Remogliflozin attenuates cyclophosphamide-associated peripheral neurotoxicity in rats: concomitant changes in redox, inflammatory, neurotrophic, and apoptosis-related markers.

Abstract

Peripheral neurotoxicity represents a debilitating complication of cancer chemotherapy. Although cyclophosphamide (CP) is an alkylating agent with lower clinical propensity for classic peripheral neuropathy than platinum compounds or taxanes, its reactive metabolites provoke significant neurotoxic injury in experimental settings. This study investigated whether remogliflozin (Remo), a sodium-glucose cotransporter-2 inhibitor (SGLT2) with pleiotropic antioxidant and anti-inflammatory properties, attenuates CP-associated peripheral neurotoxicity in an experimental rat model. Twenty-four male Wistar rats were divided into four groups: control, CP alone (100 mg/kg intraperitoneally once weekly), CP plus Remo 25 mg/kg/day orally, and CP plus Remo 50 mg/kg/day orally, all for one month. Behavioral assessments revealed that CP treatment was associated with altered motor coordination and nociceptive responses, which showed dose-related numerical improvements with Remo treatment. Biochemically, Remo treatment was associated with a favorable shift in redox markers, evidenced by higher Nrf2, glutathione, and superoxide dismutase levels, alongside reduced malondialdehyde. Remo treatment was associated with lower concentrations of inflammatory markers, including NF-κB, MCP-1, TNF-α, IL-6, and IL-1β. Furthermore, Remo treatment was associated with increased BDNF and CREB concentrations, PI3K, and total/phosphorylated Akt (with an improved p-Akt/total Akt ratio), along with lower concentrations of caspase-3 and BAX, and higher BCL-2. Histopathological and immunohistochemical analyses demonstrated that Remo was associated with preserved nerve structural integrity, attenuated myelin loss, and elevated Nrf2 and p-Akt immunoreactivity. These findings suggest that Remo is associated with attenuation of CP-induced peripheral neurotoxicity in rats, presenting a phenotypically consistent biomarker profile that warrants further causal and mechanistic evaluation.