Curry Alecia, Guo Miao, Patel Rohit, Liebelt Brandon, Sprague Shane, Lai Qin, Zwagerman Nathan, Cao Frank X, Jimenez David, Ding Yuchuan
Department of Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Neurol Res. 2010 Sep;32(7):756-62. doi: 10.1179/174313209X459101. Epub 2009 Aug 13.
We sought to determine whether cerebral inflammation in ischemic rats was reduced by a neuroprotective action of pre-ischemic tumor necrosis factor-alpha up-regulation, which down-regulated matrix metalloproteinase-9 activity via extracellular signal-regulated kinase 1/2 phosphorylation.
Adult male Sprague-Dawley rats were subjected to 30 minutes of exercise on a treadmill for 3 weeks. Stroke was induced by a 2 hour middle cerebral artery occlusion using an intraluminal filament. The exercised animals were treated with tumor necrosis factor-alpha antibody, UO126 (extracellular signal-regulated kinase 1/2 inhibitor), or both UO126 and doxycycline (matrix metalloproteinase-9 inhibitor). Brain infarct volume was assessed using Nissl staining. Leukocyte infiltration was evaluated using myeloperoxidase immunostaining. Intercellular adhesion molecule-1 and matrix metalloproteinase protein levels were determined by Western blot, and enzyme activity was evaluated using zymography.
There was a significant decrease in neurological deficits, brain infarct volume and leukocyte infiltration, in association with reduction in matrix metalloproteinase-9 and intercellular adhesion molecule-1 expression in exercised animals. Exercised animals treated with either tumor necrosis factor-alpha antibody or with UO126 showed a reversal of neurological outcome, infarct volume and leukocyte infiltration. Matrix metalloproteinase-9 activity was reversed, at least partially, but the intercellular adhesion molecule-1 expression was not. Neuroprotection remained when the exercised ischemic rats were treated with both UO126 and doxycycline.
These results suggest that exercise-induced up-regulation of tumor necrosis factor-alpha before stroke and extracellular signal-regulated kinase 1/2 phosphorylation play a role in decreasing brain inflammation by regulating matrix metalloproteinase-9 activity.
我们试图确定缺血前肿瘤坏死因子-α上调的神经保护作用是否能减轻缺血大鼠的脑炎症，该上调作用通过细胞外信号调节激酶1/2磷酸化来下调基质金属蛋白酶-9的活性。
成年雄性Sprague-Dawley大鼠在跑步机上进行3周、每次30分钟的运动。采用腔内细丝法阻断大脑中动脉2小时诱导中风。对运动后的动物给予肿瘤坏死因子-α抗体、UO126（细胞外信号调节激酶1/2抑制剂）或UO126与强力霉素（基质金属蛋白酶-9抑制剂）联合治疗。使用尼氏染色评估脑梗死体积。使用髓过氧化物酶免疫染色评估白细胞浸润。通过蛋白质印迹法测定细胞间黏附分子-1和基质金属蛋白酶的蛋白水平，并使用酶谱法评估酶活性。
运动后的动物神经功能缺损、脑梗死体积和白细胞浸润显著减少，同时基质金属蛋白酶-9和细胞间黏附分子-1的表达降低。用肿瘤坏死因子-α抗体或UO126治疗的运动后动物神经功能结局、梗死体积和白细胞浸润出现逆转。基质金属蛋白酶-9的活性至少部分得到逆转，但细胞间黏附分子-1的表达未逆转。当对运动后的缺血大鼠联合使用UO126和强力霉素治疗时，神经保护作用仍然存在。
这些结果表明，中风前运动诱导的肿瘤坏死因子-α上调和细胞外信号调节激酶1/2磷酸化通过调节基质金属蛋白酶-9的活性在减轻脑炎症中发挥作用。
