New hope for sex-specific personalized medications for brain disorders

It is well-known that genetic differences between men and women can play a key role in susceptibility to disease. The underlying mechanisms and physiology contributing to these differences are numerous and complex—sorting them out is similar to trying to solve a puzzle with an infinite number of pieces.

Currently, a major concern for neuroscience 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. Often, this can cause additional problems by introducing undesirable side effects and providing inadequate neuroprotection against epilepsy.

“You can’t just ask women to take the same epilepsy medication that a man is taking,” said D. Samba Reddy, PhD, RPh, professor of neuroscience and experimental therapeutics 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.”

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 women with epilepsy.

“Women tend to have more extrasynaptic δGABA -A receptors than men,” 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. This indicates the need for lower doses of neurosteroid therapy in women and higher doses in men.

In the experiment, Reddy’s team first used a pilocarpine model to induce status epilepticus, or a prolonged seizure state. Then, they tested the effects of three different neurosteroids that bind preferentially with δGABA-A receptors.  Their findings showed a sex-dependent protective potency to neurosteroid therapy in the pilocarpine model. This essentially means that there was a direct relationship between neurosteroid level and protection against seizures, with females having more protection at a lower level of neurosteroids. The pilocarpine model also showed that when you take away the δGABA-A receptors by using subjects who have had their δGABA-A receptors knocked out, there is no difference between sexes in the neuroprotective ability of neurosteroids. This 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.

Reddy’s team repeated the experiment using a kindling model, where the brain is repeatedly stimulated with mild electricity to induce epilepsy. In this model, males needed fewer stimulations to reach their fully kindled state and become epileptic. Then, one group was given neurosteroid therapy before kindling. The findings showed that females had a greater delay in the rate of developing epilepsy than males when given neurosteroids prior to kindling. Next, subjects were treated with neurosteroids after developing epilepsy from kindling. The suppression of seizure activity was neurosteroid dose-dependent and females showed a higher rate of suppression of seizure activity with therapy. Finally, δGABA-A knockout subjects were given neurosteroid therapy after kindling, but there was no difference in protective effects of neurosteroid therapy between sexes. This use of the kindling model further proves that the presence of extrasynaptic δGABA-A receptors is what contributes to increased tonic inhibition in females, since neuroprotection differences were only seen in subjects that had receptors 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 treatment for epilepsy for both men and women, as long as dosage is properly adjusted for sex differences. 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 migraines, depression and excitability disorders.

“This proves beyond doubt that it’s the delta extrasynaptic receptor numbers that contribute to the effect of neurosteroid therapy,” Reddy said.

Sarah Elmer contributed to the writing of this article.