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Ertugliflozin Mitigates Cisplatin‑Induced Peripheral Neuropathy in Rats via Nrf2/HO‑1 and p38 MAPK/NF-κB Pathways
Marwa Qadri1,2, Abdulaziz Alarifi3,4, Shaimaa A Gad5
1Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, postal code 45142, Saudi Arabia.
Objective:
Cisplatin (Cis) is an effective chemotherapeutic agent whose use may be limited by chemotherapy-induced peripheral neuropathy (CIPN), involving oxidative stress, inflammation, and apoptosis. This study investigated the neuroprotective effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin (Ertu) in a rat model of cisplatin-induced peripheral neuropathy.
Methods:
Twenty-four male rats were assigned to control, cisplatin, or cisplatin plus ertugliflozin groups receiving 5 or 10 mg/kg for 4 weeks. Motor and sensory functions were assessed using rotarod, tail-flick, hot-plate, and cold-allodynia tests. Sciatic nerve levels of superoxide dismutase, reduced glutathione, malondialdehyde, tumor necrosis factor-alpha, interleukin-6, phosphorylated nuclear factor-kappa B p65, p38 mitogen-activated protein kinase, nuclear factor erythroid 2-related factor 2, heme oxygenase-1, phosphoinositide 3-kinase, protein kinase B, and caspase-3 were measured. Histopathological and immunohistochemical examinations were also performed.
Results:
Cisplatin decreased antioxidant and pro-survival markers and increased oxidative, inflammatory, and apoptotic markers, accompanied by behavioral deficits and sciatic nerve degeneration. Both ertugliflozin doses improved behavioral performance, enhanced antioxidant and pro-survival markers, reduced inflammatory and apoptotic markers, and ameliorated histopathological changes. The 10 mg/kg dose produced numerically greater effects for several endpoints; however, superiority over the 5 mg/kg dose was not established for all outcomes.
Conclusion:
Ertugliflozin mitigated cisplatin-induced neuropathic changes in rats. These findings provide a preclinical rationale for further investigation of ertugliflozin as a potential neuroprotective adjunct during cisplatin-based chemotherapy. Tumor-bearing studies, pharmacokinetic investigations, and clinical studies are required to determine its translational potential.
