Pharmacological Prolyl Hydroxylase Domain Inhibition as a Therapeutic Target for Parkinson’s Disease
Subramanian Rajagopalan, Shankar J. Chinta and Julie K. Andersen
Affiliation: 8001 Redwood Blvd, Novato, CA 94945, USA.
Keywords: Drug therapy, mitochondrial function, nigrostriatal cell loss, Parkinson’s disease, prolyl hydroxylase domain
proteins, transgenic mouse model, age, progressive, chronic.
Previously published data from our laboratory demonstrated that pharmacological inhibition of a family of
enzymes known as prolyl hydroxylase domain proteins prevents neurotoxicity associated with the acute 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine intoxication model of Parkinson’s disease in young animals. In this study, we assessed
whether prolyl hydroxylase domain inhibition was neuroprotective in an inducible genetic dopaminergic glutathione
depletion model previously characterized by our laboratory that more closely recapitulates the age-related and progressive
nature of the human disease. Pharmacological prolyl hydroxylase domain inhibition via 3,4-dihydroxybenzoate was found
to significantly attenuate hallmark mitochondrial dysfunction and loss of dopaminergic substantia nigral pars compacta
neurons associated with this model. These studies further validate the possibility that prolyl hydroxylase domain
inhibition may constitute a viable therapy for Parkinson’s disease.
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