Dias-Carvalho Ana, Ferreira Mariana, Reis-Mendes Ana, Ferreira Rita, de Lourdes Bastos Maria, Fernandes Eduarda, Sá Susana Isabel, Capela João Paulo, Carvalho Félix, Costa Vera Marisa
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.
Heliyon. 2024 May 24;10(11):e31608. doi: 10.1016/j.heliyon.2024.e31608. eCollection 2024 Jun 15.
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.
多柔比星（DOX）是一种用于治疗多种肿瘤的蒽环类药物。尽管其疗效显著，但它会引发一系列不良反应，其中认知缺陷尤为突出。本研究旨在评估两种临床相关累积剂量的DOX的神经不良结局途径。成年雄性CD-1小鼠每两周接受一次腹腔注射，持续3周，直至累积剂量达到9mg/kg（DOX9）或18mg/kg（DOX18）。在最后一次给药一周后对动物实施安乐死，并评估全脑的氧化应激和脑代谢生物标志物。使用固定脑的冠状切片对前额叶皮质（PFC）和海马结构（HF）进行特定测定。在全脑中，DOX18倾向于破坏抗氧化防御，影响谷胱甘肽水平和锰超氧化物歧化酶表达。考虑到区域分析，DOX18增加了所有评估脑区的体积，而胶质纤维酸性蛋白免疫反应性星形胶质细胞在齿状回（DG）中减少，在HF的CA3区域中增加，两者均呈剂量依赖性。关于细胞凋亡途径，Bax在DOX9组中增加，而在DOX18组中减少。仅在后者组中，Bcl-2水平也降低。虽然p53仅在DOX9组的CA3区域中增加，但AIF在DOX18的PFC和DG中增加。最后，Tau的磷酸化在DG和CA3中随着最高DOX剂量而降低，而DOX18的CA1中TNF-α水平增加。我们的结果表明了尚未描述的新途径，这些途径可能是治疗患者中观察到的认知障碍的原因。
