δ-Opioid receptor activation attenuates oxidative injury in the ischemic rat brain

Yilin Yang,Qiang Wang,Xiwei Xia,Lu Li,Ying Xia,Yi Zhang,Guanghua Luo

doi:10.1186/1741-7007-7-55

Abstract

BackgroundWe have recently shown that δ-opioid receptors (DORs) play an important role in neuroprotection from hypoxic injury via the regulation of extracellular signaling-regulated kinase (ERK) and cytochrome c release. Since ERK and cytochrome c are differentially involved in caspase signaling of oxidative injury that significantly contributes to neuronal damage in ischemia/reperfusion, we considered if DOR activation protects the ischemic brain by attenuating oxidative injury.ResultsWe observed that, in a model of cerebral ischemia with middle cerebral artery occlusion, DOR activation increased the activity of major antioxidant enzymes, glutathione peroxidase and superoxide dismutase, and decreased malondialdehyde and nitric oxide levels in the cortex exposed to cerebral ischemia/reperfusion. In addition, DOR activation reduced caspase 3 expression, though it did not significantly affect the increase in interleukin (IL)1β and tumor necrosis factor (TNF)α expression at the same timepoint. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) extracellular signaling-regulated kinase kinase, accelerated animal death during ischemia/reperfusion.ConclusionDOR activation attenuates oxidative injury in the brain exposed to ischemia/reperfusion by enhancing antioxidant ability and inhibiting caspase activity, which provides novel insights into the mechanism of DOR neuroprotection.

Highlights

We have recently shown that δ-opioid receptors (DORs) play an important role in neuroprotection from hypoxic injury via the regulation of extracellular signaling-regulated kinase (ERK) and cytochrome c release
Since ERK and cytochrome c are differentially involved in caspase signaling of oxidative injury that significantly contributes to ischemia/reperfusion (I/ R) injury [24,25,26], we considered in this work the question of whether DOR activation can enhance antioxidant ability and attenuate oxidative injury in the brain exposed to I/R stress
Our previous work and those of others have clearly demonstrated that DOR activation with DADLE or other DOR agonists attenuates hypoxic/ischemic injury in cortical neurons and reduces ischemic infarction in the cortex [323]

Summary

Introduction

We have recently shown that δ-opioid receptors (DORs) play an important role in neuroprotection from hypoxic injury via the regulation of extracellular signaling-regulated kinase (ERK) and cytochrome c release. Since ERK and cytochrome c are differentially involved in caspase signaling of oxidative injury that significantly contributes to neuronal damage in ischemia/ reperfusion, we considered if DOR activation protects the ischemic brain by attenuating oxidative injury. Substantial data generated from other independent laboratories has demonstrated that DORs are neuroprotective against hypoxic or ischemic stress, either in in vitro neurons or in vivo models of brain or spinal ischemia [14,15,16,17,18,19,20,21,22,23]. DORs may be tonically involved in neuroprotection [4,22] through a Gi-dependent manner [22]

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Conclusion