Lacosamide as a chemoprotective agent beyond anticonvulsant activity: Pharmacological modulation of Notch-1/NF-κB axis to restore antioxidant defense, inhibit apoptosis, and preserve testosterone-androgen receptor signaling in cyclophosphamide-induced prostate injury

Cyclophosphamide (CPX)-induced prostatic toxicity remains a clinically relevant concern, with limited strategies available to mitigate its adverse effects. This study investigates the potential protective effects of lacosamide (LCS), an FDA-approved anticonvulsant with antioxidant, anti-inflammatory, and anti-apoptotic properties, against CPX-induced prostate injury in rats. We examined LCS's effects on the Notch-1 signaling pathway and its potential interaction with nuclear factor kappa B (NF-κB). Male Wistar albino rats were divided into five groups: normal control, LCS control (40 mg/kg/day), CPX control (200 mg/kg), and two LCS treatment groups (10 and 40 mg/kg/day) co-administered with CPX. CPX exposure significantly increased oxidative stress markers (elevated malondialdehyde; reduced glutathione, superoxide dismutase, glutathione peroxidase, and catalase), upregulated proinflammatory markers (phosphorylated NF-κB p65, interleukin-6, interleukin-1β, tumor necrosis factor-α), and increased apoptotic markers (downregulation of B-cell lymphoma 2; upregulation of Bcl-2 associated X protein and cleaved caspase-3). Additionally, CPX enhanced Notch-1 receptor and Notch-1 intracellular domain expression, decreased serum testosterone levels, altered prostate-specific antigen levels, and suppressed androgen receptor expression. LCS co-administration, particularly at the higher dose, improved these parameters, suggesting modulation of oxidative stress, inflammation, and apoptotic pathways. These findings indicate that LCS treatment may provide protective effects against CPX-induced prostatic alterations and suggest its potential consideration as an adjuvant agent during CPX-based therapy.