Semaglutide alleviates diabetic neuropathic pain by inhibiting neuroinflammation in the spinal cord of diabetic rats

Aims: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established for their anti-diabetic properties, but their potential role in diabetic neuropathic pain (DNP) is underexplored. This study investigates the effects of semaglutide on pain behaviours and inflammation, focusing on its capacity to reduce spinal glial cell activation and modulate systemic metabolic and inflammatory markers.

Methods: Male Wistar rats were injected with streptozotocin (60 mg/kg) to induce diabetic neuropathy. Rats with blood glucose >250 mg/dL were classified as diabetic. Animals were divided into a non-diabetic control group, a diabetic group receiving saline, and two diabetic groups treated with oral semaglutide at low (1.44 mg/kg) or high (2.88 mg/kg) doses for 4 weeks. Pain behaviours were assessed using standardised tests for mechanical allodynia and thermal hyperalgesia. Systemic parameters, including HbA1c, lipids, and AGEs, were evaluated. Spinal neuroinflammation was assessed by measuring inflammatory cytokines (TNF-α, IL-1β, and IL-6) and glial cell activation (microglia and astrocytes) using immunohistochemistry and ELISA.

Results: Semaglutide improved pain behaviours in diabetic rats, with paw withdrawal thresholds increasing by 25% and thermal withdrawal latencies improving by 18% after 4 weeks. Both doses effectively reduced pain, with the higher dose demonstrating superior efficacy in lowering HbA1c. Semaglutide also improved AGE levels and lipid abnormalities, including reductions in LDL, triglycerides, VLDL, and FFA, while HDL levels remained unaffected. In terms of spinal neuroinflammation, semaglutide reduced microglial and astrocytic activation in the spinal dorsal horn and significantly decreased levels of TNF-α, IL-1β, and IL-6. These findings highlight semaglutide’s dual benefits in mitigating local spinal inflammation and systemic metabolic dysfunction.

Conclusions: This study underscores semaglutide’s anti-inflammatory and neuroprotective effects in DNP, moving beyond nerve regeneration to address systemic and local mechanisms. By reducing spinal glial activation and improving metabolic dysfunction, semaglutide emerges as a promising candidate for multi-modal DNP therapy.

Comments. This study provides valuable insights into the therapeutic potential of semaglutide in DNP management. Its novelty lies in its mechanistic focus on spinal neuroinflammation, specifically the reduction of microglial and astrocytic activation. Additionally, semaglutide’s ability to modulate systemic markers, such as AGEs and pro-inflammatory cytokines, suggests a dual mechanism addressing both local inflammation and systemic metabolic dysfunction.

However, the study has limitations. The rodent model, while robust, does not fully capture the complexities of human DNP. The four-week treatment duration also leaves questions about long-term efficacy. Furthermore, the absence of assessments for small nerve fibre function, such as intraepidermal nerve fibre density or corneal nerve analysis, limits the understanding of semaglutide’s broader neuroprotective effects.

Future research should prioritise long-term studies to establish the sustainability and applicability of semaglutide’s benefits in humans. Clinical trials assessing both small and large nerve fibre function, alongside inflammatory and metabolic biomarkers, are crucial. Investigating the combination of semaglutide with standard DNP treatments could further enhance its therapeutic potential. By addressing both inflammatory and metabolic dimensions, semaglutide represents a promising approach to improving the quality of life in individuals with diabetes and neuropathic pain.

Maryam Ferdousi

Reference. Lee SO, Kuthati Y, Huang WH, Wong CS. Semaglutide Ameliorates Diabetic Neuropathic Pain by Inhibiting Neuroinflammation in the Spinal Cord. Cells. 2024 Nov 8;13(22):1857. doi: 10.3390/cells13221857. PMID: 39594606; PMCID: PMC11593193.

https://www.mdpi.com/2073-4409/13/22/1857