Document Type : Original Research Articles
Authors
1
Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran.
2
Department of Physiology and Pharmacology "V. Erspamer" University Sapienza of Rome, Rome, Italy.
3
Department of Anatomical Science, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran.
4
Department of Pharmacotherapy, School of Pharmacy. Mazandaran University of Medical Sciences, Sari, Iran.
5
Department of Statistics and Epidemiology, Faculty of Health, Isfahan University of Medical Sciences, Isfahan, Iran.
6
Department of Plastic and Reconstructive Surgery, Hazrat Fatemeh Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Abstract
Background: Peripheral nerve injury frequently leads to persistent neuropathic pain accompanied by sensory and motor dysfunction. The chronic constriction injury (CCI) model reproduces key pathological features of peripheral neuropathy, providing a well-established experimental platform for evaluating neuroprotective therapies. This study investigated the neuroprotective effects of sitagliptin and examined the contribution of glucagon-like peptide-1 receptor (GLP-1R) signaling to its therapeutic effects in CCI-induced neuropathic pain.
Materials and Methods: Twenty-eight adult male Wistar rats were randomly allocated into four groups: Sham, CCI, CCI + Sitagliptin, and CCI + Sitagliptin + Exendin (9–39), a GLP-1R antagonist. Pain-related behaviors, motor nerve conduction velocity (MNCV), inflammatory biomarkers (IL-1β and CRP), and sciatic nerve histopathology were evaluated.
Results: CCI induced marked pain hypersensitivity, reduced MNCV, increased inflammatory biomarker levels, and severe sciatic nerve injury. Sitagliptin significantly alleviated pain-related behaviors, improved MNCV, reduced IL-1β and CRP levels, and preserved nerve architecture. Co-administration of Exendin (9–39) partially attenuated these protective effects, supporting the involvement of GLP-1R signaling while suggesting the contribution of additional GLP-1-independent mechanisms.
Conclusion: Sitagliptin exerts neuroprotective and anti-inflammatory effects in experimental neuropathic pain, with GLP-1R signaling contributing to these protective actions. These findings support the therapeutic potential of sitagliptin as a promising pharmacological strategy for the management of neuropathic pain.
Mechanistic and Translational Relevance: Sitagliptin-mediated neuroprotection in CCI-induced neuropathic pain involves partial contribution of GLP-1 receptor signaling, as pharmacological GLP-1R blockade attenuated its beneficial effects on pain behaviors, nerve conduction, inflammatory responses, and nerve morphology. The incomplete reversal by Exendin (9–39) suggests the involvement of additional GLP-1R-independent mechanisms. These findings highlight the potential repurposing of sitagliptin as a neuroprotective strategy beyond its established metabolic indications and provide a rationale for further investigation in peripheral neuropathic conditions.
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