Interactive Responses of Enkephalin, δ-opioid Receptor and Dopamine Receptor D1/D2 to Hypoxia and/or MPP+ Stress in PC12 Cells

Abstract Hypoxic/ischemic brain injury is a potential etiology of Parkinson’s disease (PD). There is evidence suggesting that the up-regulation of enkephalin, an endogenous opioid, in the midbrain may have a compensatory effect against Parkinson’s disease (PD) related motor symptoms. To explore the potential mechanism underlying this action, we investigated the effects of hypoxia and MPP+, a pathological inducer PD, on enkephalin, δ-opioid receptor (DOR, an enkephalin receptor), and prohormone convertases 1 and 2 (PC1/PC2) on in- vitro PD model of PC12 cells. We found that (1) short-term hypoxia could inducing cell protection by up-regulating the level of enkephalin, accompanied by the synergistic up-regulation of δ-opioid receptor (DOR) ; (2) a longer period of hypoxia or MPP+ insult accelerated the proteolysis of proenkephalin by up-regulating PC1/PC2 which might produce more active enkephalin and thus activating DOR for cell protection; (3) The levels of enkephalin and DOR decreased significantly after a prolonged hypoxia or MPP+ insult; and (4) a certain degree of hypoxia improved cell viability and enhance the transcription of dopamine D1/D2 receptorby increasing their mRNA level. Our findings suggest that hypoxia may induce an interactive reaction of enkephalin, DOR and dopamine receptor D1/D2, which is potentially beneficial for cell surviving to severe/prolonged hypoxia and PD condition.