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烟酰胺腺嘌呤二核苷酸(NAD)是一种经典辅酶,对线粒体电子转移反应至关重要,在许多生物学功能中起着关键作用[1]。烟酰胺单核苷酸(NMN)是NAD生物合成的关键中间体。NMN在心脑血管疾病、肝肾功能、血管和内皮功能,以及免疫和炎症、衰老等各类疾病治疗方面都具有相当强的潜力[2],常被人称为“万能药”。NMN能够通过口服、静脉注射、腹腔注射(小鼠)等多种给药途径进入体内,通常具有较高的安全性。在急性毒性实验中,小鼠连续7 d给予最大灌胃剂量和饱和浓度的NMN,每天1次,耐受性良好,除血清丙氨酸氨基转移酶略有升高外,其余生物标志物基本保持不变,而相同处理条件下的比格犬,会有轻度的肌酐和尿酸升高[3];在长期给药实验中,小鼠连续12个月给予100和300 mg/kg的NMN,均未出现不良反应[4]。在出血性休克治疗方面,对出血性休克大鼠模型,术前连续5 d的NMN饮水给药和术后静脉推注NMN均能缩短休克复苏时间和提高复苏后的存活率[5]。据报道[6-9],在炎症治疗方面,NMN及相关代谢产物烟酰胺核糖、烟酰胺都具有一定抗炎作用。
内毒素休克是由感染引起的全身炎症反应综合征,会导致各系统衰竭,包括循环系统、呼吸系统、血液系统,损害肝脏和肾脏功能[10]。相关研究显示,最佳的治疗时间在发病6 h内,能够提高患者的生存率,降低病死率[11]。目前临床内毒素休克以药物治疗为主(如血管活性药物、激素、抗菌素等)[12],同时辅以液体复苏、脑神经保护、吸氧等常规治疗。为便于对内毒素休克开展研究治疗,通常使用LPS进行内毒素休克动物造模,LPS是G-菌细胞壁外膜上的主要成分,也叫内毒素,能引起严重的炎症级联反应,是G-菌的主要致病成分之一[13]。
目前,NMN对内毒素休克的治疗作用尚未知。本研究旨在探究NMN对LPS诱导的内毒素休克小鼠模型的死亡率影响,为阐明NMN在内毒素休克治疗方面的作用提供线索。
Effect of nicotinamide mononucleotide on mortality of mice with endotoxic shock
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摘要:
目的 探究烟酰胺单核苷酸(NMN)对脂多糖(LPS)诱导的内毒素休克小鼠死亡率的影响。 方法 将10周龄C57BL/6J雄性小鼠随机分组,均腹腔注射LPS(10 mg/kg)造模。NMN腹腔注射给药,分为3种方式:①造模后0.5 h给药,剂量为10、30、100、300 mg/kg;②造模前0.5 h给药,剂量为30、100、300、600 mg/kg;③造模后0.5 h和12 h两次给药,每次300 mg/kg。观察记录每组小鼠的死亡情况,并绘制生存曲线。 结果 与溶剂对照组相比,造模后0.5 h或造模前0.5 h给予不同剂量NMN,均不能改善小鼠死亡率或延缓死亡时间;造模后0.5 h和12 h两次给予NMN会加速小鼠死亡,增加小鼠死亡率。两个厂家的NMN产品效果类似。 结论 NMN对LPS诱导的内毒素休克小鼠不具有治疗作用,小鼠内毒素休克发生后进行NMN多次给药会增加死亡率。 Abstract:Objective To study the effect of nicotinamide mononucleotide (NMN) on the mortality of the lipopoly-saccharide (LPS)-induced endotoxic shock mouse model. Methods 10-week-old C57BL/6J male mice were randomly divided into groups, and were injected intraperitoneally (i.p.) with LPS (10 mg/kg) to induce endotoxic shock models. NMN was i.p. injected in three ways: (1) 0.5 h after modeling, doses of 10, 30, 100 and 300 mg/kg; (2) 0.5 h before modeling, doses of 30, 100, 300 and 600 mg/kg; or (3) 0.5 and 12 h after modeling, dose of 300 mg/kg each time. The death times of each group were recorded, and the survival curves were drawn. Results Compared with the solvent control group, NMN at different doses given 0.5 h after or before modeling didn’t improve the survival rate or delay the death time of endotoxic shock mice; But when given at 0.5 and 12 h 300 mg/kg after modeling, NMN accelerated the death of mice and increased the mortality of mice. NMN products by two manufacturers showed similar effects. Conclusion NMN has no therapeutic effect on LPS-induced endotoxic shock, and repeated administration of NMN after endotoxic shock will increase the mortality. -
Key words:
- nicotinamide mononucleotide /
- lipopolysaccharide /
- endotoxic shock /
- mortality
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