Blockade of AMPA-receptors attenuates 4-aminopyridine seizures, decreases the activation of inhibitory neurons but is ineffective against seizure-related astrocytic swelling.

Abstract

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.

• Authors: Roland Weiczner, Beáta Krisztin-Péva, András Mihály
• Journal: Epilepsy research (Epilepsy Res) Vol. 78 Issue 1 Pg. 22-32 (Jan 2008) ISSN: 0920-1211 [Print] Netherlands
• PMID: 18036781 (Publication Type: Journal Article)

Chemical References

• Excitatory Amino Acid Antagonists
• Parvalbumins
• Proto-Oncogene Proteins c-fos
• Receptors, AMPA
• GYKI 52466
• Benzodiazepines
• 4-Aminopyridine

Topics

• 4-Aminopyridine
• Analysis of Variance
• Animals
• Astrocytes (drug effects, pathology, ultrastructure)
• Behavior, Animal (drug effects)
• Benzodiazepines (pharmacology)
• Brain (drug effects, pathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists (pharmacology)
• Gene Expression Regulation (drug effects)
• Male
• Microscopy, Electron, Transmission
• Motor Activity (drug effects)
• Neural Inhibition (drug effects, physiology)
• Parvalbumins (metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• Rats
• Rats, Wistar
• Receptors, AMPA (metabolism)
• Seizures (chemically induced, drug therapy, metabolism, physiopathology)