title: δ-Opioid receptor activation reduces α-synuclein overexpression and oligomer formation induced by MPP(+) and/or hypoxia.
abstract: 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.
authors.affiliation: Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Department of Neurology, Hainan General Hospital, Haikou, Hainan 570311, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Dongman
authors.initials: D
authors.lastname: Chao
authors.affiliation: Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Harleen K
authors.initials: HK
authors.lastname: Sandhu
authors.affiliation: Department of Neurology, Hainan General Hospital, Haikou, Hainan 570311, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Neurology, Hainan General Hospital, Haikou, Hainan 570311, China.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Hainan General Hospital, Haikou, Hainan 570311, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Wen
authors.affiliation: Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA. Electronic address: ying.xia@uth.tmc.edu.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D002534:Hypoxia, Brain / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D051844:alpha-Synuclein; D009271:Naltrexone; C055382:naltrindole
keywords: CREB; Cytoprotection; Hypoxia; MPP(+); Parkinson's disease; δ-Opioid receptor