Departments of Neurosurgery, Stanford University.
Transl Stroke Res. 2010 Sep;1(3):202-9. doi: 10.1007/s12975-010-0017-5.
Although the protective mechanisms of delayed ischemic preconditioning have received extensive studies, few have addressed the mechanisms associated with rapid ischemic postconditioning. We investigated whether ischemic tolerance induced by rapid preconditioning is regulated by the Akt survival signaling pathway. Stroke was generated by permanent occlusion of the left distal middle cerebral artery (MCA) plus 30 min or 1 h occlusion of the bilateral common carotid artery (CCA) in male rats. Rapid preconditioning performed 1h before stroke onset reduced infarct size by 69% in rats with 30 min CCA occlusion, but by only 19% with 1 h occlusion. After control ischemia with 30 min CCA occlusion, Western Blot showed that P-Akt was transiently increased while Akt kinase assay showed that Akt activity was decreased. Although preconditioning did not change P-Akt levels at 1h and 5h compared with control ischemia, it attenuated reduction in Akt activity at 5h in the penumbra. However, preconditioning did not change the levels of P-PDK1, P-PTEN, and P-GSK3β in the Akt pathway, all of which were decreased after stroke. At last, the PI3K kinase inhibitor, LY294002, completely reversed the protection from ischemic preconditioning. In conclusion, Akt contributes to the protection of rapid preconditionin against stroke.
虽然延迟性缺血预处理的保护机制已经得到了广泛的研究，但很少有人关注与快速缺血后处理相关的机制。我们研究了快速预处理诱导的缺血耐受是否受 Akt 生存信号通路的调节。通过永久性阻塞左侧大脑中动脉（MCA）远端加上双侧颈总动脉（CCA）30 分钟或 1 小时阻塞，在雄性大鼠中产生中风。在中风发作前 1 小时进行快速预处理，可使 30 分钟 CCA 阻塞大鼠的梗死面积减少 69%，但在 1 小时 CCA 阻塞大鼠中仅减少 19%。在 30 分钟 CCA 阻塞的对照缺血后，Western blot 显示 P-Akt 短暂增加，而 Akt 激酶测定显示 Akt 活性降低。虽然预处理与对照缺血相比，在 1 小时和 5 小时时并未改变 P-Akt 水平，但它减轻了缺血后 5 小时半影区中 Akt 活性的降低。然而，预处理并未改变 Akt 通路中的 P-PDK1、P-PTEN 和 P-GSK3β 水平，这些水平在中风后均降低。最后，PI3K 激酶抑制剂 LY294002 完全逆转了缺血预处理的保护作用。总之，Akt 有助于快速预处理对中风的保护作用。
