Age-related cognitive function and cerebral plasticity in miceafter chemotherapy: Important role of drug adjuvants.

Abstract

e11082 Background: Evidence is emerging that cancer and treatments can induce cognitive impairments such as deficits of visual and spatial memories, and of psychomotor processing speed, now referred to as chemofog of chemobrain. Thus, the objective of the current project is to explore the direct impact of chemotherapy on cognitive disorders among elderly patients with treatment for a breast or colon cancer by means of animal mice models. Methods: We investigated long-term behavioral effects of a chronic administration of 5-fluorouracil (5-FU) or a combination of 5-FU/oxaliplatin in young and aged mice. Results: 5-FU alone or in combination with oxaliplatin, neither altered anxiety- and depressive-like behaviors, nor spatial learning and memory performances, in young or aged mice. However, compared to saline, the 5-FU-treated mice were impaired in the cognitive flexibility-dependant task in the Morris water-maze test, and exhibited a more pronounced preference for the novel object in the object recognition test, suggesting a hyper-reactivity to novelty. Coadministration of glucose with 5-FU alone or in combination with oxaliplatin, protected animals against chemotherapy-evoked cognitive function impairments. In order to assess the direct neurotoxic role of chemotherapy on cell brain plasticity, neural stem cell (NSC) culture were incubated with increasing concentrations of 5-FU and oxaliplatin, in the absence or presence of glucose or insulin. Preliminary data showed that chemotherapy provoked a dose-dependent decrease of NSC survival, and that insulin counteracted this negative effect. Conclusions: Our study demonstrates that 5-FU-treated animals are impaired in term of behavioral flexibility whatever the age, as a consequence of substantially reduced number of adult generated hippocampal neurons. The neuroprotective role of blood glucose or glucose-induced insulin levels opens new clinical perspectives in the modality of chemotherapy administration. No significant financial relationships to disclose.