2. Academic Validation
  3. DADLE promotes motor function recovery by inhibiting cytosolic phospholipase A2 mediated lysosomal membrane permeabilization after spinal cord injury

DADLE promotes motor function recovery by inhibiting cytosolic phospholipase A2 mediated lysosomal membrane permeabilization after spinal cord injury

  • Br J Pharmacol. 2023 Sep 27. doi: 10.1111/bph.16255.
Yituo Chen 1 2 3,  Haojie Zhang 1 2 3,  Liting Jiang 1 2 3,  Wanta Cai 1 2 3,  Jiaxuan Kuang 4,  Yibo Geng 1 2 3,  Hui Xu 1 2 3,  Yao Li 1 2 3,  Liangliang Yang 5,  Yuepiao Cai 5,  Xiangyang Wang 1 2 3,  Jian Xiao 5,  Wenfei Ni 1 2 3,  Kailiang Zhou 1 2 3
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
  • 2 Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325027, China.
  • 3 The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, 325027, China.
  • 4 Cixi Biomedical Research Institute, Wenzhou Medical University, Ningbo, 315300, Zhejiang, China.
  • 5 School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
PMID: 37766498 DOI: 10.1111/bph.16255
Abstract

Background and purpose: Autophagy is a protective factor for controlling neuronal damage, while Necroptosis promotes neuroinflammation after spinal cord injury (SCI). DADLE (d-Ala2, d-Leu5) is a selective agonist for delta Opioid Receptor (DOR) and has been identified as a promising drug for its neuroprotective effects. Our present work aims to investigate the therapeutic effect of DADLE on locomotive function recovery following SCI and its concrete mechanism.

Experimental approach: Spinal cord contusion model was constructed and DADLE was delivered though intraperitoneal administration (16mg/kg) in mice for following experiments. Motor function was assessed by footprint and BMS score analysis. Western blotting evaluated related protein expression. Immunofluorescence exhibited protein expression in each cell and its distribution. Network pharmacology analysis was used to find related signalling pathways.

Key results: DADLE promoted functional recovery after SCI. In SCI model of mice, DADLE significantly promoted autophagic flux and inhibited Necroptosis. Concurrently, DADLE restored autophagic flux by decreasing lysosomal membrane permeabilization (LMP). And chloroquine administration reversed the protective effect of DADLE to inhibit Necroptosis. Further analysis identified that DADLE decreased phosphorylated cPLA2 and overexpression of cPLA2 partially reversed DADLE inhibition effect of LMP and Necroptosis, as well as the promotion effect of Autophagy. Finally, AMPK/SIRT1/p38 signalling pathway regulated cPLA2 after DADLE treatment following SCI, and administration of naltrindole to block interaction between DADLE and DOR abolished DADLE effect on AMPK signalling pathway.

Conclusion and implication: DADLE exerts neuroprotective effects on SCI by promoting autophagic flux and inhibiting Necroptosis by decreasing LMP via activating DOR/AMPK/SIRT1/p38/cPLA2 pathway.

Keywords

Autophagic flux; Cytosolic phospholipase A2; DADLE; Lysosomal membrane permeabilization; Necroptosis.

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