Berti R, Williams A J, Velarde L C, Moffett J R, Elliott P J, Adams J, Yao C, Dave J R, Tortella F C
Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Neurotox Res. 2003;5(7):505-14. doi: 10.1007/BF03033160.
Anti-inflammatory treatment with the proteasome inhibitor MLN519 has been previously reported to be neuroprotective against ischemic brain injury in rats. These effects have been related to inhibition of the transcription factor NF-kappaB, which is activated through ubiquitin-proteasomal degradation. The aim of this study was to evaluate the effects of MLN519 to alter the expression of several inflammatory genes under the control of NF-kappaB. Male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAo) followed by vehicle or MLN519 (1.0 g/kg, i.v.) treatment immediately after reperfusion of blood to the brain at 2h. Gene expression was evaluated 3-72 h post-MCAo. The most striking effects of intravenous treatment with MLN519 were associated with reductions in ICAM-1 expression at 3 h followed by reductions in E-selectin (12-72 h). Less dramatic reductions were observed in IL-1Beta (3-24 h) and TNF-Alpha (24 h) with no apparent effects on IL-6 and VCAM-1 mRNA levels. Immunohistochemical analysis revealed that the genes most dramatically affected by MLN519 had highest expression in endothelial cells and leukocytes (E-selectin, ICAM-1),indicating that these cell types may be the primary targets of intravenously delivered MLN519 treatment.
先前有报道称，蛋白酶体抑制剂MLN519的抗炎治疗对大鼠缺血性脑损伤具有神经保护作用。这些作用与转录因子NF-κB的抑制有关，NF-κB是通过泛素-蛋白酶体降解被激活的。本研究的目的是评估MLN519对改变几种受NF-κB控制的炎症基因表达的影响。雄性Sprague-Dawley大鼠在大脑再灌注2小时后立即接受大脑中动脉闭塞（MCAo），随后接受载体或MLN519（1.0 g/kg，静脉注射）治疗。在MCAo后3-72小时评估基因表达。静脉注射MLN519最显著的作用与3小时时ICAM-1表达的降低有关，随后是E-选择素（12-72小时）表达的降低。在IL-1β（3-24小时）和TNF-α（24小时）中观察到的降低不太明显，对IL-6和VCAM-1 mRNA水平没有明显影响。免疫组织化学分析显示，受MLN519影响最显著的基因在内皮细胞和白细胞（E-选择素、ICAM-1）中表达最高，这表明这些细胞类型可能是静脉注射MLN519治疗的主要靶点。
