Temporal lobe epilepsy (TLE) is a common and often devastating form of human epilepsy that currently lacks preventive therapy. Evidence from clinical and preclinical studies supports the idea that an episode of prolonged seizures (status epilepticus or SE) contributes to development of TLE. Defining the molecular mechanisms by which SE transforms a normal brain into an epileptic brain is essential for identifying molecular targets for preventive therapies. As part of our longstanding commitment to discover treatments for epilepsy, we conducted an extensive series of target validation experiments and have now identified a druggable molecular target that can prevent TLE in mice. We recently reported the brain-derived neurotrophic factor (BDNF) receptor tyrosine kinase, TrkB, is required for SE-induced TLE. We have identified the major signaling pathway by which TrkB signaling promotes epileptogenesis and conducted a high-throughput screen seeking small molecule inhibitors of this pathway. Hits have been identified from multiple chemotypes. Here we propose: 1) To develop additional cell free and cell based assays to facilitate characterization of these hits. 2) To confirm chemical integrity and biological activity of current hits and to develop a medicinal chemistry portfolio for entry to Blueprint program.
Temporal lobe epilepsy is a common and commonly devastating form of human epilepsy for which there is no method of prevention. The proposed studies seek to develop small molecule inhibitors of TrkB signaling for prevention of epilepsy.
