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.
Smolders
Ilse
I
Department of Pharmaceutical Chemistry & Drug Analysis, Pharmaceutical Institute, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
Bortolotto
Zuner A
ZA
Clarke
Vernon R J
VR
Warre
Ruth
R
Khan
Ghous M
GM
O'Neill
Michael J
MJ
Ornstein
Paul L
PL
Bleakman
David
D
Ogden
AnnMarie
A
Weiss
Brianne
B
Stables
James P
JP
Ho
Ken H
KH
Ebinger
Guy
G
Collingridge
Graham L
GL
Lodge
David
D
Michotte
Yvette
Y
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004558:Electric Stimulation; D004597:Electroshock; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008032:Limbic System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D051379:Mice; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity; D016896:Treatment Outcome
D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D007608:Kainic Acid; D010862:Pilocarpine; D018092:Kainic Acid Receptors; C400802:LY382884