Correlation between NFκB Signaling and Na+, K+‑ATPase Inhibition in Vincristine-Induced Emotional and Cognitive Comorbidities in Mice: Neuroprotective Potential of 4‑PSQ

Vincristine (VCR), a widely used chemotherapeutic agent, is associated with persistent neurotoxic effects including psychiatric and cognitive impairments in Cancer survivors. In contrast, 7-chloro-4-(phenylselanyl)-quinoline (4-PSQ) is a synthetic compound with potential neuroprotective effects. This study investigated the neurobehavioral and molecular effects of VCR in male and female Swiss mice, with a focus on sex-specific outcomes and the neuroprotective efficacy of 4-PSQ. Mice received daily intraperitoneal injections of VCR (0.1 mg/kg) or vehicle (0.9% saline solution) for 5 days, followed by daily oral administration of 4-PSQ (1 mg/kg) or vehicle (canola oil) from days 7 to 16. Behavioral assessments for depressive- and anxiety-like responses and cognitive performance were conducted, followed by biochemical analyses of the cerebral cortex and spinal cord. VCR significantly increased nuclear factor kappa B (NFκB) expression and inhibited Na⁺,K⁺-ATPase activity in both sexes while selectively upregulating protein-21 (protein 21 (p21)) mRNA in the cerebral cortex of females. These molecular alterations correlated with behavioral impairments, as shown by a robust pattern of sex-specific associations: in males, behavioral changes were strongly correlated with Na⁺,K⁺-ATPase inhibition, while in females, increased NFκB expression was more strongly associated with emotional and cognitive deficits. Notably, p21 overexpression has emerged as a unique marker of neurotoxicity in females. Treatment with 4-PSQ attenuated molecular and behavioral alterations in both sexes, supporting its neuroprotective efficacy. By establishing specific correlations between biochemical and behavioral parameters, this study provides mechanistic insights into VCR-induced neurotoxicity. It proposes 4-PSQ as a promising therapeutic candidate for preventing or reversing chemotherapy-related cognitive and emotional dysfunctions.