Excitatory amino acid induced oligodendrocyte cell death in vitro: receptor-dependent and -independent mechanisms.
Oligodendroglia play an important role in axonal conduction in the CNS and are sensitive to oxidative toxicity induced by glutamate in the absence of ionotropic glutamate receptors. In this study, oligodendrocyte signalling cascades were examined, in response to glutamate-induced oxidative injury and to excitotoxicity. Rat cortical oligodendrocytes, differentiated in culture, were highly vulnerable to glutamate-induced cell death. Competitive inhibition of cystine uptake and increased oxidative stress appeared responsible for this death, and caused an accumulation of intracellular peroxides as well as chromatin fragmentation and condensation. Glutamate receptor subtype agonists (quisqualate, ibotenate) known to inhibit cystine uptake were cytotoxic, but not NMDA itself; moreover, glutamate receptor antagonists were not protective. Oligodendrocytes were also vulnerable to overactivation of glutamate receptors, as kainic acid and AMPA proved to be toxic. AMPA toxicity required the presence of cyclothiazide, suggesting rapid desensitization of AMPA receptors. Glutamate-induced oxidative stress and kainate/AMPA receptor stimulation activated the mitogen-activated protein kinase (MAP kinase) pathway, as well as the transcription factor ELK. However, MAP kinase kinase inhibitors only protected against injury from glutamate-induced oxidative stress. Oligodendrocytes were sensitive to oxygen-glucose deprivation injury as well, in a MAP kinase dependent fashion. Glutamate toxicity may conceivably be operative in neuropathological conditions that disrupt neuronal/oligodendrocyte interactions in axons, e.g. multiple sclerosis and ischaemia-reperfusion injury.
Neuro Cell Sciences, Neurology & GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Limited, Harlow, Essex, UK.
Claudia
C
Rosin
Timothy E
TE
Bates
Stephen D
SD
Skaper
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017304:Annexin A5 / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D003553:Cystine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000494:pharmacology*; D005452:Fluoresceins; D005677:G(M1) Ganglioside / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000860:Hypoxia; D007150:Immunohistochemistry / Q000379:methods; D007211:Indoles; D048031:JNK Mitogen-Activated Protein Kinases; D007608:Kainic Acid / Q000494:pharmacology; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D000070798:Nogo Proteins; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects*; D009842:Oligopeptides / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
D017304:Annexin A5; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018846:Excitatory Amino Acids; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000070798:Nogo Proteins; D009842:Oligopeptides; D010545:Peroxides; D011810:Quinoxalines; C111711:RNAIII inhibiting peptide; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; C000603197:Rtn4 protein, rat; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D005677:G(M1) Ganglioside; D018698:Glutamic Acid; C007293:DAPI; D003553:Cystine; C084577:5-carboxyfluorescein diacetate; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D005947:Glucose; D007608:Kainic Acid