Lee Sang Mi, Zhao Heng, Maier Carolina M, Steinberg Gary K
Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, California 94305-5327, USA.
J Cereb Blood Flow Metab. 2009 Sep;29(9):1589-600. doi: 10.1038/jcbfm.2009.81. Epub 2009 Jun 24.
We recently showed that intraischemic moderate hypothermia (30 degrees C) reduces ischemic damage through the Akt pathway after permanent distal middle cerebral artery occlusion in rats. The only Akt pathway component preserved by hypothermia is phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (p-PTEN), which suggests that p-PTEN may have a central role in neuroprotection. Reactive oxygen species (ROS) are critically involved in mediating ischemic damage after stroke by interacting with signaling molecules, including Akt, PTEN, and delta-protein kinase C (PKC). We investigated the protective mechanisms of moderate hypothermia on these signaling proteins after transient focal ischemia in rats. Early moderate hypothermia (3 h) was administered 15 mins before reperfusion, and delayed moderate hypothermia (3 h) was applied 15 mins after reperfusion. Our results indicate that early hypothermia reduced infarction, whereas delayed hypothermia did not. However, both early and delayed hypothermia maintained levels of Mn-SOD (superoxide dismutase) and phosphorylated Akt and blocked delta-PKC cleavage, suggesting that these factors may not be critical to the protection of hypothermia. Nevertheless, early hypothermia preserved p-PTEN levels after reperfusion, whereas delayed hypothermia did not. Furthermore, ROS inhibition maintained levels of p-PTEN after stroke. Together, these findings suggest that phosphorylation levels of PTEN are closely associated with the protective effect of early hypothermia against stroke.
我们最近发现，在大鼠大脑中动脉远端永久性闭塞后，缺血期间的中度低温（30摄氏度）可通过Akt信号通路减轻缺血损伤。低温唯一保留的Akt信号通路成分是10号染色体缺失的磷酸酶及张力蛋白同源物的磷酸化形式（p-PTEN），这表明p-PTEN可能在神经保护中起核心作用。活性氧（ROS）通过与包括Akt、PTEN和δ-蛋白激酶C（PKC）在内的信号分子相互作用，在介导中风后的缺血损伤中起关键作用。我们研究了大鼠短暂局灶性缺血后中度低温对这些信号蛋白的保护机制。在再灌注前15分钟给予早期中度低温（3小时），在再灌注后15分钟给予延迟中度低温（3小时）。我们的结果表明，早期低温可减少梗死面积，而延迟低温则不能。然而，早期和延迟低温均能维持锰超氧化物歧化酶（Mn-SOD）和磷酸化Akt的水平，并阻止δ-PKC的裂解，这表明这些因素可能对低温保护作用并不关键。尽管如此，早期低温在再灌注后能维持p-PTEN水平，而延迟低温则不能。此外，抑制ROS可在中风后维持p-PTEN水平。综上所述，这些发现表明PTEN的磷酸化水平与早期低温对中风的保护作用密切相关。
