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Unveiling the neurotoxicity of mitoxantrone: oxidative stress, apoptosis, and autophagy in the brain of adult CD-1 mice
* 1, 2 , 1, 2, 3 , 1, 2 , 3 , 1, 2 , 4 , 5, 6 , 1, 2, 7 , 1, 2 , 1, 2
1  Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
2  UCIBIO - Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313 Porto, Portugal
3  LAQV/REQUIMTE, Chemistry Department, University of Aveiro, Aveiro, Portugal
4  LAQV/REQUIMTE, University of Porto, Porto, Portugal
5  Unit of Anatomy, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
6  CINTESIS@RISE, Unit of Anatomy, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
7  FP-ENAS (Unidade de Investigação UFP em Energia, Ambiente e Saúde), CEBIMED (Centro de Estudos em Biomedicina), Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Porto, Portugal
Academic Editor: Alfredo Berzal-Herranz

Published: 01 November 2022 by MDPI in 8th International Electronic Conference on Medicinal Chemistry session General (registering DOI)

Mitoxantrone (MTX) is a topoisomerase II inhibitor with anticancer and immunomodulatory properties, however its neurotoxicity is poorly understood. Our work aimed to evaluate the neurotoxicity of a clinically relevant dose of MTX in adult mice.

Three-month-old CD-1 male mice received bi-weekly administrations of MTX for 3 weeks, until they achieved a total cumulative dose of 6 mg/kg. They were sacrificed one week later. Biomarkers of oxidative stress, neuronal damage, apoptosis, and autophagy were analyzed in whole brain, whereas brain sections were used for analysis of the hippocampal formation (HF) and prefrontal cortex (PFC).

Our results demonstrated that MTX induced redox imbalance in the whole brain, namely an increase in endothelial nitric oxide synthase and reduced manganese superoxide dismutase content. Brain oxidative metabolism was altered as seen by diminished subunit β adenosine triphosphate synthase content. MTX increased autophagic microtubule-associated protein light chain 3 II and decreased postsynaptic density protein 95. Regarding regional brain analysis, a reduction in volume was observed in the dentate gyrus and CA1 region of the HF. Total number of glial fibrillary acid protein immunoreactive astrocytes increased in all regions of the HF except in the DG, suggesting extensive astrogliosis. The apoptotic marker Bax increased in the PFC and CA3 region, whereas p53 decreased in all areas evaluated. In the PFC, MTX caused hyperphosphorylation of Tau.

MTX disrupts several pathways in the brain of adult CD-1 mice in a clinically relevant dose, which can lead to cognitive impairment, but further studies are needed to evaluate the putative consequences.

Keywords: mitoxantrone; neurotoxicity; chemobrain; mice; chemotherapy