hypoxia research::blog

The detrimental effect of severe hypoxia (SH) on neurons can be mitigated by hypoxic preconditioning (HPC), but the molecular mechanisms involved remain unclear and an understanding of these may provide novel solutions for hypoxic/ischemic disorders (e.g., stroke). Here, we show that the delta-opioid receptor (DOR), an oxygen-sensitive membrane protein, mediates the HPC protection through specific signaling pathways. Although severe hypoxia (SH) caused a decrease in DOR expression and neuronal injury, HPC induced an increase in DOR mRNA and protein levels and reversed the reduction in levels of the endogenous DOR peptide, leucine enkephalin, normally seen during SH, thus protecting the neurons from SH insult. The HPC-induced protection could be blocked by DOR antagonists. The DOR-mediated HPC protection depended on an increase in ERK and Bcl 2 activity, which counteracted the SH-induced increase in p38 MAP kinase activities and cytochrome c release. The crosstalk between ERK and p38 MAP kinases displays a “yin-yang” antagonism under the control of the DOR-G protein-PKC pathway. Our findings demonstrate a novel mechanism of HPC neuroprotection, i.e., the intracellular upregulation of DOR-regulated survival signals.