The present pioneer proposal defines the glial cystine/glutamate antiporter or system xc- as a completely new drug target for epilepsy. This membrane-bound amino acid transporter exchanges intracellular glutamate for extracellular cystine molecules, which makes this glial antiporter crucial for maintaining the intracellular levels of the antioxidant glutathione. Nevertheless, this property also points to system xc- as a non-negligible player in regulating extracellular glutamatergic neurotransmission. Since both oxidative stress and enhanced glutamate-mediated excitatory action are thought to be active contributors to seizures and epileptogenesis, the implication of the cystine/glutamate antiporter in the pathogenesis of epilepsy can be dual.
The applicant discovered in mice lacking xCT, the specific subunit of the cystine/glutamate antiporter, that the latter is the major source of extracellular glutamate in the hippocampus. Moreover, these xCT knockout mice were clearly less prone to acute limbic seizures than their wild type littermates. This breakthrough is the fundament to further unveil the role and mechanisms of action of system xc- in hippocampus-related normal brain functions as well as in pathophysiological conditions, such as seizure and epilepsy models. The possible involvement of the cystine/glutamate antiporter in mechanisms of learning and depression will also be investigated, because we aim to discover a ground braking way of treating epilepsy without interfering with cognitive function and mood, or that would ameliorate epilepsy-associated cognitive decline and depression.
To reach these objectives, a wide range of validated rodent models for seizures and epilepsy, tasks for learning and memory and depression-like behaviour, xCT knockout as well as inducible xCT overexpressing mice, in vitro and ex vivo molecular, immunobiotechnological and electrophysiological techniques, in vivo neuropharmacological approaches, microdialysis and 24h-video EEG monitoring, will be used. The PI aims to attract an expert chemist who will develop selective, stable and blood-brain-barrier permeable inhibitors of system xc- that might become leads for novel generation antiepileptic drug. Development of innovative approaches for the treatment of refractory epilepsy and its disabling co-morbidities is indeed of utmost importance. The current project focuses on a glial drug target which is in view of the well-established neuron-glia communication a relevant choice as well as an innovative and unconventional approach that can have a major impact on the field of epilepsy.