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.
Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Szeged, Hungary. weiczner@anatomy.szote.u-szeged.hu
Roland
R
Weiczner
Beáta
B
Krisztin-Péva
András
A
Mihály
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