Delta Opioid Peptide [d-Ala2, D-Leu5] Enkephalin Confers Neuroprotection by Activating Delta Opioid Receptor-AMPK-autophagy Axis Against Global Ischemia

Overview

Journal Cell Biosci

Publisher Biomed Central

Specialty Biology

Date 2020 Jun 19

PMID 32549974

Citations 9

Authors

Zelin Lai

Lingling Gu

Lu Yu

Huifen Chen

Zhenhua Yu

Cheng Zhang

Xiaoqing Xu

Mutian Zhang

Min Zhang

Mingliang Ma

Zheng Zhao

Jun Zhang

Affiliations

Soon will be listed here.

Abstract

Background: Ischemic stroke poses a severe risk to human health worldwide, and currently, clinical therapies for the disease are limited. Delta opioid receptor (DOR)-mediated neuroprotective effects against ischemia have attracted increasing attention in recent years. Our previous studies revealed that DOR activation by [d-Ala2, d-Leu5] enkephalin (DADLE), a selective DOR agonist, can promote hippocampal neuronal survival on day 3 after ischemia. However, the specific molecular and cellular mechanisms underlying the DOR-induced improvements in ischemic neuronal survival remain unclear.

Results: We first detected the cytoprotective effects of DADLE in an oxygen-glucose deprivation/reperfusion (OGD/R) model and observed increased viability of OGD/R SH-SY5Y neuronal cells. We also evaluated changes in the DOR level following ischemia/reperfusion (I/R) injury and DADLE treatment and found that DADLE increased DOR levels after ischemia in vivo and vitro. The effects of DOR activation on postischemic autophagy were then investigated, and the results of the animal experiment showed that DOR activation by DADLE enhanced autophagy after ischemia, as indicated by elevated LC3 II/I levels and reduced P62 levels. Furthermore, the DOR-mediated protective effects on ischemic CA1 neurons were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Moreover, the results of the cell experiments revealed that DOR activation not only augmented autophagy after OGD/R injury but also alleviated autophagic flux dysfunction. The molecular pathway underlying DOR-mediated autophagy under ischemic conditions was subsequently studied, and the in vivo and vitro data showed that DOR activation elevated autophagy postischemia by triggering the AMPK/mTOR/ULK1 signaling pathway, while the addition of the AMPK inhibitor compound C eliminated the protective effects of DOR against I/R injury.

Conclusion: DADLE-evoked DOR activation enhanced neuronal autophagy through activating the AMPK/mTOR/ULK1 signaling pathway to improve neuronal survival and exert neuroprotective effects against ischemia.

Citing Articles

Neuronal Responses to Ischemia: Scoping Review of Insights from Human-Derived In Vitro Models.

Voogd E, Frega M, Hofmeijer J Cell Mol Neurobiol. 2023; 43(7):3137-3160.

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Delta Opioid Peptide Targets Brain Microvascular Endothelial Cells Reducing Apoptosis to Relieve Hypoxia-Ischemic/Reperfusion Injury.

Zhang R, Chen M, Deng Z, Kong L, Shen B, Zhang L Pharmaceutics. 2023; 15(1).

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A novel link between silent information regulator 1 and autophagy in cerebral ischemia-reperfusion.

Tang Y, Xie J, Chen X, Sun L, Xu L, Chen X Front Neurosci. 2022; 16:1040182.

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Reinventing the Penumbra - the Emerging Clockwork of a Multi-modal Mechanistic Paradigm.

Walther J, Kirsch E, Hellwig L, Schmerbeck S, Holloway P, Buchan A Transl Stroke Res. 2022; 14(5):643-666.

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