Prolyl Hydroxylase Inhibitors Depend on Extracellular Glucose and Hypoxia-Inducible Factor (HIF)-2α to Inhibit Cell Death Caused by Nerve Growth Factor (NGF) Deprivation: Evidence that HIF-2α Has a Role in NGF-Promoted Survival of Sympathetic Neurons

Neurotrophins are critical for the survival of neurons during development and insufficient access to neurotrophins later in life may contribute to the loss of neurons in neurodegenerative disease, spinal cord injury, and stroke. The prolyl hydroxylase inhibitors ethyl 3,4-dihydroxybenzoic acid (DHB) and dimethyloxalylglycine (DMOG) were shown to inhibit cell death in a model of neurotrophin deprivation that involves depriving sympathetic neurons of nerve growth factor (NGF). Here we show that treatment with DMOG or DHB reverses the decline in 2-deoxyglucose uptake caused by NGF withdrawal and suppresses the NGF deprivation-induced accumulation of reactive oxygen species. Neither DMOG nor DHB prevented death when NGF deprivation was carried out under conditions of glucose starvation, and both compounds proved toxic to NGF-maintained neurons deprived of glucose, suggesting that their survival-promoting effects are mediated through the preservation of glucose metabolism. DHB and DMOG are well known activators of hypoxia-inducible factor (HIF), but whether activation of HIF underlies their survival-promoting effects is not known. Using gene disruption and RNA interference, we provide evidence that DMOG and, to a lesser extent, DHB require HIF-2α expression to inhibit NGF deprivation-induced death. Furthermore, suppressing basal HIF-2α expression, but not HIF-1α, in NGF-maintained neurons is sufficient to promote cell death. These results implicate HIF-2α in the neuroprotective mechanisms of prolyl hydroxylase inhibitors and in an endogenous cell survival pathway activated by NGF in developing neurons

Thyroid Hormone Regulates the Expression of the Sonic Hedgehog Signaling Pathway in the Embryonic and Adult Mammalian Brain

Expression of the morphogen Shh and its receptors is robustly regulated in the embryonic and adult mammalian brain following maternal or adult-onset thyroid hormone perturbations