Therapeutic Effects of GLP-1 Receptor Agonists and DPP-4 Inhibitors in Neuropathic Pain: Mechanisms and Clinical...

Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by the small intestine upon food intake. GLP-1 enhances insulin secretion, suppresses glucagon release, and promotes satiety, resulting in reduced food consumption and subsequent weight loss. Endogenous GLP-1 has a very short half-life and is rapidly degraded by the enzyme dipeptidyl-peptidase-IV (DPP-4). To address this limitation, GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors (DPP-4is) were developed and have demonstrated potency in clinical practice. In recent years, GLP-1RA and DPP4-i therapies are known to have pleiotropic effects, such as a reduction in oxidative stress, autophagy regulation, metabolic reprogramming, enhancement of anti-inflammatory signaling, regulation of gene expression, and being neuroprotective. These effects imply a therapeutic perspective for GLP-1RA and DPP-4i therapies in neuropathic pain treatment. Preclinical and clinical studies increasingly support the hypothesis that these therapies may alleviate neuropathic pain by targeting multiple mechanisms that induce neuropathic pain, such as inflammation, oxidative stress, and mitochondrial dysfunction. This review explores the mechanisms by which GLP-1RAs and DPP-4is alleviate neuropathic pain. It also highlights current advancements in incretin research, focusing on the therapeutic effects of GLP-1RAs and DPP-4-is for neuropathic pain.