Researchers at Georgetown University Medical Center have found that targeting aging brain cells could offer a new therapeutic strategy for temporal lobe epilepsy (TLE), a condition characterized by recurring seizures and cognitive problems. The study, funded by the National Institutes of Health, was published in the Annals of Neurology on December 22.
"A third of individuals living with epilepsy don't achieve freedom from seizures with current medications," said Patrick A. Forcelli, Ph.D., professor and chair of Georgetown School of Medicine's Department of Pharmacology & Physiology. "Our hope is that senotherapy, which involves using medications to remove senescent, or aging cells, could potentially minimize the need for surgery and/or improve outcomes after surgery."
Temporal lobe epilepsy can result from various causes such as traumatic brain injuries, infections like meningitis, brain tumors, blood vessel malformations, and genetic syndromes. TLE is the most common form of drug-resistant epilepsy and affects about 40% of patients who have epilepsy.
In their research, scientists examined human brain tissue removed during surgery from people with TLE. They observed a five-fold increase in aging glial cells compared to tissue from individuals without the disease. Glial cells play a supportive role for neurons but do not transmit electrical signals themselves.
Using these findings as a basis, the researchers studied mice that had been given an injury to mimic TLE. Within two weeks following the initial injury in mice, there was an increase in cellular markers indicating senescence at both gene and protein levels. When treatments were used to remove these aging cells in mice, researchers saw a 50% reduction in senescent cell numbers. Treated animals also showed improved performance navigating mazes, experienced fewer seizures, and about one-third were protected from developing epilepsy altogether.
The treatment tested involved dasatinib—a drug already approved by the FDA for certain types of leukemia—and quercetin, an antioxidant found naturally in many fruits and vegetables. This combination has previously been used to target senescent cells in other animal studies modeling various diseases. According to Forcelli, dasatinib’s established safety profile could speed up clinical trials for its use against epilepsy.
Tahiyana Khan, Ph.D., and David J. McFall—first co-authors on the study—note that glial cell senescence has recently been linked not only to aging but also neurodegenerative conditions such as Alzheimer’s disease.
"We have ongoing studies using other repurposed drugs that can impact senescence as well as studies in other rodent models of epilepsy. We would like to understand the critical windows for intervention in epilepsy, and the hope is that these studies will lead to clinically useful treatments," said Forcelli.
Other authors from Georgetown include Abbas I. Hussain; Logan A. Frayser; Timothy P. Casilli; Meaghan C. Steck; Irene Sanchez-Brualla, Ph.D.; Noah M. Kuehn; Michelle Cho; Jacqueline A. Barnes, M.D.; Brent T. Harris, M.D., Ph.D.; and Stefano Vicini, Ph.D.
