Williams Anthony J, Dave Jitendra R, Tortella Frank C
Walter Reed Army Institute of Research, Department of Applied Neurobiology, Silver Spring, MD 20910, United States.
Neurochem Int. 2006 Jul;49(2):106-12. doi: 10.1016/j.neuint.2006.03.018. Epub 2006 Jun 8.
The ubiquitin proteasome system (UPS) is a major cellular protein degradation pathway that involves the modulation of key proteins controlling inflammation, cell cycle regulation and gene expression. Modulation of the UPS with proteasome inhibitors has indicated efficacy in the treatment of several disease states including cancer and neuro-inflammatory disorders. In particular, a series of recent reports have evaluated the pre-clinical efficacy of the proteasome inhibitor MLN519 for the treatment of focal ischemic/reperfusion brain injury in rats. Evidence from these studies indicate that the neuroprotection provided by MLN519 is related to an anti-inflammatory effect linked to the modulation of nuclear factor kappaB (NF-kappaB) activity, attenuation of cytokine (TNF-alpha, IL-1beta, and IL-6) and cellular adhesion molecule (ICAM-1 and E-selectin) expression, and reduction of neutrophil and macrophage infiltration into the injured rat brain. It is the aim of this paper to review the experimental neuroprotection data reported using MLN519 with a focus on the molecular and cellular mechanisms of anti-inflammatory action.
泛素蛋白酶体系统（UPS）是一种主要的细胞蛋白质降解途径，涉及对控制炎症、细胞周期调节和基因表达的关键蛋白质的调控。用蛋白酶体抑制剂调节UPS已显示出对包括癌症和神经炎症性疾病在内的多种疾病状态的治疗效果。特别是，最近一系列报告评估了蛋白酶体抑制剂MLN519对大鼠局灶性缺血/再灌注脑损伤的临床前疗效。这些研究的证据表明，MLN519提供的神经保护作用与抗炎作用有关，这种抗炎作用与核因子κB（NF-κB）活性的调节、细胞因子（肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6）和细胞粘附分子（细胞间粘附分子-1和E-选择素）表达的减弱以及中性粒细胞和巨噬细胞向受损大鼠脑内浸润的减少有关。本文旨在综述使用MLN519报道的实验性神经保护数据，重点关注抗炎作用的分子和细胞机制。
