Department of Pharmacology, Second Military Medical University / Naval Medical University, 325 Guo He Road, Shanghai, 200433, China.
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
Curr Pharm Biotechnol. 2023;24(2):299-309. doi: 10.2174/1389201023666220518113219.
This study determined for the first time the distribution of intravenous nicotinamide mononucleotide (NMN) and its metabolite nicotinamide adenine dinucleotide (NAD) in normal and ischemic stroke mice, examined the therapeutic effect of NMN on ischemic brain infarction, and evaluated acute toxicity of NMN after intravenous injection of NMN.
NMN and NAD levels were determined using ultra-high-performance liquid chromatography tandem mass spectrometry in biological samples from mice with or without middle cerebral artery occlusion (MCAO) at different time points post intravenous NMN injection (300 mg/kg). Brain infarction was evaluated 24 h post-MCAO. 2 g/kg NMN was used in the acute toxicity test.
Under either normal or MCAO conditions, serum NMN levels sharply increased after intravenous NMN administration and then decreased rapidly within 15 min, while serum NAD levels remained unchanged during 30 min observation. Both substances displayed tissue accumulation over time and stored faster under MCAO conditions, with kidney having the highest concentrations. Particularly, NMN accumulated earlier than NAD in the brain. Moreover, NMN reduced cerebral infarction at 24 h post-MCAO. No acute toxicity was observed for 14 days. NRK1 and SLC12A8 involved in two pathways of NMN uptake exhibited the highest expressions in kidney and colon, respectively, among 11 different tissues.
NMN distributes to various tissues after intravenous injection and has the ability to enter the brain to boost NAD levels, and exhibits safety and therapeutic effect on acute ischemic stroke injury. High renal distribution of NMN indicates its importance in the kidney.
本研究首次测定了静脉注射烟酰胺单核苷酸（NMN）及其代谢物烟酰胺腺嘌呤二核苷酸（NAD）在正常和缺血性中风小鼠中的分布，考察了 NMN 对缺血性脑梗死的治疗作用，并评估了静脉注射 NMN 后的急性毒性。
采用超高效液相色谱-串联质谱法测定不同时间点（静脉注射 NMN 后 300mg/kg，30min）给予大脑中动脉闭塞（MCAO）模型或假手术（Sham）小鼠 NMN 及 NAD 的生物样本中的水平。在 MCAO 后 24h 评估脑梗死。采用 2g/kg 的 NMN 进行急性毒性试验。
在正常或 MCAO 条件下，静脉给予 NMN 后血清 NMN 水平迅速升高，15min 内迅速下降，而血清 NAD 水平在 30min 观察期间保持不变。两种物质随着时间的推移都有组织积累，在 MCAO 条件下积累更快，肾脏中的浓度最高。特别是，NMN 在大脑中的积累早于 NAD。此外，NMN 可降低 MCAO 后 24h 的脑梗死。14 天内未观察到急性毒性。NRK1 和 SLC12A8 分别参与 NMN 摄取的两条途径，在 11 种不同组织中，在肾脏和结肠中的表达最高。
静脉注射后 NMN 分布于多种组织，并具有进入大脑提高 NAD 水平的能力，对急性缺血性中风损伤具有安全性和治疗作用。NMN 在肾脏中的高分布表明其在肾脏中的重要性。
