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GLP1 and DPP4 Compounds: Emerging Areas of Investigation in Neurological Pain Models
Recent scientific literature has explored how glucagon-like peptide-1 receptor agonists (GLP1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) compounds originally developed for metabolic research may influence cellular pathways relevant to neuropathic pain. A 2025 review published in *Biomolecules*, titled *Therapeutic Effects of GLP-1 Receptor Agonists and DPP-4 Inhibitors in Neuropathic Pain: Mechanisms and Clinical Implications*, outlines emerging findings from both preclinical and early clinical investigations.
Neuropathic pain is associated with changes in the central and peripheral nervous system and is often linked to inflammation, mitochondrial dysfunction, oxidative stress, and impaired autophagy. These biological processes have been studied in models of diabetic neuropathy, chemotherapy-induced neurotoxicity, and spinal cord injury
GLP1RAs and DPP4is have demonstrated activity in modulating inflammation, oxidative signaling, and mitochondrial homeostasis in animal and in vitro models. Several studies report that these compounds reduce oxidative stress markers, suppress microglial activation, and influence the expression of cytokines and other genes associated with neural resilience. Some studies also suggest a role in autophagy regulation and neuronal energy balance.
Rodent studies have shown changes in pain-related behavior following administration of GLP1RAs such as exenatide and liraglutide. These behavioral findings were accompanied by differences in biochemical indicators of inflammation and cellular metabolism. DPP4 inhibitors produced similar trends in some models, though effects appeared variable depending on dosage and condition.
While most of the current evidence is derived from non-human studies, a limited number of observational reports have explored the relationship between GLP1RA exposure and sensory symptoms in individuals with metabolic disorders. These associations remain under investigation, and the review authors highlight the need for placebo-controlled trials to determine whether GLP1 based compounds have a clinically meaningful effect on pain outcomes.
From a research perspective, the potential overlap between metabolic signaling and neuronal regulation represents a growing area of inquiry. Studies focused on neuroinflammation, mitochondrial support, and gene expression profiling continue to inform our understanding of how incretin-based compounds may impact the nervous system.
Future investigations will require rigorous trial design, long-term observation, and molecular biomarker analysis to clarify both the mechanisms and limits of these effects. While research is ongoing, GLP1RAs and DPP4is remain of interest within preclinical neurobiology and translational metabolic studies.
Reference
PMCID: PMC12108864 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12108864/)
Disclaimer
This article is intended for informational and educational purposes only. The compounds mentioned are sold exclusively for laboratory research use and are not approved by the FDA for human consumption, treatment, or diagnosis of any disease. Nothing in this article should be interpreted as medical advice or an endorsement of therapeutic use. All references to studies are intended to highlight ongoing areas of scientific investigation.
