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Pyruvate limits zinc‐induced rat oligodendrocyte progenitor cell death
Author(s) -
Kelland Eve E.,
Kelly Mary D.,
Toms Nick J.
Publication year - 2004
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.0953-816x.2003.03134.x
Subject(s) - staurosporine , extracellular , programmed cell death , apoptosis , microbiology and biotechnology , biology , chemistry , kainate receptor , biochemistry , glutamate receptor , protein kinase c , receptor , kinase , ampa receptor
A growing body of evidence suggests that excessive Zn 2+ release plays a key role in inducing neuronal death during central nervous system injury. However, the possible cytotoxicity of extracellular Zn 2+ to oligodendrocyte lineage cells remains unknown. Employing cultures of rat oligodendrocyte progenitor cells (OPC), we report here that OPC are vulnerable to increased extracellular Zn 2+ levels and that pyruvate limits Zn 2+ ‐induced OPC death. Zn 2+ ‐induced concentration‐dependent (pEC 50 = −4.1 ± 0.1) OPC death, which was insensitive to both α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (Evans Blue) and l ‐type Ca 2+ channel (nicardipine) inhibition. Neither kainate nor nicardipine influenced OPC 65 Zn 2+ accumulation, in contrast with the Zn 2+ ionophore, pyrithione. Cytotoxic extracellular Zn 2+ concentrations failed to increase OPC reactive oxygen species production and the antioxidant reagents, trolox, N,N′‐diphenyl‐1,4‐phenylenediamine and N‐tert‐butyl‐α‐phenylnitrone did not afford significant protection from Zn 2+ insults. The apoptotic inducer staurosporine induced the appearance of known apoptotic markers [pyknotic nuclei and caspase‐3 specific (120 kDa) α‐fodrin cleavage fragment], events not reproduced with Zn 2+ insults. Zn 2+ insults were also insensitive to the pan‐caspase inhibitor Z‐VAD‐fmk. However, pyruvate afforded significant OPC protection from lethal Zn 2+ insults. We conclude that cultured OPC are vulnerable to Zn 2+ insults, via a nonoxidative stress and noncaspase‐3‐based mechanism, involving Zn 2+ inhibition of OPC glycolysis.