Posted February 2, 2015
Audrey S. Yee, M.D., University of Colorado, and Amy S. Yee, Ph.D., Tufts University School of Medicine
The development of epilepsy resulting from brain injury follows a pattern. A serious trauma or toxic insult will give rise to seizures immediately, but then there is a variable quiet period after which seizures start to recur. Seizures may then go on to persist over a lifetime. Researchers are studying the mechanisms of epileptogenesis during this quiet period in order to develop interventions that can prevent the onset of chronic seizures. Drs. Audrey S. Yee and Amy S. Yee received partnering Peer Reviewed Medical Research Program Investigator-Initiated Research Awards to examine the role of the Wnt signaling pathway in epileptogenesis. Together they sought to establish a time course of Wnt signaling activation and to test whether modulation of that signaling early after epilepsy induction can prevent epileptogenic progression. Dr. Audrey Yee brings her experience in seizure-related neurophysiology, and Dr. Amy Yee brings her expertise in Wnt signaling from her studies in cancer research to the collaboration, making this a truly synergistic research team.
Through their combined efforts, the partners found that after inducing seizures in an animal model, Wnt signaling increases during the epileptogenic period and that negative regulators of this signaling are decreased. One of the negative regulators that was found to decrease during the epileptogenic period is HBP1. Using an online database of human genetic variation called "DECIPHER," they found that patients with deletions in the region of the HBP1 gene often exhibited seizures or abnormal EEG (electroencephalogram) activity. Dr. Amy Yee had previously studied the roles of HBP1 and Wnt signaling in breast cancer and knew that a compound in green tea called epigallocatechin 3-gallate, or EGCG, can increase levels of HBP1. Another drug they explored (in cancer) was decitabine, which blocks DNA methylation and activates the genes for several Wnt inhibitors. Together, this combination was effective at blocking Wnt and other pathways important for cancer and neuronal disease. Decitabine is already approved by the Food and Drug Administration for treatment of myelodysplastic syndromes, making it an attractive candidate to pursue for the treatment of epilepsy.
The collaborators then treated the animals with a combination of EGCG and decitabine and then induced seizures using two different methods. They found that the combination treatment decreased the number of subsequent seizures. Furthermore, they also observed that the combination treatment is effective when given within 6 hours of inducing seizures, and then for several days into the early epileptogenic period. The collaborators are continuing these studies to determine if the combination treatment can lessen the onset of chronic seizures and ultimately, whether this promising therapy can help patients at risk for post-traumatic epilepsy.