Abstract
The pathological changes of Parkinson’s disease (PD) are, at least partially, associated with the dysregulation of PTEN-induced putative kinase 1 (PINK1) and caspase 3. Since hypoxic and neurotoxic insults are underlying causes of PD, and since δ-opioid receptor (DOR) is neuroprotective against hypoxic/ischemic insults, we sought to determine whether DOR activation could protect the cells from damage induced by hypoxia and/or MPP+ by regulating PINK1 and caspase 3 expressions. We exposed PC12 cells to either severe hypoxia (0.5%–1% O2) for 24–48 h or to MPP+ at different concentrations (0.5, 1, 2 mM) and then detected the levels of PINK1 and cleaved caspase 3. Both hypoxia and MPP+ reduced cell viability, progressively suppressed the expression of PINK1 and increased the cleaved caspase 3. DOR activation using UFP-512, effectively protected the cells from hypoxia and/or MPP+ induced injury, reversed the reduction in PINK1 protein and significantly attenuated the increase in the cleaved caspase 3. On the other hand, the application of DOR antagonist, naltrindole, greatly decreased cell viability and increased cleaved caspase 3. These findings suggest that DOR is cytoprotective against both hypoxia and MPP+ through the regulation of PINK1 and caspase 3 pathways.
Highlights
Parkinson’s disease (PD) is characterized by the accumulation of cytoplasmic protein inclusions called Lewy bodies in neurons, and the insufficient production of dopamine, which is produced in the substantia nigra of the midbrain [1]
Hypoxia/ischemia and neurotoxins should be recognized as critical pathogenic factors that contribute to the development of PD
Since caspase 3 is a critical factor in hypoxia and MPP+ injury, we further investigated whether DOR activation and inhibition affects caspase 3 signaling
Summary
Parkinson’s disease (PD) is characterized by the accumulation of cytoplasmic protein inclusions called Lewy bodies in neurons, and the insufficient production of dopamine, which is produced in the substantia nigra of the midbrain [1]. Chronic pharmacological therapies that use dopaminergic drugs, are associated with a series of side effects such as L-dopa-induced dyskinesias [2,3] and the risk of tumor formation. The etiopathogenesis of PD is complex, the vulnerability of midbrain dopaminergic neurons to oxidative stress, and environmental neurotoxins affecting the dopamine biosynthetic pathways [4] has long been implicated as potential causes of PD. As the morbidity of PD is greater among older people, it might be associated with age-related conditions such as prolonged ischemia or hypoxia in the brain. Hypoxia/ischemia and neurotoxins should be recognized as critical pathogenic factors that contribute to the development of PD
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