Biochem J：新方法防止糖尿病眼疾视网膜受损

近日，密歇根大学凯洛格眼科中心研究人员发现了一种化合物，可以中断糖尿病视网膜病变的视网膜造成损害的事件链。这一发现具有重大意义，因为它可能会导致出现一种新的能根治疾病的治疗方法，该化合物主要作用于两种机制：炎症和削弱保护视网膜的血液屏障。这一化合物通过针对关键蛋白质阻断糖尿病视网膜病变的血管渗漏有关的两个重要途径。

到目前为止，糖尿病性视网膜病变已经为工作年龄段美国人失明的首要原因。在糖尿病性视网膜病变中，视网膜损坏部分因为血管内皮生长因子（VEGF）活性引发的，VEGF蛋白质削弱了保护血-视网膜屏障。近一半的糖尿病视网膜病变患者对血管内皮生长因子的药物已经表现出了良好反应。但研究人员相信，也有炎症因子推动疾病进程。

这项研究发表在Biochemical Journal杂志，研究发现一个特定的蛋白质在调节血管疾病的过程中发挥重要作用，提示抗VEGF治疗药物单独使用治疗干预是不够的。

眼科及视觉科学学系、分子和综合生理学教授David A. Antonetti博士说：在糖尿病视网膜病变的其他视网膜疾病中，增加血管内皮生长因子和炎症因子（一些有助于感染的反应的相同因素），会导致眼血管泄漏，最终导致液体聚集在视网膜的神经组织。

该化合物靶向作用于非典型蛋白激酶C（aPKC），aPKC对血管内皮生长因子促使血管泄漏是必须的。此外，Antonetti实验室已证实，该化合物有效地阻断糖尿病性视网膜病变中肿瘤坏死因子升高带来的损害。

在动物模型中，研究人员已经确定了调节眼睛中血管泄漏的一个重要靶点，并开发出一种治疗方法。但研究是处于初期阶段，仍然有很长的路要走，以证明这种化合物在人身上也是有效性的。

编译自：Study finds novel therapy that may prevent damage to the retina in diabetic eye diseases

doi:10.1042/BJ20111961
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Novel Atypical PKC Inhibitors Prevent Vascular Endothelial Growth Factor-Induced Blood-Retinal Barrier Dysfunction

Titchenell PM, Lin CM, Keil JM, Sundstrom JM, Smith CD, Antonetti DA.

Pro-inflammatory cytokines and growth factors such as vascular endothelial growth factor (VEGF) contribute to the loss of the blood-retinal barrier (BRB) and subsequent macular edema in various retinal pathologies. VEGF signaling requires conventional PKC (PKCβ) activity; however, PKCβ inhibition only partially prevents VEGF-induced endothelial permeability and does not affect pro-inflammatory cytokine-induced permeability suggesting the involvement of alternative signaling pathways. Here, we provide evidence for the involvement of atypical protein kinase C (aPKC) signaling in VEGF-induced endothelial permeability and identify a novel class of inhibitors of aPKC that prevent BRB breakdown in vivo. Genetic and pharmacological manipulations of aPKC isoforms were used to assess their contribution to endothelial permeability in culture. A chemical library was screened using an in vitro kinase assay to identify novel small molecule inhibitors and further medicinal chemistry was performed to delineate a novel pharmacophore. We demonstrate that aPKC isoforms are both sufficient and required for VEGF-induced endothelial permeability. Furthermore, these specific, potent, non-competitive, small molecule inhibitors prevented VEGF-induced tight junction internalization and retinal endothelial permeability in response to VEGF in both primary culture and in rodent retina. These data suggest that aPKC inhibition with 2-amino-4-phenyl-thiophene derivatives may be developed to preserve the BRB in retinal diseases such as diabetic retinopathy or uveitis and the blood-brain barrier (BBB) in the presence of brain tumors.