Doxorubicin-induced neurotoxicity differently affects the hippocampal formation subregions in adult mice

Abstract

Doxorubicin (DOX) is an anthracycline used to treat a wide range of tumours. Despite its effectiveness, it is associated to 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 on 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 (MnSOD) 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 apoptosis pathway, whereas Bax increased in the DOX9 group, it decreased in the DOX18 group, but only in the latter group, Bcl-2 levels also decreased. 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.

Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition

“…Longstanding data from rodents, macaques and humans have shown increased KYNA levels in CNS with advanced age [31][32][33]85 , consistent with greater inflammation with age 9,86,87 . The current data are consonant with these findings, as aged macaques were more responsive to KAT-II inhibitors than younger adult macaques, and showed greater levels of plasma kynurenine.…”