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.