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Article

A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study

by
Ana Dias-Carvalho
1,2,*,
Ana Margarida-Araújo
1,2,†,
Ana Reis-Mendes
1,2,
Catarina Oliveira Sequeira
3,
Sofia Azeredo Pereira
3,
Paula Guedes de Pinho
1,2,
Félix Carvalho
1,2,
Susana Isabel Sá
4,5,
Eduarda Fernandes
6 and
Vera Marisa Costa
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
iNOVA4Health, LS4Future, NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), Universidade Nova de Lisboa, 1150-082 Lisboa, Portugal
4
Unit of Anatomy, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
5
Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
6
LAQV-REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
*
Authors to whom correspondence should be addressed.
†
Current address: LAQV-REQUIMTE, Laboratory of Bromatology and Hydrology, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
Int. J. Mol. Sci. 2023, 24(17), 13126; https://doi.org/10.3390/ijms241713126
Submission received: 15 June 2023 / Revised: 26 July 2023 / Accepted: 9 August 2023 / Published: 23 August 2023
(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)
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Abstract

Long-term cognitive dysfunction, or “chemobrain”, has been observed in cancer patients treated with chemotherapy. Mitoxantrone (MTX) is a topoisomerase II inhibitor that binds and intercalates with DNA, being used in the treatment of several cancers and multiple sclerosis. Although MTX can induce chemobrain, its neurotoxic mechanisms are poorly studied. This work aimed to identify the adverse outcome pathways (AOPs) activated in the brain upon the use of a clinically relevant cumulative dose of MTX. Three-month-old male CD-1 mice were given a biweekly intraperitoneal administration of MTX over the course of three weeks until reaching a total cumulative dose of 6 mg/kg. Controls were given sterile saline in the same schedule. Two weeks after the last administration, the mice were euthanized and their brains removed. The left brain hemisphere was used for targeted profiling of the metabolism of glutathione and the right hemisphere for an untargeted metabolomics approach. The obtained results revealed that MTX treatment reduced the availability of cysteine (Cys), cysteinylglycine (CysGly), and reduced glutathione (GSH) suggesting that MTX disrupts glutathione metabolism. The untargeted approach revealed metabolic circuits of phosphatidylethanolamine, catecholamines, unsaturated fatty acids biosynthesis, and glycerolipids as relevant players in AOPs of MTX in our in vivo model. As far as we know, our study was the first to perform such a broad profiling study on pathways that could put patients given MTX at risk of cognitive deficits.
Keywords: chemotherapy; adverse outcome pathways; cancer; multiple sclerosis; topoisomerase inhibitors; metabolomics approach chemotherapy; adverse outcome pathways; cancer; multiple sclerosis; topoisomerase inhibitors; metabolomics approach

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MDPI and ACS Style

Dias-Carvalho, A.; Margarida-Araújo, A.; Reis-Mendes, A.; Sequeira, C.O.; Pereira, S.A.; Guedes de Pinho, P.; Carvalho, F.; Sá, S.I.; Fernandes, E.; Costa, V.M. A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study. Int. J. Mol. Sci. 2023, 24, 13126. https://doi.org/10.3390/ijms241713126

AMA Style

Dias-Carvalho A, Margarida-Araújo A, Reis-Mendes A, Sequeira CO, Pereira SA, Guedes de Pinho P, Carvalho F, Sá SI, Fernandes E, Costa VM. A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study. International Journal of Molecular Sciences. 2023; 24(17):13126. https://doi.org/10.3390/ijms241713126

Chicago/Turabian Style

Dias-Carvalho, Ana, Ana Margarida-Araújo, Ana Reis-Mendes, Catarina Oliveira Sequeira, Sofia Azeredo Pereira, Paula Guedes de Pinho, Félix Carvalho, Susana Isabel Sá, Eduarda Fernandes, and Vera Marisa Costa. 2023. "A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study" International Journal of Molecular Sciences 24, no. 17: 13126. https://doi.org/10.3390/ijms241713126

APA Style

Dias-Carvalho, A., Margarida-Araújo, A., Reis-Mendes, A., Sequeira, C. O., Pereira, S. A., Guedes de Pinho, P., Carvalho, F., Sá, S. I., Fernandes, E., & Costa, V. M. (2023). A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study. International Journal of Molecular Sciences, 24(17), 13126. https://doi.org/10.3390/ijms241713126

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