Modulation of Anxiety-like and Depression-like Dysfunction by Maropitant in Methotrexate-Induced Chemobrain in Mice

Abstract

Abstract Background: Chemotherapy-related cognitive impairment (CICI) is a major clinical problem. Moreover, significantly reduces the quality of life. Methotrexate (MTX), a widely used antineoplastic agent, is often associated with CICI and causes significant inflammatory, oxidative, and neuroendocrine responses. Maropitant (MAR), a neurokinin-1 receptor blocker, inhibits substance P signaling and may have anti-inflammatory and antioxidant effects. It has become a possible option for reducing chemotherapy-related neurotoxicity; however, its protective effects against MTX-induced neurobehavioral changes are still unclear. Methods: An experimental model of MTX-induced chemobrain was created in mice. The animals received a single dose of MTX (40 mg/kg) 24 hours before behavioral testing. MAR (10 mg/kg, SC) was given in two doses before the MTX injection. Anxiety- and depression-like behaviors were measured using the open field test (OFT) and forced swim test (FST). ELISA tests were performed to measure hippocampal levels of tumor necrosis factor-α (TNF-α) and glutathione GSH. Whereas adrenocorticotropic hormone (ACTH), and corticosterone (CORT) levels were determined using plasma samples. The data were analyzed using one-way ANOVA, followed by the appropriate post hoc tests. Results: MTX caused evident physiological stress; increased corticosterone levels were also detected, along with decreased glutathione levels. MAR treatment significantly mitigated these alterations, reducing the MTX-induced increases in TNF-α, ACTH, and corticosterone, while partially restoring GSN levels and reinstating antioxidant capacity. Conclusion: MAR reduces MTX-induced neuroinflammatory, oxidative, and neuroendocrine changes and improves related behavioral issues. This suggests it may have a therapeutic role in chemotherapy-related neurobehavioral impairment.

Keywords

• Chemotherapy-induced cognitive impairment
• Methotrexate
• Maropitant
• Neuroinflammation
• Oxidative stress

Supporting Institution

None

Project Number

not applicable

Ethical Statement

All experimental procedures were approved by the KONÜDAM Institutional Animal Ethics Committee (Approval No: 2024-096) and conducted in accordance with national and international guidelines.

Thanks

The authors gratefully acknowledge the Experimental Medicine Application and Research Center (KONÜDAM), Necmettin Erbakan University, for providing the animal facilities and technical support required for this study.

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