Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating
iron,
antioxidant defense, and mitochondrial function. Pharmacological inhibitors of the
iron-dependent
enzyme class
prolyl hydroxylases (PHD), which target alpha subunits of HIF
proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with
stroke and hypoxic-ischemic
injuries. Here we report that inhibition of PHD by
3,4-dihydroxybenzoate (DHB) protects against
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1alpha within these neurons. Elevations in
mRNA and
protein levels of HIF-dependent genes
heme oxygenase-1 (Ho-1) and
manganese superoxide dismutase (Mnsod) following DHB pretreatment alone are also maintained in the presence of
MPTP.
MPTP-induced reductions in
ferroportin and elevations in nigral and striatal
iron levels were reverted to levels comparable with that of untreated controls with DHB pretreatment. Reductions in
pyruvate dehydrogenase mRNA and activity resulting from
MPTP were also found to be attenuated by DHB. In vitro, the HIF pathway was activated in N27 cells grown at 3%
oxygen treated with either PHD inhibitors or an
iron chelator. Concordant with our in vivo data, the MPP(+)-elicited increase in total
iron as well as decreases in cell viability were attenuated in the presence of DHB. Taken together, these data suggest that protection against
MPTP neurotoxicity may be mediated by alterations in
iron homeostasis and defense against oxidative stress and
mitochondrial dysfunction brought about by cellular HIF-1alpha induction. This study provides novel data extending the possible therapeutic utility of HIF induction to a
Parkinson disease model of neurodegeneration, which may prove beneficial not only in this disorder itself but also in other diseases associated with
metal-induced oxidative stress.