Testing of the effect of E2730 treatment on multimodality in-vivo biomarkers of GABAergic function in healthy rats and preclinical chronic epilepsy models

Epilepsy is a chronic neurological disorder characterised by recurrent spontaneous seizures. It affects around 65 million people in the world. Current pharmacological treatment options are only symptomatic, and in around one third of patients are unable to provide adequate seizure control because of drug-resistant epilepsy or adverse effects (Kwan and Brodie, 2000). Epilepsy is often associated with an imbalance in the excitatory and inhibitory processes of the brain due to either genetic malformations/channelopathies (i.e. genetic epilepsy) or an epileptogenic insult (i.e. acquired epilepsy). Accordingly, most current treatment options aim to restore the lost excitation/inhibition balance in the brain. This is achieved by either altering the levels of excitatory/inhibitory neurotransmitters within the synaptic cleft, mimicking/inhibiting their receptor activity/channel function, or altering downstream signalling mechanisms to modulate the overall neuronal activity.

This proposal will investigate the effect of treatment with the novel GABA Transporter 1 (GAT1) inhibitor, E2730, on state-of-the-art multimodality MRI, PET, electrophysiological (i.e. gamma frequency EEG recordings and TMS), and molecular biomarkers of GABAergic function in healthy rats and rat models of chronic genetic and acquired epilepsy, and relate this to its efficacy to suppress spontaneous recurrent seizures