δ-Opioid receptor activation reduces α-synuclein overexpression and oligomer formation induced by MPP(+) and/or hypoxia.

Hypoxic/ischemic brain injury is a potential cause of Parkinson's disease (PD) with ɑ-synuclein playing a critical role in the pathophysiology. Since δ-opioid receptor (DOR) is neuroprotective against hypoxic/ischemic insults, we sought to determine if DOR regulates ɑ-synuclein under hypoxia and/or MPP(+) stress. We found that in HEK293 cells 1) MPP(+) in normoxia enhanced ɑ-synuclein expression and the formation of ɑ-synuclein oligomers thereby causing cytotoxic injury; 2) hypoxia at 1% O2 for 48h or at 0.5% O2 for 24h also induced ɑ-synuclein overexpression and its oligomer formation with cell injury; 3) however, hypoxia at 1% O2 for 24h, though increasing ɑ-synuclein expression, did not cause ɑ-synuclein oligomer formation and cell injury; 4) UFP-512 mediated DOR activation markedly attenuated the hypoxic cell injury and ɑ-synuclein overexpression, which was largely attenuated by DOR antagonism with naltrindole or siRNA "knock-down" of the DOR; and 5) DOR activation enhanced CREB phosphorylation and prevented the collapse of mitochondrial membrane potential (△ψm). These findings suggest that DOR activation attenuates MPP(+) or severe hypoxia induced ɑ-synuclein expression/aggregation via a CREB pathway.