Epileptogenesis is the collective of processes that underlie the transition of a healthy neural network into a network that can generate epileptic seizures. In Temporal Lobe Epilepsy (TLE), epileptogenesis is often associated with cell loss, inflammation, oxidative stress, and axonal sprouting in the hippocampus. Also, hyper-activation of the mammalian target of rapamycin (mTOR) pathway is thought to be involved in epileptogenesis. Interfering with mTOR activation or epileptogenic processes such as inflammation could reduce or prevent epileptogenesis, and thus lead to the development of anti-epileptogenic treatments for TLE.
This thesis investigates epileptogenesis and the role of the mTOR pathway in TLE, and the anti-epileptogenic potential of two compounds: rapamycin and curcumin, using several experimental models for TLE in vivo and in vitro.
Rapamycin, the main inhibitor of the mTOR pathway, was found to suppress epilepsy in vivo, but it did not completely reverse or prevent epileptogenesis. Also, rapamycin treatment was associated with side effects on growth. As an alternative mTOR inhibitor, curcumin, the anti-oxidant and anti-inflammatory component of turmeric, was investigated. Whereas effects of rapamycin were strongly related to mTOR inhibition, experiments in vitro demonstrated that curcumin rather targeted inflammatory pathways. Curcumin reduced epileptogenesis in vitro, but its low bioavailability likely limited its efficacy in vivo.
Although this suggests that the road towards a safe and effective anti-epileptogenic treatment is long, this thesis argues that combining anti-seizure, anti-inflammatory, neuroprotective, anti-oxidant and anti-growth effects could be a promising anti-epileptogenic strategy in TLE.