Kleinschnitz Christoph, Mencl Stine, Kleikers Pamela W M, Schuhmann Michael K, López Manuela G, Casas Ana I, Sürün Bilge, Reif Andreas, Schmidt Harald H H W
Department of Neurology, University Hospital Würzburg, Würzburg, Germany Department of Neurology, University Hospital Essen, Essen, Germany
Department of Neurology, University Hospital Würzburg, Würzburg, Germany Department of Neurology, University Hospital Essen, Essen, Germany.
J Cereb Blood Flow Metab. 2016 Sep;36(9):1508-12. doi: 10.1177/0271678X16657094. Epub 2016 Jun 28.
Promising results have been reported in preclinical stroke target validation for pharmacological principles that disrupt the N-methyl-D-aspartate receptor-post-synaptic density protein-95-neuronal nitric oxide synthase complex. However, post-synaptic density protein-95 is also coupled to potentially neuroprotective mechanisms. As post-synaptic density protein-95 inhibitors may interfere with potentially neuroprotective mechanisms and sufficient validation has often been an issue in translating basic stroke research, we wanted to close that gap by comparing post-synaptic density protein-95 inhibitors with NOS1(-/-) mice and a NOS inhibitor. We confirm the deleterious role of NOS1 in stroke both in vivo and in vitro, but find three pharmacological post-synaptic density protein-95 inhibitors to be therapeutically ineffective.
对于破坏N-甲基-D-天冬氨酸受体-突触后致密蛋白95-神经元型一氧化氮合酶复合物的药理学原理，临床前卒中靶点验证已报告了有前景的结果。然而，突触后致密蛋白95也与潜在的神经保护机制相关联。由于突触后致密蛋白95抑制剂可能会干扰潜在的神经保护机制，并且在基础卒中研究转化中充分验证常常是个问题，我们希望通过将突触后致密蛋白95抑制剂与NOS1基因敲除小鼠和一种NOS抑制剂进行比较来填补这一空白。我们证实了NOS1在体内和体外卒中中的有害作用，但发现三种药理学突触后致密蛋白95抑制剂在治疗上无效。
