Paul Ornstein - Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures

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      Publication Details (including relevant citation   information):

      Smolders, Ilse, Bortolotto, Zuner A., Clarke, Vernon R. J.,   Warre, Ruth, Khan, Ghous M., O'Neill, Michael J., Ornstein, Paul   L., Bleakman, David, Ogden, AnnMarie, Weiss, Brianne, Stables,   James P., Ho, Ken H., Ebinger, Guy, Collingridge, Graham L.,   Lodge, David, Michotte, Yvette Nature Neuroscience  2002 5 (8) 796-804

      Abstract: Developments in the molecular biology   and pharmacology of GLUK5, 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   GLUK5-containing kainate receptors in pathological conditions. We   report here that, in hippocampal slices, selective antagonists of   GLUK5-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 GLUK5 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.   GLUK5 antagonism also prevented epileptiform activity induced by   electrical stimulation, both in vitro and in vivo. Therefore, we   propose that subtype-selective GLUK5 kainate receptor antagonists   offer a potential new therapy for epilepsy.

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