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首页> 外文期刊>American Journal of Physiology >Novel plasminogen activator inhibitor-1-derived peptide protects against impairment of cerebrovasodilation after photothrombosis through inhibition of JNK MAPK.
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Novel plasminogen activator inhibitor-1-derived peptide protects against impairment of cerebrovasodilation after photothrombosis through inhibition of JNK MAPK.

机译：新型纤溶酶原激活剂抑制剂-1衍生的肽通过抑制JNK MAPK来防止脑膜瘤后的脑外衰退。

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摘要

The sole FDA-approved treatment for acute stroke is recombinant tissue-type plasminogen activator (rtPA). However, rtPA aggravates the impairment of cerebrovasodilation induced by global hypoxia/ischemia; this impairment is attenuated by the preinjury treatment with the plasminogen activator inhibitor derivative EEIIMD. MAPK (a family of kinases, p38, and JNK) is upregulated after cerebral ischemia. In this study, we determined whether the novel plasminogen activator inhibitor-derived peptide, Ac-RMAPEEIIMDRPFLYVVR-amide, (PAI-1-DP) given 30 min before or 2 h after, focal central nervous system injury induced by photothrombosis would preserve responses to cerebrovasodilators and the role of p38 and JNK MAPK in such effects. Cerebrospinal fluid JNK and p38 levels were elevated by photothrombotic injury, an effect potentiated by rtPA. Cerebrovasodilation was blunted by photothrombosis and reversed to vasoconstriction by rtPA but restored to dilation by PAI-1-DP pre- and posttreatment. PAI-1-DP blocked JNK, but preserved p38 MAPK upregulation after photothrombosis. The JNK MAPK antagonist SP600125 prevented, and the p38 antagonist SB203580 potentiated, impaired cerebrovasodilation after photothrombosis. These data indicate that rtPA impairs cerebrovasodilation after injury by activating JNK, while p38 MAPK is protective, and that the novel peptide PAI-1-DP protects by inhibiting activation of JNK by rtPA. JNK MAPK inhibitors, including PAI-1-DP, may offer a novel approach to increase the benefit-to-risk ratio of thrombolytic therapy and enable its use in central nervous system ischemic disorders.
机译：急性卒中的唯一FDA批准的处理是重组组织型纤溶酶原激活剂（RTPA）。然而，RTPA加剧了全球缺氧/缺血诱导的脑加湿的损害;该损伤通过与纤溶酶原激活素抑制剂衍生物EEIMD进行了预先治疗。 MAPK（一系列激酶，P38和JNK）在脑缺血后上调。在这项研究中，我们确定了新的纤溶酶原激活剂抑制剂衍生的肽，AC-RMAPEEIIMDRPFLYVVR-酰胺，（PAI-1-DP）在30分钟之后，由phercoctrombosis诱导的局灶性中枢神经系统损伤将保持响应脑革处理器和P38和JNK MAPK在这些效果中的作用。脑脊液JNK和P38水平升高，通过光学损伤升高，RTPA具有增强的效果。通过去肌蛋白繁殖脑致血管脱落，并通过RTPA逆转到血管收缩，但通过PAI-1-DP预先恢复为扩张。 PAI-1-DP阻塞JNK，但保留了P38 MAPK上调了光鼠中化后。 JNK MAPK拮抗剂SP600125预防，P38拮抗剂SB203580具有增强的，在光学胶质形成后的颅内拓疾病。这些数据表明，通过激活JNK，RTPA损害损伤后的脑疏松沉积，而P38 MAPK是保护性的，并且通过抑制RTPA的抑制JNK的激活来保护新型肽PAI-1-DP保护。 JNK MAPK抑制剂包括PAI-1-DP，可以提供一种新的方法，可以提高溶栓治疗的效益到风险比，并使其在中枢神经系统缺血性疾病中使用。

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