Williams Anthony J, Berti Rossana, Dave Jitendra R, Elliot Peter J, Adams Julian, Tortella Frank C
Department of Neuropharmacology and Molecular Biology, Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Stroke. 2004 May;35(5):1186-91. doi: 10.1161/01.STR.0000125721.10606.dc. Epub 2004 Apr 1.
Clinical development of novel neuroprotection therapies for the treatment of brain injury has been unsuccessful. One critical limitation is the lack of a viable therapeutic treatment window (TW). In this study, we evaluated the neuroprotection TW for the proteosome inhibitor MLN519 after ischemia/reperfusion brain injury in rats as related to its antiinflammatory mechanism.
Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo), followed by 70 hours of reperfusion and recovery. MLN519 was administered after injury (starting 6 to 12 hours after MCAo) to evaluate the full TW. Brain infarction, neuronal degeneration, neurological recovery, leukocyte infiltration, and inflammatory gene mRNA levels were assessed.
Core infarct volume in vehicle-treated rats (216+/-25 mm3) was reduced with delayed MLN519 treatments of 6, 8, or 10 hours after injury (45+/-13, 86+/-28, and 150+/-27 mm3, respectively, P<0.05) and was associated with reductions in neuronal and axonal degeneration. MLN519-treated rats had reduced brain mRNA levels of TNF-alpha (46%, P<0.05), ICAM-1 (58%, P<0.05), IL-6 (58%, P<0.05), and E-selectin (72%, P<0.05) at 24 hours after injury. Furthermore, MLN519 treatment reduced leukocyte infiltration by 32% to 80% (P<0.05) in ischemic brain regions.
Neuroprotection treatment with MLN519 provides an extended TW of up to 10 hours after ischemia/reperfusion brain injury, in part by attenuating the inflammatory response. As such, the delayed onset of brain inflammation after an ischemic injury offers a prime target for extending the neuroprotective TW with compounds such as MLN519, used either alone or possibly as an adjunctive therapy with thrombolytic agents.
用于治疗脑损伤的新型神经保护疗法的临床研发尚未成功。一个关键限制是缺乏可行的治疗时间窗（TW）。在本研究中，我们评估了蛋白酶体抑制剂MLN519在大鼠缺血/再灌注脑损伤后的神经保护时间窗，及其与抗炎机制的关系。
雄性Sprague-Dawley大鼠接受2小时的大脑中动脉闭塞（MCAo），随后进行70小时的再灌注和恢复。损伤后（MCAo后6至12小时开始）给予MLN519以评估完整的时间窗。评估脑梗死、神经元变性、神经功能恢复、白细胞浸润和炎症基因mRNA水平。
损伤后6、8或10小时延迟给予MLN519治疗，可使 Vehicle 处理组大鼠（216±25 mm³）的核心梗死体积减小（分别为45±13、86±28和150±27 mm³，P<0.05），且与神经元和轴突变性的减少相关。MLN519处理的大鼠在损伤后24小时，脑内TNF-α（46%，P<0.05）、ICAM-1（58%，P<0.05）、IL-6（58%，P<0.05）和E-选择素（72%，P<0.05）的mRNA水平降低。此外，MLN519治疗使缺血脑区的白细胞浸润减少32%至80%（P<0.05）。
MLN519神经保护治疗在缺血/再灌注脑损伤后可提供长达10小时的延长时间窗，部分原因是减轻了炎症反应。因此，缺血性损伤后脑炎症的延迟发生为使用MLN519等化合物延长神经保护时间窗提供了一个主要靶点，这些化合物可单独使用，也可能作为溶栓药物的辅助治疗。
