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 boxed dot-synuclein playing a critical role in the pathophysiology. Since delta-opioid receptor (DOR) is neuroprotective against hypoxic/ischemic insults, we sought to determine if DOR regulates boxed dot-synudein under hypoxia and/or MPP+ stress. We found that in HEK293 cells 1) MPP+ in normoxia enhanced boxed dot-synuclein expression and the formation of a-synuclein oligomers thereby causing cytotoxic injury; 2) hypoxia at 1% 02 for 48 h or at 0.5% O-2 for 24 h also induced boxed dot-synuclein overexpression and its oligomer formation with cell injury; 3) however, hypoxia at 1% O-2 for 24 h, though increasing boxed dot-synuclein expression, did not cause p-synuclein oligomer formation and cell injury; 4) UFP-512 mediated DOR activation markedly attenuated the hypoxic cell injury and B-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 (Delta psi m). These findings suggest that DOR activation attenuates MPP+ or severe hypoxia induced boxed dot-synuclein expression/aggregation via a CREB pathway. (c) 2014 Elsevier Inc All rights reserved.