Epilepsy is one of the most common acquired chronic neurologic disorders, not only characterized by neuronal hyperexcitability and sudden, synchronized electrical discharges that can manifest as seizures, but also by an increased incidence of comorbid conditions such as anxiety, depression, cognitive dysfunction, and sudden unexpected death. About 70 million people worldwide suffer from epilepsy, with temporal lobe epilepsy (TLE) being is the most common and progressive form. Surprisingly, up to one-third of all people with epilepsy are refractory to current medications. As such, the development of new, more effective and specific drugs is still of upmost importance. It is generally accepted that glutamate is a key player in the initiation as well as the maintenance of epileptic seizures. Some anti-seizure drugs (ASDs) exert their effect via antagonism of glutamate receptors, however up to date, no ASDs are available that specifically target glutamate transporters. Glutamate transporters might represent innovative targets as their malfunctioning can lead to altered glutamate levels and worsening of seizures. Yet, the importance of vesicular glutamate transporters (VGLUTs) and the cystine-glutamate antiporter (system xc-) in TLE remain poorly investigated. In this thesis we demonstrated for the first time the involvement of astrocytic vesicular (VLGUT3) and non-vesicular (system xc-) glutamate release in human TLE samples. Next, we highlighted the importance of the use of proper negative controls when performing histological analyses in xCT research in order to avoid generating conflicting data and drawing wrong conclusions. Finally, the potential of system xc- as a novel target for anti-epileptogenic and/or disease-modifying therapies was demonstrated for the first time in three distinct chronic epilepsy mouse models.
|Date of Award||18 Sep 2018|
- Vrije Universiteit Brussel
|Supervisor||Ann Massie (Promotor)|