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Seizing the opportunity |
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 U.S. researchers have demonstrated that the efficacy of the anticonvulsant ganaxolone is enhanced during neurosteroid withdrawal in rats, supporting its potential as an effective treatment for women suffering the exacerbation of seizures in association with menstruation.
In at least 72% of women suffering from catamenial epilepsy, menstruation exacerbates their seizures. In part, this may be due to withdrawal of the progesterone metabolite allopregnanolone, an endogenous anticonvulsant neurosteroid that modulates GABAA receptors. Neurosteroid replacement has been proposed as a potential therapy for menstrual-associated seizures, but the bioavailibility of natural neurosteroids is poor and they are metabolized to compounds with progestational side effects, including breakthrough bleeding, breast tenderness, and amenorrhea. However, some synthetic neurosteroids, such as ganaxolone, are orally active analogues of allopregnanolone but are not converted to the hormonally active 3-keto form. These drugs might provide an alternative approach to seizure therapy. At the National Institute of Neurological Disorders and Stroke (part of the National Institutes of Health) in Bethesda, MD, Michael Rogawski and Doodipala Reddy have found that ganaxolone might indeed be an effective treatment of catamenial seizure exacerbations (J. Pharmacol. Exp. Therap. 2000, 294, 909–915). To simulate the period from ovulation through the menstrual bleed, the team induced a persistently high serum progesterone level in 26-day-old rats by using gonadotropins. Neurosteroids were abruptly withdrawn on postnatal day 39 using the 5a-reductase inhibitor finasteride to mimic the natural premenstrual drop. The inhibitor causes a decrease in allopregnanolone and so reduces the threshold at which seizures occur. The susceptibility to seizure was then evaluated using the convulsant pentylenetetrazol. In this sensitized state, the rats responded far better (some three times) to the anticonvulsant ganaxolone without showing motor disabilities. The plasma concentrations of the drug were similar in control and neurosteroid-withdrawn animals, indicating that it was not a simple matter of higher levels of circulating ganaxolone in one group. Since publication, the team has found that long-term use of ganaxolone shows no tolerance or cross-tolerance, but further research will be required to demonstrate that the drug does not induce the behavioral effects of neurosteroids, including sedative– hypnosis, anxiolysis, and cognitive impairment. — |
