Chemobrain: the neurotoxic mechanisms of doxorubicin and mitoxantrone

• Autor(a) principal: Ferreira, Mariana Lopes
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/32578
• topic: Chemobrain; Cognitive dysfunction; Doxorubicin; Mitoxantrone; Oxidative stress; Inflammation; Cell death

The combination of earlier diagnosis and anti-cancer treatment has led to an increase in cancer survivors. Despite their effectiveness, chemotherapeutic anticancer drugs have adverse effects, such as declining cognitive functions. Doxorubicin (DOX) and mitoxantrone (MTX) are two anti-cancer drugs, both topoisomerase II inhibitors that can cause chemotherapy-induced cognitive impairment, also known as ‘chemobrain’. Its underlying mechanisms need further research in order to reduce or prevent chemobrain’s incidence. Therefore, the present dissertation aimed to evaluate the underlying neurotoxicity mechanisms of clinically relevant doses of DOX and MTX when given to adult mice. Two cumulative doses of DOX (9 mg/kg or 18 mg/kg) and one cumulative dose of MTX (6 mg/kg) were intraperitoneally (i.p.) given to adult mice for 3 weeks. Mice were sacrificed one week after the last administration, and then the brains were collected. Brain hemispheres were homogenized with RIPA or phosphate buffer. Afterwards, relevant neuronal proteins were assessed by Western blotting, as well as the protein carbonyl content and the expression of p62. The lowest cumulative dose of DOX tended to change the expression of adenosine triphosphate (ATP) synthase β. MTX showed a tendency to change the expression of manganese superoxide dismutase (MnSOD), p62 and postsynaptic density protein 95 (PSD95). Moreover, MTX provoked a meaningful alteration in the expression of microtubule-associated protein light chain 3-II (LC3-II). When compared with the control group, none of the drugs affected the protein carbonyl content, the expression of glycogen synthase kinase 3b (GSK- 3b), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), heat shock protein 27 (HSP27), the subunits p50 and p65 of nuclear fator kappa B (NF-κB), autophagy related protein 5 (ATG5), phosphorylated protein tau (pTau) and synaptophysin. Both drugs modulated in different ways the evaluated proteins, with higher impact seen in MTX. However, further research is needed to evaluate the neurotoxicity after chemotherapy and elucidate the underlying mechanisms of ‘chemobrain’ after the administration of these and other anti-cancer drugs.