Nicotinamide mononucleotide prevents cisplatin-induced cognitive impairments

Ki Hyun Yoo, Jason J. Tang, Mohammad Abdur Rashid, Chang Hoon Cho, Ana Corujo-Ramirez, Jonghoon Choi, Mun Gyeong Bae, Danielle Brogren, John R Hawse, Xiaonan Hou, S. John Weroha, Alfredo Oliveros, Lindsey A. Kirkeby, Joseph A. Baur, Mi Hyeon Jang

Research output: Contribution to journalArticlepeer-review

Abstract

Chemotherapy-induced cognitive impairment (CICI) is often reported as a neurotoxic side effect of chemotherapy. Although CICI has emerged as a significant medical problem, meaningful treatments are not currently available due to a lack of mechanistic understanding underlying CICI pathophysiology. Using the platinum- based chemotherapy cisplatin as a model for CICI, we show here that cisplatin suppresses nicotinamide adenine dinucleotide (NAD ) levels in the adult female mouse brain in vivo and in human cortical neurons derived from induced pluripotent stem cells in vitro. Increasing NAD levels through nicotinamide mononucleotide (NMN) administration prevented cisplatin-induced abnormalities in neural progenitor proliferation, neuronal morphogenesis, and cognitive function without affecting tumor growth and antitumor efficacy of cisplatin. Mechanistically, cisplatin inhibited expression of the NAD biosynthesis rate-limiting enzyme nicotinamide phosphoribosyl transferase (Nampt). Selective restoration of Nampt expression in adult-born neurons was sufficient to prevent cisplatin-induced defects in dendrite morphogenesis and memory function. Taken together, our findings suggest that aberrant Nampt-mediated NAD metabolic pathways may be a key contributor in cisplatin-induced neurogenic impairments, thus causally leading to memory dysfunction. Therefore, increasing NAD levels could represent a promising and safe therapeutic strategy for cisplatin-related neurotoxicity.

Original languageEnglish (US)
Pages (from-to)3727-3737
Number of pages11
JournalCancer research
Volume81
Issue number13
DOIs
StatePublished - Jul 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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