Melatonin attenuates diabetic peripheral neuropathy through modulation of the COX2-IRE1α-mediated endoplasmic reticulum stress axis.

BACKGROUND: Diabetic peripheral neuropathy (DPN) involves Schwann cell injury closely linked to endoplasmic reticulum (ER) stress. Melatonin shows neuroprotective potential, but the specific regulatory mechanisms involving the COX2-IRE1α axis remain to be clarified.

OBJECTIVES: To investigate the potential regulatory role of melatonin in attenuating DPN through the modulation of the COX2-IRE1α ER-stress signaling axis.

METHODS: In-vitro, RSC96 Schwann cells were exposed to high glucose (HG) and treated with melatonin (MT), COX2 overexpression, or IRE1α knockdown. Cell viability, apoptosis, and ER stress markers were assessed. In-vivo, 30 rats were divided into control, DPN and MT-treated DPN groups (n=10). After 4 weeks of treatment, sensory nerve conduction velocity (SNCV), motor nerve conduction velocity (MNCV), sciatic nerve morphology and protein expression in nerve tissues were analyzed.

RESULTS: HG significantly reduced cell viability and upregulated ROS and ER-stress markers (P < 0.05). MT treatment dose-dependently mitigated these effects. COX2 overexpression partially reversed MT-mediated protection, while IRE1α knockdown attenuated the damage induced by COX2. In DPN rats, 4-week MT treatment significantly improved MNCV and attenuated nerve morphological degeneration compared to the DPN group (P < 0.05). MT administration was associated with a significant reduction in COX2 and IRE1α protein expression in sciatic nerve tissue, paralleling the in vitro findings.

CONCLUSION: Melatonin treatment is associated with improved nerve function and reduced ER stress in DPN models. These protective effects may be mediated via the modulation of the COX2-IRE1α signaling axis, suggesting a potential therapeutic target for DPN.