Bright Rachel, Sun Guo-Hua, Yenari Midori A, Steinberg Gary K, Mochly-Rosen Daria
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA.
Neurosci Lett. 2008 Aug 15;441(1):120-4. doi: 10.1016/j.neulet.2008.05.080. Epub 2008 May 27.
In response to mild ischemic stress, the brain elicits endogenous survival mechanisms to protect cells against a subsequent lethal ischemic stress, referred to as ischemic tolerance. The molecular signals that mediate this protection are thought to involve the expression and activation of multiple kinases, including protein kinase C (PKC). Here we demonstrate that epsilonPKC mediates cerebral ischemic tolerance in vivo. Systemic delivery of psiepsilonRACK, an epsilonPKC-selective peptide activator, confers neuroprotection against a subsequent cerebral ischemic event when delivered immediately prior to stroke. In addition, activation of epsilonPKC by psiepsilonRACK treatment decreases vascular tone in vivo, as demonstrated by a reduction in microvascular cerebral blood flow. Here we demonstrate the role of acute and transient epsilonPKC in early cerebral tolerance in vivo and suggest that extra-parenchymal mechanisms, such as vasoconstriction, may contribute to the conferred protection.
作为对轻度缺血应激的反应，大脑会引发内源性存活机制，以保护细胞免受随后的致死性缺血应激，这被称为缺血耐受。介导这种保护作用的分子信号被认为涉及多种激酶的表达和激活，包括蛋白激酶C（PKC）。在此，我们证明εPKC在体内介导脑缺血耐受。当在中风前立即给予εPKC选择性肽激活剂psiepsilonRACK进行全身给药时，可对随后的脑缺血事件起到神经保护作用。此外，通过psiepsilonRACK处理激活εPKC可降低体内血管张力，这可通过脑微血管血流减少得到证明。在此，我们证明了急性和短暂的εPKC在体内早期脑耐受中的作用，并表明血管收缩等实质外机制可能有助于所赋予的保护作用。
