Pharmacoresistance in epilepsy : modelling and prediction of disease progression

Abstract

Despite the availability of a wide range of antiepileptic drugs, in about one third of people who suffer from epilepsy, seizures cannot be adequately controlled by pharmacotherapy. The mechanisms underlying this pharmacoresistance are still unclear. This thesis investigates the relationship between the time course of epileptogenesis, the associated changes in GABA mediated inhibition and the development of pharmacoresistance. Impairment of GABA, the brain's major inhibiting neurotransmitter, may lead to excessive activation of excitatory neuronal circuits, as is the case in epilepsy. In vivo studies using an animal model for epilepsy show that the GABA(A) receptor changes early in the epileptogenic process. Alterations include decreased expression and altered subunit composition, resulting in a receptor that is less sensitive to some ligands and more sensitive to others.