Pharmacologically targeting transient receptor potential channels for seizures and epilepsy: Emerging preclinical evidence of druggability.

As one of the most prevalent and disabling brain disorders, epilepsy is characterized by spontaneous seizures that result from aberrant, excessive hyperactivity of a group of highly synchronized brain neurons. Remarkable progress in epilepsy research and treatment over the first two decades of this century led to a dramatical expansion in the third-generation antiseizure drugs (ASDs). However, there are still over 30% of patients suffering from seizures resistant to the current medications, and the broad unbearable adversative effects of ASDs significantly impair the quality of life in about 40% of individuals affected by the disease. Prevention of epilepsy in those who are at high risks is another major unmet medical need, given that up to 40% of epilepsy patients are believed to have acquired causes. Therefore, it is important to identify novel drug targets that can facilitate the discovery and development of new therapies engaging unprecedented mechanisms of action that might overcome these significant limitations. Also over the last two decades, calcium signaling has been increasingly recognized as a key contributory factor in epileptogenesis of many aspects. The intracellular calcium homeostasis involves a variety of calcium-permeable cation channels, the most important of which perhaps are the transient receptor potential (TRP) ion channels. This review focuses on recent exciting advances in understanding of TRP channels in preclinical models of seizure disorders. We also provide emerging insights into the molecular and cellular mechanisms of TRP channels-engaged epileptogenesis that might lead to new antiseizure therapies, epilepsy prevention and modification, and even a cure.