N-Acetylcysteine Attenuates Epirubicin-Induced Neurobehavioral, Inflammatory, and Neuroplasticity-Related Alterations in Rats

Chemotherapy-induced cognitive impairment (CICI) is increasingly understood as a systems-to-brain disorder in which peripheral inflammatory activation, together with other systemic stress responses described in previous studies, may contribute to central inflammatory responses, disruption of neuroplasticity-related processes, and cognitive dysfunction. Anthracyclines have been implicated in these effects, yet the acute neurobehavioral consequences of epirubicin exposure and their pharmacological modulation remain incompletely characterized. The present study investigated whether N-acetylcysteine (NAC), a thiol-containing compound with established redox-modulating pharmacological properties, attenuates behavioral, biochemical, and histopathological alterations following a single epirubicin administration in rats. Thirty-five male Wistar albino rats were randomized into five groups: control, epirubicin (EPI; 9.6 mg/kg, i.p.), NAC alone (300 mg/kg, i.p.), EPINAC50, and EPINAC300. In the combination groups, NAC was administered 1 h after EPI. Anxiety-like behavior, altered stress-coping behavior, and recognition memory were assessed using the open field, elevated plus maze, forced swim, and novel object recognition tests. Hippocampal TNF-α, IFN-γ, COX-2, cleaved caspase-3, BDNF, and CREB levels were quantified by ELISA, and cortical histopathological alterations were evaluated in hematoxylin–eosin-stained sections. EPI administration was associated with anxiety-like and altered stress-coping behavioral changes, impaired recognition memory, increased hippocampal TNF-α, IFN-γ, and COX-2 levels, reduced BDNF and CREB levels, and H&E-detectable cortical tissue alterations characterized by degenerative neuronal morphology and disruption of tissue organization. Cleaved caspase-3 levels were not significantly altered under the present experimental conditions. NAC treatment was associated with improvements in behavioral, biochemical, and histopathological outcomes, with the 300 mg/kg dose showing the most consistent effects. These findings indicate that, in this single-dose experimental model, short-term epirubicin-associated neurobehavioral impairment was accompanied by increased hippocampal inflammatory mediators, reductions in the neuroplasticity-related markers BDNF and CREB, and cortical morphological alterations. A single NAC administration given 1 h after epirubicin attenuated several of these changes, supporting further investigation of NAC as an early post-treatment intervention for acute anthracycline-associated neurobehavioral toxicity. Because this model used a single epirubicin exposure and a short observation period, the findings should not be extrapolated directly to persistent CICI associated with repeated chemotherapy cycles. In addition, oxidative stress parameters and specific intracellular signaling pathways were not directly assessed; therefore, the mechanisms underlying the observed effects, including any contribution of NAC-mediated redox modulation, require direct investigation in future studies.