Sinn Dong-In, Lee Soon-Tae, Chu Kon, Jung Keun-Hwa, Kim Eun-Hee, Kim Jeong-Min, Park Dong-Kyu, Song Eun-Cheol, Kim Byung-Su, Yoon Sung-Soo, Kim Manho, Roh Jae-Kyu
Stroke & Neural Stem Cell Laboratory in Clinical Research Institute, Department of Neurology, Seoul National University Hospital, Program in Neuroscience, Neuroscience Research Institute of SNUMRC, Seoul National University, Seoul, South Korea.
Neurosci Res. 2007 May;58(1):12-8. doi: 10.1016/j.neures.2007.01.006. Epub 2007 Jan 19.
Inflammation is an important pathophysiologic mechanism of injury induced by intracerebral hemorrhage (ICH). The ubiquitin-proteasome system (UPS) regulates the inflammatory responses via the up-regulation of several pro-inflammatory molecules. In this study, we determined that a potent proteasome inhibitor, bortezomib, exerted therapeutic effects in experimental model of ICH. Either bortezomib (0.05, 0.2, 0.5, 1mg/kg) or vehicle was intravenously administered 2h after ICH induction. The high doses of bortezomib caused high mortality rates. Bortezomib at 0.2 mg/kg reduced the early hematoma growth and alleviated hematoma volume and brain edema at 3 days after ICH, compared with the ICH-vehicle group. The numbers of myeloperoxidase(+) neutrophils, Ox42(+) microglia, and TUNEL(+) cells in the perihematomal regions were decreased by bortezomib. Bortezomib induced significant decrements of mRNA expression of TNF-alpha and IL-6. The production of iNOS and COX2 was also reduced significantly by bortezomib. We concluded that the early treatment with bortezomib induced a reduction in the early hematoma growth and mitigated the development of brain edema, coupled with a marked inhibitory effect on inflammation in ICH.
炎症是脑出血（ICH）所致损伤的重要病理生理机制。泛素-蛋白酶体系统（UPS）通过上调多种促炎分子来调节炎症反应。在本研究中，我们确定一种强效蛋白酶体抑制剂硼替佐米在ICH实验模型中发挥了治疗作用。在ICH诱导后2小时静脉注射硼替佐米（0.05、0.2、0.5、1mg/kg）或赋形剂。高剂量硼替佐米导致高死亡率。与ICH-赋形剂组相比，0.2mg/kg的硼替佐米在ICH后3天减少了早期血肿扩大，并减轻了血肿体积和脑水肿。硼替佐米减少了血肿周围区域髓过氧化物酶（+）中性粒细胞、Ox42（+）小胶质细胞和TUNEL（+）细胞的数量。硼替佐米显著降低了TNF-α和IL-6的mRNA表达。硼替佐米还显著降低了诱导型一氧化氮合酶（iNOS）和环氧化酶2（COX2）的产生。我们得出结论，早期使用硼替佐米可减少早期血肿扩大并减轻脑水肿的发展，同时对ICH中的炎症有显著抑制作用。
