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

## TL;DR

This study explores how vincristine chemotherapy causes emotional and cognitive issues in mice and finds that 4-PSQ may help protect the brain.

## Contribution

The study identifies sex-specific molecular and behavioral correlations in vincristine-induced neurotoxicity and proposes 4-PSQ as a neuroprotective treatment.

## Key findings

- Vincristine increases NFκB and inhibits Na+, K+-ATPase in both male and female mice.
- 4-PSQ reduces neurotoxic effects and behavioral impairments in both sexes.
- p21 mRNA upregulation is a unique female-specific marker of neurotoxicity.

## Abstract

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.