Doxorubicin-induced neurotoxicity differently affects the hippocampal formation subregions in adult mice
Ana Dias-Carvalho,
Mariana Ferreira,
Ana Reis-Mendes,
Rita Ferreira,
Maria de Lourdes Bastos,
Eduarda Fernandes,
Susana Isabel Sá,
João Paulo Capela,
Félix Carvalho,
Vera Marisa Costa
Affiliations
Ana Dias-Carvalho
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; UCIBIO–Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313, Porto, Portugal; Corresponding author.
Mariana Ferreira
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; UCIBIO–Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313, Porto, Portugal; LAQV/REQUIMTE, Chemistry Department, University of Aveiro, Aveiro, Portugal
Ana Reis-Mendes
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; UCIBIO–Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313, Porto, Portugal
Rita Ferreira
LAQV/REQUIMTE, Chemistry Department, University of Aveiro, Aveiro, Portugal
Maria de Lourdes Bastos
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; UCIBIO–Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313, Porto, Portugal
Eduarda Fernandes
LAQV/REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
Susana Isabel Sá
Unit of Anatomy, Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal; Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, Porto, Portugal
João Paulo Capela
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; UCIBIO–Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313, Porto, Portugal; FP-I3ID, Faculdade de Ciências da Saúde, Universidade Fernando Pessoa, Porto, Portugal
Félix Carvalho
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; UCIBIO–Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313, Porto, Portugal
Vera Marisa Costa
Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; UCIBIO–Applied Molecular Biosciences Unit, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050‐313, Porto, Portugal; Corresponding author. UCIBIO/REQUIMTE, Laboratório de Toxicologia, Faculdade de Farmácia, Universidade do Porto Rua de Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
Doxorubicin (DOX) is an anthracycline used to treat a wide range of tumours. Despite its effectiveness, it is associated with a long range of adverse effects, of which cognitive deficits stand out. The present study aimed to assess the neurologic adverse outcome pathways of two clinically relevant cumulative doses of DOX. Adult male CD-1 mice received biweekly intraperitoneal administrations for 3 weeks until reaching cumulative doses of 9 mg/kg (DOX9) or 18 mg/kg (DOX18). Animals were euthanized one week after the last administration, and biomarkers of oxidative stress and brain metabolism were evaluated in the whole brain. Coronal sections of fixed brains were used for specific determinations of the prefrontal cortex (PFC) and hippocampal formation (HF). In the whole brain, DOX18 tended to disrupt the antioxidant defences, affecting glutathione levels and manganese superoxide dismutase expression. Considering the regional analysis, DOX18 increased the volume of all brain areas evaluated, while GFAP-immunoreactive astrocytes decreased in the dentate gyrus (DG) and increased in the CA3 region of HF, both in a dose-dependent manner. Concerning the apoptosis pathway, whereas Bax increased in the DOX9 group, it decreased in the DOX18 group. Only in the latter group did Bcl-2 levels also decrease. While p53 only increased in the CA3 region of the DOX9 group, AIF increased in the PFC and DG of DOX18. Finally, phosphorylation of Tau decreased with the highest DOX dose in DG and CA3, while TNF-α levels increased in CA1 of DOX18. Our results indicate new pathways not yet described that could be responsible for the cognitive impairments observed in treated patients.