In:
British Journal of Pharmacology, Wiley
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
0007-1188
,
1476-5381
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2023
ZDB Id:
2029728-2
SSG:
15,3
