How do we break the cycle of epilepsy in women?
US researchers have made an important discovery about a form of epilepsy that affects women most severely during menstruation. The findings could lead to a new treatment based on manipulating levels of the hormone progesterone.
Epilepsy affects about 40 million people worldwide, with a proportion of sufferers being women where their symptoms are related to the menstrual cycle, so-called catamenial epilepsy. In at least 72% of catamenial epilepsy sufferers, menstruation exacerbates their seizures. Women with catamenial epilepsy tend to have seizures clustered around their monthly cycle, sometimes as many as three or four a day. Seizures are generally mild, partial seizures, but some women experience severe generalized seizures and lose consciousness. Scientists have learned that the hormone progesterone provides some protection from the seizures, and it may be that as levels of that hormone fall near the end of the menstrual cycle that women are suddenly more vulnerable to a seizure.
According to Doodipala Reddy of North Carolina State University, catamenial epilepsy is an often neglected area but they are hoping to improve the options available to sufferers through their research. They have discovered how progesterone is involved in protecting against seizures and identified how the protection happens. “Scientists have known for many decades that progesterone has anti-convulsive properties, but we didn’t fully understand how,” Reddy explains. Recent developments in transgenic mouse technology and availability of specific 5a-reductase enzyme inhibitors made it possible to elucidate the biochemical mechanisms of progesterone in seizure susceptibility.
Reddy and his colleagues have worked with Bert O’Malley of the Baylor College of Medicine and Michael Rogawski from the National Institute of Neurological Disorders and Stroke (NINDS) to elucidate the protective role of progesterone. Progesterone plays two important roles in brain function, they explain. First, it binds to progesterone receptors and helps regulate reproductive functions. Secondly, it is metabolized to the neurosteroid allopregnanolone. “It had been thought that the progesterone binding to the progesterone receptor is what provided the protection from seizures, but we discovered that it’s the neurosteroid allopregnanolone that actually provides the protection” Reddy explains.
The team used a model to show that allopregnanolone also activates another brain receptor GABA-A. This is a subtype of the receptors that usually control inhibitory neurotransmission in the brain, when it malfunctions, seizures can result as excitatory neurotransmission goes out of control. The researchers found that the neurosteroid acts as a “positive allosteric modulator” for this receptor, it binds to it and temporarily opens this chloride ion channel and thereby causes hyperpolarization. This stops the runaway neuronal activity and precludes the seizure. Reddy explains that withdrawal from this neurosteroid, which occurs naturally during menstruation, removes the controlling factor and allows a seizure to occur.
Currently, there are no approved drugs specifically for treating catamenial epilepsy. “We tested the traditional anti-convulsants like Valproate and Diazepam, but they don’t work well in this disorder,” Reddy says. Progesterone is not the answer either, as administering it during susceptible periods of the menstrual cycle could disturb the reproductive system causing breakthrough bleeding, breast tenderness, and other side-effects.
Reddy now proposes that neurosteroid replacement could be used at times when the allopregnanolone metabolite of progesterone tapers off. “If you can maintain those levels, that should take care of the seizure problem,” he explains. Allopregnanolone may produce some hormonal side effects. An allopregnanolone analog, ganaxolone, overcomes this limitation.
Ganaxolone is a synthetic neuroactive steroid that was originally discovered at CoCensys for the treatment of epilepsy. It was acquired by Purdue Pharma in 1999 for further clinical evaluation (phase III). This drug was developed as a result of an elegant series of studies by Kelvin Gee and colleagues in the 1990s, which was turn based on some clues from earlier studies of progesterone in 1940s. “There’s still a lot more for us to learn about this disease,” adds Reddy. “It’s a very ambitious goal, but we’d like to try and find novel treatment options for prevention or cure of this disease.”
The researchers also suggest that their findings could have implications for understanding the symptoms of premenstrual syndrome, such as mood swings and headaches, which are also associated with fluctuations in neurosteroids during the menstrual cycle.
Reddy, D. (2004). Anticonvulsant Activity of Progesterone and Neurosteroids in Progesterone Receptor Knockout Mice Journal of Pharmacology and Experimental Therapeutics, 310 (1), 230-239 DOI: 10.1124/jpet.104.065268