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Nicotinamide mononucleotide ameliorates chemotherapy-induced cognitive impairment

Catherine Li (1), Ian Johnston (2), Antigone Matsos (2), Emily Si (2), Abhirup Das (1), David Sinclair (3) and Lindsay Wu (1)

  1. Laboratory for Ageing Research, School of Medical Sciences, UNSW Sydney, Australia 

  2. School of Psychology, The University of Sydney, Australia

  3. Paul F. Glenn Labs for the Biological Mechanisms of Ageing, Harvard University, USA 

The improvement in survival rates of cancer patients has rapidly increased due to the development of chemotherapeutic treatment regimes. With improved survival rates, there has been a focus on the long-term health outcomes of cancer survivors, in particular an increased incidence of age associated conditions. One of the most prevailing side effect is chemotherapy-induced cognitive impairment (CICI), which is the deterioration of cognitive function after cessation of chemotherapy, for which currently there are no available treatments. Clinically relevant chemotherapy drugs induce widespread DNA damage, including in healthy tissue such as the brain, leading to cognitive impairments that impact the day to day life of cancer patients. The response to this DNA damage involves the activation of enzymes that consume nicotinamide adenine dinucleotide (NAD+), a prominent metabolite required for a range of important processes. We speculated that increased consumption of NAD+ during chemotherapy treatment might underlie chemotherapy induced cognitive impairment (CICI), and to address this we tested the ability of the NAD+ precursor nicotinamide mononucleotide (NMN) to prevent CICI. Treatment with NMN could reverse cognitive impairments induced by oxaliplatin, as measured by the novel object test. We undertook a detailed proteomic analysis of hippocampus from these animals, and found that mammalian target of rapamycin (mTOR) signaling was disrupted with oxaliplatin treatment. In a separate cohort of animals treated with doxorubicin, we also observed dysregulation of mTOR signaling in the hippocampal proteome. These data point to a new potential mechanism for CICI, as well as a therapeutic strategy that could intervene in this process