Dr. Samba Reddy identified a key neural mechanism for sex-specific treatment of brain disorders
It is well-known that genetic differences between men and women can play a key role in susceptibility to disease. However, the underlying mechanisms contributing to these differences are unclear. Currently, a major concern for researchers and physicians is the difference in the incidence rate and severity of epilepsy between males and females. A key player in many of these differences is the variation in hormone levels and receptor types between the two sexes. Clinical research has shown that men are more likely to have epilepsy than women, but women have epilepsy that is harder to treat. These differences have made it increasingly difficult to find therapeutic interventions for epilepsy, because physicians often prescribe the same medication to patients, regardless of sex.
“You can't just ask women to take the same epilepsy medication that a man is taking,” said Dr. D. Samba Reddy, Professor at the Texas A&M College of Medicine. “Lots of times they will complain: ‘Hey doc, it's not working.’ So, the doctor will increase the dose, but then the women start experiencing adverse side effects. Physicians should understand that the female brain is different and responds differently to medication.”
Dr. Reddy and his team recently published research in the journal Epilepsia that has served as the missing puzzle piece in the overall picture of using neurosteroid therapy to treat epilepsy in men and women. It is the final product of 15 years of research on receptor distribution, neurosteroid therapy, catamenial epilepsy, and mechanisms for extrasynaptic δGABA-A receptors. This latest paper has indicated that the difference in extrasynaptic δGABA-A receptor levels between men and women is responsible for the difference in response to neurosteroid therapy for epilepsy. Essentially, this means that designing personalized, sex-specific treatment is critical for treating epilepsy.
“Women tend to have more extrasynaptic δGABA -A receptors than men,” Dr. Reddy said. “These receptors are sensitive to neurosteroids and play a crucial role in mediating tonic inhibition in the brain, which keeps the electrical activity at a safe level. Without tonic inhibition, the brain can get overexcited and fire when it should not, which causes seizures. This higher number of δGABA-A receptors in women is why they react much better to neurosteroids and are more protected from epilepsy with neurosteroid treatment. In men, there are fewer δGABA-A receptors, which means they have a lower level of tonic inhibition, so they are more prone to seizures.”
The study took a three-pronged approach to demonstrate that women react more potently to neurosteroid therapy than men. The elegant series of pharmacological and electrophysiological studies shows that the increased neuroprotection in females is indeed due to the presence of δGABA-A receptors, because differences in neuroprotection were only observed when the receptors were present. Finally, the Reddy lab group examined the receptor distribution of δGABA-A receptors in the hippocampus, a region of the brain that is important in memory and plays a crucial role in the development of epilepsy. The histological findings showed that there was a higher expression of the extrasynaptic δGABA-A receptors in the hippocampus of females than in males. This confirms that women are genetically endowed with a larger number of receptors, which confers greater tonic inhibition with the use of neurosteroid therapy.
These findings ultimately indicate that neurosteroid therapy has the potential to serve as a sex-specific, personalized treatment for epilepsy for both men and women. This key piece of the puzzle has the potential to improve the treatment of epilepsy in individuals who do not adequately respond to typical anti-epileptics. These findings may have broader implications in designing personalized, sex-specific therapies for other conditions such as migraine, depression, and excitability disorders.
“This proves beyond doubt that it's the delta extrasynaptic receptor numbers that contribute to the effect of neurosteroid therapy,” Dr. Reddy said.