Antagonists of GLU_K5-containing kainate receptors prevent pilocarpine-induced limbic seizures

Developments in the molecular biology and pharmacology of GLU_K5, a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLU_K5-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLU_K5-containing kainate receptors prevented development of epileptiform activity - evoked by the muscarinic agonist, pilocarpine - and inhibited the activity when it was pre-established. In conscious rats, these GLU_K5 antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLU_K5 antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLU_K5 kainate receptor antagonists offer a potential new therapy for epilepsy.