NEUROPROTECTION BY HYPOXIC PRECONDITIONING INVOLVES UP-REGULATION OF HIF-1 IN A PRENATAL MODEL OF HYPOXIA

FISZER DE PLAZAS, SARA; GIUSTI, SEBASTIÁN

Chicago, USA.

Congreso; Society for Neuroscience; 2009

A major goal of research in the field of neuroprotection is to understand the mechanisms underlying the beneficial effects of preconditioning, in an attempt to identify genes and proteins as potential drug targets for effective therapies. In this study, we developed a chick embryo  model of prenatal hypoxic preconditioning consisting in 8% O2, 40 min on embryonic day (ED) 11, followed by a hypoxic insult (8% O2, 60 min) 24 h later. Also, we studied the modulation of HIF-1 in the optic lobe of hypoxic and preconditioned embryos and the relationship between HIF-1 induction and neuroprotection afforded by preconditioning. We determined that hypoxic preconditioning on ED 11 significantly reduced cytochrome c release and DNA fragmentation, two markers of hypoxia-induced apoptotic cell death. HIF-1 induction was assessed by western blot of soluble nuclear fractions. The kinetics of HIF-1 accumulation showed a transient and strong increase immediately after hypoxia, confirmed by EM-immunogold analysis. Interestingly, HIF-1 induction was found to be significantly increased in preconditioned embryos (~40%) compared to the hypoxic ones.  Cobalt chloride administration (0.1 mM on ED 11), a known inducer of HIF-1, mimicked the neuroprotective effects of the hypoxic preconditioning. On the other hand, ascorbate, a negative regulator, administered 20 min before preconditioning reduced HIF-1 induction and prevented neuroprotection in a dose-dependent manner. In conclusion, our results suggest that HIF induction may mediate the neuroprotective effects of hypoxic preconditioning.