamenial epilepsy

Theme 5: Hormonal and Dietary Therapy

DOI: 10.1016/j.nurt.2009.01.006

Cite this article as:
Reddy, D.S. & Rogawski, M.A. Neurotherapeutics (2009) 6: 392. doi:10.1016/j.nurt.2009.01.006

Summary

Perimenstrual catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation, affects a high proportion of women of reproductive age with drug-refractory epilepsy. Enhanced seizure susceptibility in perimenstrual catamenial epilepsy is believed to be due to the withdrawal of the progesterone-derived GABAA receptor modulating neurosteroid allopregnanolone as a result of the fall in progesterone at the time of menstruation. Studies in a rat pseudopregnancy model of catamenial epilepsy indicate that after neurosteroid withdrawal there is enhanced susceptibility to chemoconvulsant seizures. There is also a transitory increase in the frequency of spontaneous seizures in epileptic rats that had experienced pilocarpine-induced status epilepticus. In the catamenial epilepsy model, there is a marked reduction in the antiseizure potency of anticonvulsant drugs, including benzodiazepines and valproate, but an increase in the anticonvulsant potency and protective index of neurosteroids such as allopregnanolone and the neurosteroid analog ganaxolone. The enhanced seizure susceptibility and benzodiazepine-resistance subsequent to neurosteroid withdrawal may be related to reduced expression and altered kinetics of synaptic GABAA receptors and increased expression of GABAA receptor subunits (such as α4) that confer benzodiazepine insensitivity. The enhanced potency of neurosteroids may be due to a relative increase after neurosteroid withdrawal in the expression of neurosteroid-sensitive δ-subunit-containing perisynaptic or extrasynaptic GABAA receptors. Positive allosteric modulatory neurosteroids and synthetic analogs such as ganaxolone may be administered to prevent catamenial seizure exacerbations, in what we call neurosteroid replacement therapy.

Key Words

Catamenial epilepsy progesterone neurosteroid allopregnanolone ganaxolone GABAA receptor 

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2009

Authors and Affiliations

  1. 1.Department of Neuroscience and Experimental Therapeutics, College of MedicineTexas A&M Health Science CenterCollege Station
  2. 2.Department of Neurology, School of MedicineUniversity of California, DavisSacramento

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