Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China.
Neurosci Lett. 2012 Mar 23;512(2):67-71. doi: 10.1016/j.neulet.2012.01.007. Epub 2012 Jan 12.
Nicotinamide adenine dinuleotide (NAD(+)) plays critical roles in multiple biological functions. Previous studies have indicated that NAD(+) treatment decreases oxidative stress-induced death of primary neurons and astrocytes. Intranasal administration of NAD(+) also reduces brain damage in a rat model of transient focal brain ischemia. However, the mechanisms underlying this protective effect remain unknown. In this study, we used a mouse model of brain ischemia to test our hypothesis that NAD(+) decreases ischemic brain damage partially by preventing autophagy. Adult male mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 90min, and NAD(+) was administered intraperitoneally (i.p.) immediately after reperfusion started. We found that administration with 50mg/kg NAD(+) led to significant decreases in infarct size, edema formation, and neurological deficits at 48h after ischemia. NAD(+) administration also significantly decreased brain ischemia-induced autophagy in the cortex and hippocampus. We further found that prevention of autophagy by 3-methyladenine (3-MA), a selective autophagy inhibitor, significantly reduced ischemic brain damage, suggesting an important role of autophagy in the ischemic brain injury in our animal model. Collectively, our findings have suggested that NAD(+) administration decreases ischemic brain damage at least partially by blocking autophagy. This is the first suggested mechanism regarding the protective effects of NAD(+) in cerebral ischemia, which further highlights the promise of NAD(+) for treating brain ischemia.
烟酰胺腺嘌呤二核苷酸 (NAD(+)) 在多种生物学功能中发挥着关键作用。先前的研究表明，NAD(+) 处理可降低氧化应激诱导的原代神经元和星形胶质细胞死亡。NAD(+) 的鼻腔内给药也可减少短暂性局灶性脑缺血大鼠模型中的脑损伤。然而，这种保护作用的机制尚不清楚。在这项研究中，我们使用了脑缺血的小鼠模型来检验我们的假设，即 NAD(+) 通过防止自噬来部分减轻缺血性脑损伤。成年雄性小鼠接受短暂性大脑中动脉闭塞 (tMCAO) 90 分钟，再灌注开始后立即腹膜内 (i.p.) 给予 NAD(+)。我们发现，给予 50mg/kg NAD(+) 可使缺血后 48 小时的梗死面积、水肿形成和神经功能缺损显著减少。NAD(+) 给药还显著降低了皮质和海马中的脑缺血诱导的自噬。我们进一步发现，选择性自噬抑制剂 3-甲基腺嘌呤 (3-MA) 可预防自噬，从而显著减轻缺血性脑损伤，这表明自噬在我们的动物模型中的缺血性脑损伤中起着重要作用。总之，我们的研究结果表明，NAD(+) 通过阻断自噬来减少缺血性脑损伤，至少部分是这样。这是 NAD(+) 在脑缺血中发挥保护作用的第一个被提出的机制，进一步强调了 NAD(+) 治疗脑缺血的潜力。
