Induction of hypoxia inducible factor‐1 attenuates metabolic insults induced by 3‐nitropropionic acid in rat C6 glioma cells

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‐1α 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‐κB (NF‐κB), 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.