GABAA receptor active steroids are altered in epilepsy patients with tuberous sclerosis

Abstract

Background: The neuroactive steroid 3α, 5α-tetrahydroprogesterone is the most potent endogenous positive modulator of γ-amino-butyric acid (GABA)_A receptors. There is evidence for a relation between neuroactive steroids and seizure susceptibility. Objective: To evaluate the putative role of counteregulator neuroactive steroids in the occurrence of seizures in patients with tuberous sclerosis. Methods: Plasma concentrations of the enantiomers 3α, 5α- and 3α, 5β-tetrahydroprogesterone (3α_s-THP), which are positive modulators of GABA_A receptors, were measured in 18 patients, along with their endogenous functional antagonists 3β, 5α- and 3β, 5β-THP (3β_s-THP), to assess their possible modification compared with control subjects. Neuroactive steroids were assayed using a highly sensitive and specific gas chromatographic/mass spectrometric method. Results: In the tuberous sclerosis patients with poorly controlled seizures, there was a significantly lower 3α_s/3β_s-THP ratio than in seizure-free patients or control subjects. Conclusions: The reduced 3α_s/3β_s-THP ratio may decrease GABAergic tone, contributing to the appearance of seizures in tuberous sclerosis patients with epilepsy.