Chemobrain: mitoxantrone-induced oxidative stress, apoptotic and autophagic neuronal death in adult CD-1 mice

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Dias Carvalho, A (Author) Other; Ferreira, M (Author) Other; Reis Mendes, A (Author) Other; Ferreira, R (Author) Other; Maria de Lourdes Bastos (Author) FFUP; Eduarda Fernandes (Author) FFUP; Sa, SI (Author) FMUP; Capela, JP (Author) Other; Felix Carvalho (Author) FFUP; Costa, VM (Author) Other

Journal

Title: Archives of Toxicology

Vol. 96

Pages: 1767-1782

ISSN: 0340-5761

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 4 Citations

Scopus - 5 Citations

Other information

Authenticus ID: P-00W-9ZZ

DOI: 10.1007/s00204-022-03261-x

Abstract (EN): Mitoxantrone (MTX) is a topoisomerase II inhibitor used to treat a wide range of tumors and multiple sclerosis but associated with potential neurotoxic effects mediated by hitherto poorly understood mechanisms. In adult male CD-1 mice, the underlying neurotoxic pathways of a clinically relevant cumulative dose of 6 mg/kg MTX was evaluated after biweekly administration for 3 weeks and sacrifice 1 week after the last administration was undertaken. Oxidative stress, neuronal damage, apoptosis, and autophagy were analyzed in whole brain, while coronal brain sections were used for a closer look in the hippocampal formation (HF) and the prefrontal cortex (PFC), as these areas have been signaled out as the most affected in 'chemobrain'. In the whole brain, MTX-induced redox imbalance shown as increased endothelial nitric oxide synthase and reduced manganese superoxide dismutase expression, as well as a tendency to a decrease in glutathione levels. MTX also caused diminished ATP synthase beta expression, increased autophagic protein LC3 II and tended to decrease p62 expression. Postsynaptic density protein 95 expression decreased in the whole brain, while hyperphosphorylation of Tau was seen in PFC. A reduction in volume was observed in the dentate gyrus (DG) and CA1 region of the HF, while GFAP-ir astrocytes increased in all regions of the HF except in the DG. Apoptotic marker Bax increased in the PFC and in the CA3 region, whereas p53 decreased in all brain areas evaluated. MTX causes damage in the brain of adult CD-1 mice in a clinically relevant cumulative dose in areas involved in memory and cognition.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16