Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
Stroke. 2013 Aug;44(8):2333-7. doi: 10.1161/STROKEAHA.113.001715. Epub 2013 May 30.
Sirtuin 1 (SIRT1) is a member of NAD+-dependent protein deacetylases implicated in a wide range of cellular functions and has beneficial properties in pathologies including ischemia/reperfusion processes and neurodegeneration. However, no direct evidence has been reported on the direct implication of SIRT1 in ischemic stroke. The aim of this study was to establish the role of SIRT1 in stroke using an experimental model in mice.
Wild-type and Sirt1-/- mice were subjected to permanent focal ischemia by permanent ligature. In another set of experiments, wild-type mice were treated intraperitoneally with vehicle, activator 3 (SIRT1 activator, 10 mg/kg), or sirtinol (SIRT1 inhibitor, 10 mg/kg) for 10 minutes, 24 hours, and 40 hours after ischemia. Brains were removed 48 hours after ischemia for determining the infarct volume. Neurological outcome was evaluated using the modified neurological severity score.
Exposure to middle cerebral artery occlusion increased SIRT1 expression in neurons of the ipsilesional mouse brain cortex. Treatment of mice with activator 3 reduced infarct volume, whereas sirtinol increased ischemic injury. Sirt1-/- mice displayed larger infarct volumes after ischemia than their wild-type counterparts. In addition, SIRT1 inhibition/deletion was concomitant with increased acetylation of p53 and nuclear factor κB (p65).
These results support the idea that SIRT1 plays an important role in neuroprotection against brain ischemia by deacetylation and subsequent inhibition of p53-induced and nuclear factor κB-induced inflammatory and apoptotic pathways.
Sirtuin 1（SIRT1）是一种 NAD+依赖性蛋白去乙酰化酶，参与多种细胞功能，在包括缺血/再灌注过程和神经退行性变在内的病理学中具有有益特性。然而，目前尚无关于 SIRT1 直接参与缺血性中风的确切证据。本研究旨在使用小鼠实验模型确定 SIRT1 在中风中的作用。
野生型和 Sirt1-/-小鼠通过永久性结扎接受永久性局灶性缺血。在另一组实验中，野生型小鼠在缺血后 10 分钟、24 小时和 40 小时经腹腔内给予载体、激活剂 3（SIRT1 激活剂，10mg/kg）或 sirtinol（SIRT1 抑制剂，10mg/kg）。缺血后 48 小时取出大脑，确定梗死体积。使用改良神经功能严重程度评分评估神经功能结局。
暴露于大脑中动脉闭塞会增加同侧鼠大脑皮层神经元中的 SIRT1 表达。用激活剂 3 治疗可减少梗死体积，而 sirtinol 则增加缺血损伤。与野生型小鼠相比，Sirt1-/-小鼠在缺血后出现更大的梗死体积。此外，SIRT1 抑制/缺失与 p53 和核因子 κB（p65）的乙酰化增加有关。
这些结果支持 SIRT1 通过去乙酰化以及随后抑制 p53 诱导和核因子 κB 诱导的炎症和凋亡途径在脑缺血的神经保护中发挥重要作用的观点。
