δ-Opioid Receptor Activation Attenuates Hypoxia/MPP+-Induced Downregulation of PINK1: a Novel Mechanism of Neuroprotection Against Parkinsonian Injury.

There is emerging evidence suggesting that neurotoxic insults and hypoxic/ischemic injury are underlying causes of Parkinson's disease (PD). Since PTEN-induced kinase 1 (PINK1) dysfunction is involved in the molecular genesis of PD and since our recent studies have demonstrated that the δ-opioid receptor (DOR) induced neuroprotection against hypoxic and 1-methyl-4-phenyl-pyridimium (MPP+) insults, we sought to explore whether DOR protects neuronal cells from hypoxic and/or MPP+ injury via the regulation of PINK1-related pathways. Using highly differentiated rat PC12 cells exposed to either severe hypoxia (0.5-1% O2) for 24-48 h or varying concentrations of MPP+, we found that both hypoxic and MPP+ stress reduced the level of PINK1 expression, while incubation with the specific DOR agonist UFP-512 reversed this reduction and protected the cells from hypoxia and/or MPP+-induced injury. However, the DOR-mediated cytoprotection largely disappeared after knocking down PINK1 by PINK1 small interfering RNA. Moreover, we examined several important signaling molecules related to cell survival and apoptosis and found that DOR activation attenuated the hypoxic and/or MPP+-induced reduction in phosphorylated Akt and inhibited the activation of cleaved caspase-3, whereas PINK1 knockdown largely deprived the cell of the DOR-induced effects. Our novel data suggests a unique mechanism underlying DOR-mediated cytoprotection against hypoxic and MPP+ stress via a PINK1-mediated regulation of signaling.