New epilepsy drugs block electrical signals in the brain
Epilepsy is a recurrent, chronic disorder of the brain characterized by repeated seizures, which can endanger the person in a variety of situations due to uncontrolled movement and put them at increased risk of certain health conditions, not to mention the stigma that is associated with epilepsy in some cultures. Furthermore, seizures can be fatal if they cause breathing problems, choking, drowning, or serious injury.
In about three-quarters of epileptic patients, the epilepsy can be controlled fairly effectively by available drugs, but for the other quarter of patients who do not respond to these drugs, the quest is still on for newer, more effective, and more powerful epilepsy drugs.
A variety of scientists are taking part in this mission, including Maria Kurnikova, an associate professor of chemistry at Carnegie Mellon. Kurnikova and her team recently published a paper in the journal Neuron discussing their findings regarding how one class of anti-seizure drugs blocks certain receptors in the brain known as AMPA receptors — short for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors — from propagating the brain’s electrical signals further. Since seizures are caused by abnormally high levels of electrical activity in the brain that propagate uncontrollably via hypersensitive AMPA receptors, blocking these receptors is one way to control seizures.
In particular, Kurnikova’s work specialized in using powerful computer programs to simulate how many anti-seizure drugs have molecules that “sit” in the binding sites of AMPA receptors and thus prevent them from propagating seizure signals further. It helped identify the binding site of the receptor, which strengthened the theory that the medications act as a “block” in the receptor.
The simulations test millions of different configurations of the interactions between drug and binding site, using technology available thanks to the technological advances made by video game manufacturers. The powerful graphics technology developed by game manufacturers allowed the team to be able to use computers with more computing ability — especially important for these simulations — for a lower cost. These technologies also mean that Kurnikova is able to access more powerful computers today than when she first started this work several years ago.
Besides the computers in the laboratory, Kurnikova and her team also use a high-speed computer called ANTON, located at the Pittsburgh Supercomputing Center, which is specially designed for molecular simulations. However, this computer is used by researchers all around the nation, so the team applies for time slots on ANTON through the National Academy of Sciences. ANTON simulations are 100 times faster than the simulations in Kurnikova’s laboratory.
Currently, many anti-seizure medications have side effects such as sleepiness or headaches because AMPA receptors are necessary for normal brain function.
“Basically what you want to do with the drugs is create a situation where the excitation [in the brain] is not quite so easy to achieve, so you might create some sleepiness,” Kurnikova said in a university press release.
This study suggests that changing the drug design has the potential to make the drug more effective with fewer side effects. Together with work done by Alexander Sobolevsky of Columbia University and his team, which involved using techniques such as crystallography to study how anti-seizure drugs block the seizure signals from travelling further in the brain, Kurnikova’s work could help develop safer, more powerful anti-seizure medications in the future.