Blockade of AMPA-receptors attenuates 4-aminopyridine seizures, decreases the activation of inhibitory neurons but is ineffective against seizure-related astrocytic swelling.
The neurotransmitter glutamate plays a pivotal role in the development of the neuropathological sequelae following acute seizures. Our previous data proved the efficacy of the NMDA-receptor antagonists on the symptoms, survival and neuronal activation in the 4-aminopyridine- (4-AP) induced seizures. In this study, we examined the effects of two different doses of a non-competitive, selective, allosteric AMPA-receptor antagonist, GYKI 52466. GYKI 52466 was effective in prolonging the latency to generalised seizures and reduction of seizure mortality. However, the effects on neuronal c-fos expression and astrocyte swelling were complex. The 25mg/kg dose of GYKI 52466 was effective in reducing the c-fos immunoreactivity (IR) in the hippocampus only. In the neocortex the overall c-fos-IR cell counts were increased significantly. Investigation of the neocortical parvalbumin-containing interneuron population proved that GYKI 52466 decreased c-fos expression. The 50mg/kg dose of GYKI 52466 significantly reduced the c-fos-IR in the neo- and allocortex, not only in principal neurons, but also in the parvalbumin-positive interneurons. The GYKI 52466-pretreatment did not prevent the astrocyte swelling in the investigated cortical areas; thus we conclude that the AMPA-receptors have little if any involvement in the in the mediation of neuropathological alterations in acute convulsions.
Weiczner
Roland
R
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Szeged, Hungary. weiczner@anatomy.szote.u-szeged.hu
Krisztin-Péva
Beáta
B
Mihály
András
A
D015761:4-Aminopyridine; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000187:drug effects; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D010320:Parvalbumins; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; C061950:GYKI 52466; D001569:Benzodiazepines; D015761:4-Aminopyridine