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AMPA receptor‐mediated toxicity in oligodendrocyte progenitors involves free radical generation and activation of JNK, calpain and caspase 3
Author(s) -
Liu HsuehNing,
Giasson Benoit I.,
Mushynski Walter E.,
Almazan Guillermina
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.00981.x
Subject(s) - ampa receptor , excitotoxicity , microbiology and biotechnology , calpain , chemistry , biology , glutamate receptor , biochemistry , receptor , enzyme
The molecular mechanisms underlying AMPA (α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate) receptor‐mediated excitotoxicity were characterized in rat oligodendrocyte progenitor cultures. Activation of AMPA receptors, in the presence of cyclothiazide to selectively block desensitization, produced a massive Ca 2+ influx and cytotoxicity which were blocked by the antagonists CNQX and GYKI 52466. A role for free radical generation in oligodendrocyte progenitor cell death was deduced from three observations: (i) treatment with AMPA agonists decreased intracellular glutathione; (ii) depletion of intracellular glutathione with buthionine sulfoximine potentiated cell death; and (iii) the antioxidant N ‐acetylcysteine replenished intracellular glutathione and protected cultures from AMPA receptor‐mediated toxicity. Cell death displayed some characteristics of apoptosis, including DNA fragmentation, chromatin condensation and activation of caspase‐3 and c‐Jun N‐terminal kinase (JNK). A substrate of calpain and caspase‐3, α‐spectrin, was cleaved into characteristic products following treatment with AMPA agonists. In contrast, inhibition of either caspase‐3 by DEVD‐CHO or calpain by PD 150606 protected cells from excitotoxicity. Our results indicate that overactivation of AMPA receptors causes apoptosis in oligodendrocyte progenitors through mechanisms involving Ca 2+ influx, depletion of glutathione, and activation of JNK, calpain, and caspase‐3.