The Role of Brain Inflammation in Epileptogenesis in TSC

Principal Investigator: WONG, MICHAEL
Program: TSCRP
Proposal Number: TS110015
Award Number: W81XWH-12-1-0190
Funding Mechanism: Exploration - Hypothesis Development Award
Partnering Awards:
Award Amount: $151,991.02


Epilepsy, a condition characterized by recurrent seizures, is a very common problem in tuberous sclerosis complex (TSC), occurring in up to 90% of all individuals with TSC. The seizures in TSC can be particularly severe and impairing, causing a number of difficulties and complications for TSC patients, such as functional disability, loss of independence, social isolation, and increased risk of bodily injury and death. Furthermore, epilepsy in TSC usually does not respond well to currently available treatments, such as seizure medications, as most TSC patients continue to have seizures despite multiple trials of different drugs and other treatments. Thus, the overall goal of this project is to develop novel, more effective therapies for epilepsy in TSC, which would significantly improve the quality of life of TSC patients.

Most currently available therapies for epilepsy work by attempting to suppress the symptoms of epilepsy (i.e., the seizures), but do not actually prevent or reverse the underlying brain abnormalities causing the seizures in the first place. Recently, epilepsy researchers have realized that completely different types of treatments need to be developed that do not just mask symptoms, but truly target the key cellular and molecular mechanisms in the brain responsible for causing epilepsy. This newer "anti-epileptogenic" or "disease-modifying" approach could offer substantial improvements over current therapies and possibly even represent a cure for epilepsy. mTOR inhibitors, such as rapamycin or everolimus, represent potential novel therapies for epilepsy, but have not yet been established to be effective for epilepsy in TSC. Brain inflammation has been found in pathological specimens of cortical tubers from patients with TSC and intractable epilepsy, suggesting that anti-inflammatory drugs might also represent a rational, targeted treatment for epilepsy in TSC, but this has not been proven. This grant proposal attempts, for the first time, to determine the role of brain inflammation in causing epilepsy in a mouse model of TSC and to test the effect of anti-inflammatory drugs in preventing or decreasing epilepsy in this mouse model. The findings for this research could help establish a role for anti-inflammatory drugs as a novel, more effective treatment for epilepsy and other neurological manifestations in TSC patients.