CHEMOTHERAPY INDUCED COGNITIVE IMPAIRMENT: GENETIC MODULATIONS AND MECHANISMS

Abstract

Mounting evidence has suggested that chemotherapy can cause cognitive impairment (“chemobrain”) but current understanding is limited predominantly to breast cancer data while underlying mechanisms remain unresolved. In this study we investigated the chemobrain effect and neurobiological changes induced by acute myeloid leukemia (AML) drug cytosine arabinoside (Ara-C). Adult C57BL/6 mice treated at a clinically-converted dose exhibited remote memory impairment. At the cellular level, multiple phases of hippocampal neurogenesis were found altered: proliferation was acutely suppressed; neuronal differentiation of granule cells was reduced with increase in new oligodendrocytes; stereotactic intrahippocampal delivery of GFP revealed persistent impairment of dendritic arborization and spine density of adult-born granule neurons. Exercise post-treatment markedly attenuated drug-induced neuronal deficits but not memory changes. Our study investigated the timeline of Ara-C-induced neurobiological alterations relevant to its clinical use, highlighting differential drug effects on distinct stages of adult neurogenesis while testing the viability of exercise as a therapeutic approach.