title: The AMPA receptor antagonist NBQX exerts anti-seizure but not antiepileptogenic effects in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy.
abstract: The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy.
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Twele
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Römermann
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany. Electronic address: wolfgang.loescher@tiho-hannover.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007608:Kainic Acid; D051379:Mice; D009570:Nitriles; D010672:Phenytoin / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D013226:Status Epilepticus / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D010672:Phenytoin; C551441:perampanel; D007608:Kainic Acid
keywords: Epileptogenesis; Glutamate receptors; Ketamine; NMDA receptors; Perampanel