Abstract 226: δ-opioid Receptor Activation Protects the Brain From Hypoxic-ischemic Injury by Downregulating Inflammatory Cytokines and Upregulating Nrf-2

Abstract

Hypoxia-ischemia (HI) insult induces inflammatory/oxidative injury and causes neurological disability and mortality. However, there are limited therapeutic options at present. Our recent studies have shown that the δ-opioid receptor (DOR) is neuroprotective against hypoxic-ischemic stress. In this work, we asked if DOR activation protects the brain against hypoxic-ischemic encephalopathy (HIE) by regulating inflammatory cytokines and Nrf-2, a basic leucine zipper protein that regulates the expression of antioxidant proteins. Our results showed that DOR activation with UFP-512 treatment significantly decreased TNF-α, IL-6, and ICAM-1 expression (P<0.05) in the left cortex of the rat with HI injury, while DOR inhibition with naltrindole significantly increased their expression (P<0.05). In contrast, DOR activation induced an opposite effect on IL-10 expression (P<0.05) and had no appreciable effect on IL-18 (P>0.05). In the control group, no significant difference was detected after the vehicle treatment. Furthermore, we investigated the role of Nrf-2 in the DOR neuroprotection since our recent data suggest that DOR signaling promotes the expression and relocation of Nrf2 and thus induces cytoprotection. HI significantly increased nuclear Nrf-2 protein, while DOR activation by pretreatment with UFP-512 before HI further elevated the level of nuclear Nrf-2 protein by 70% (P<0.05) in the cortex. On the other side, DOR inhibition by the pretreatment with naltrindole completely abolished the HI- and DOR-induced increase in nuclear Nrf-2 protein. In the control, the vehicle treatment did not have any significant effect on nuclear Nrf-2 protein. These first data suggest that DOR activation protects the brain from HIE by downregulating the expression of inflammatory cytokines and upregulating Nrf-2 activity. This work was supported by NIH (AT-004422), Memorial Hermann’s Foundation and Vivian L Smith Neurologic Foundation. GD was supported by 973 Program (2012CB518502) and NSFC (81574053 & 81590953) of China.