期刊
JOURNAL OF NEUROCHEMISTRY
卷 93, 期 3, 页码 513-525出版社
WILEY
DOI: 10.1111/j.1471-4159.2005.03032.x
关键词
antisense oligodeoxynucleotide; cobalt chloride; desferrioxamine; mimosine; oligodeoxynucleotide decoy; preconditioning
Compromised mitochondrial function in neurons and glia has been observed in several neurodegenerative disorders, including Huntington's disease and Alzheimer's disease. Chemical/hypoxic preconditioning may afford protection against subsequently more severe oxidative damages. In this study, we tested whether induction of hypoxia inducible factor-1 (HIF-1) may exert cytoprotective effects against mitochondrial dysfunction caused by 3-nitropropionic acid (3-NP) in glial cells. Preconditioning of C6 astroglial cells with cobalt chloride, mimosine (MIM), and desferrioxamine (DFO), all of which known to activate HIF-1, significantly attenuated cytotoxicity induced by 3-NP, an irreversible inhibitor of mitochondrial complex II, and antimycin A, a mitochondrial complex III inhibitor. Application of cadmium chloride capable of neutralizing cobalt-induced HIF-1 activation, HIF-specific oligodeoxynucleotide (ODN) decoy, and antisense phosphorothioate ODN against HIF-1 alpha abolished the protective effect mediated by preconditioning with cobalt chloride. Preloading of C6 cells with SN50, PD98059, or SB202190, the respective inhibitor of nuclear factor-kappa B (NF-kappa B), p44/p42 extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK), failed to affect the protection afforded by cobalt preconditioning. Taken together, these results suggest that HIF-1 induction secondary to preconditioning with cobalt chloride or iron chelators may mediate the protective effects against metabolic insult induced by the mitochondrial inhibitor 3-NP in C6 astroglial cells.
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