Caspase-dependent and caspase-independent oligodendrocyte death mediated by AMPA and kainate receptors.
Oligodendrocytes are vulnerable to excitotoxic signals mediated by AMPA receptors and by high- and low-affinity kainate receptors. Here we investigated the nature of the cell death triggered by activation of these receptors in primary cultures of oligodendrocytes from the rat optic nerve. Activation of AMPA receptors at both submaximal and maximal concentrations of the agonist induced massive calcium entry, mitochondrial depolarization, and a rise in the level of reactive oxygen species that correlated with a decrease in the levels of reduced glutathione. In addition, excitotoxicity initiated by submaximal, but not maximal, activation of AMPA receptors was prevented by caspase-3 blockade and by the concomitant blockade of caspases 8 and 9. In turn, maximal activation of high- or low-affinity kainate receptors induced mitochondrial events and toxicity levels similar to those observed with submaximal activation of AMPA receptors. In contrast to AMPA receptor-mediated insults, calcineurin inhibition or caspase-9 blockade was sufficient to prevent cell death triggered by both types of kainate receptors. Consistent with these results, prolonged glutamate receptor activation in freshly isolated optic nerves caused selective activation of caspase-3 and chromatin condensation in oligodendrocytes. Overall, the evidence presented here indicates that oligodendrocyte death by excitotoxicity is mediated by caspase-dependent and -independent mechanisms.
Departamento de Neurociencias, Universidad del País Vasco, E-48940 Leioa, Vizcaya, Spain.
María Victoria
MV
Sánchez-Gómez
Elena
E
Alberdi
Gaskon
G
Ibarretxe
Iratxe
I
Torre
Carlos
C
Matute
D000818:Animals; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology; D009836:Oligodendroglia / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D009900:Optic Nerve / Q000166:cytology; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D002118:Calcium; D061945:Caspase Inhibitors; D020169:Caspases; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D005978:Glutathione; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D014475:Uncoupling Agents