Nicotinamide Mononucleotide Prevents Cisplatin-Induced Cognitive Impairments.
Nicotinamide Mononucleotide Prevents Cisplatin-Induced Cognitive Impairments.
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DOI：
10.1158/0008-5472.can-20-3290
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发表时间：
2021-07-01
期刊：
影响因子：
11.2
通讯作者：
Jang MH
中科院分区：
文献类型：
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作者：
Yoo KH;Tang JJ;Rashid MA;Cho CH;Corujo-Ramirez A;Choi J;Bae MG;Brogren D;Hawse JR;Hou X;Weroha SJ;Oliveros A;Kirkeby LA;Baur JA;Jang MH
化疗引起的认知障碍（CICI）是化疗的一种神经毒性副作用。虽然CICI已经成为一个重要的医学问题，但由于缺乏对CICI病理生理机制的理解，目前还没有有意义的治疗方法。使用基于铂的化疗顺铂作为CICI的模型，我们在这里显示，顺铂抑制烟酰胺腺嘌呤二核苷酸（NAD+）水平在成年雌性小鼠脑在体内和人皮质神经元来源于诱导多能干细胞在体外。通过烟酰胺单核苷酸（NMN）给药增加NAD+水平可以预防顺铂诱导的神经祖细胞增殖、神经元形态发生和认知功能异常，而不会影响肿瘤生长和顺铂的抗肿瘤功效。从机制上讲，顺铂抑制NAD+生物合成限速酶烟酰胺磷酸核糖转移酶（Nampt）的表达。选择性恢复Nampt在成年神经元中的表达足以防止顺铂诱导的树突形态发生和记忆功能缺陷。总而言之，我们的研究结果表明，异常的Nampt介导的NAD+代谢途径可能是顺铂诱导的神经源性损伤的关键因素，从而导致记忆功能障碍。因此，增加NAD+水平可能是顺铂相关神经毒性的一种有前景且安全的治疗策略。
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 anti-tumor 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.