Myelin loss associated with neuroinflammation in hypertensive rats.
Myelin loss associated with neuroinflammation in hypertensive rats.
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DOI：
10.1161/strokeaha.111.643080
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发表时间：
2012-04
期刊：
影响因子：
8.3
通讯作者：
Rosenberg GA
中科院分区：
文献类型：
--
作者：
Jalal FY;Yang Y;Thompson J;Lopez AC;Rosenberg GA
小血管病变是血管性认知障碍患者白色损害的主要原因。基质金属蛋白酶（MMP）介导的炎症可能参与了白色物质损伤和少突胶质细胞（Ol）死亡。因此，我们使用自发性高血压卒中易感大鼠（SHR-SP）来研究神经炎症在白色物质损害中的作用。在12周龄时对SHR-SP进行永久性单侧颈动脉闭塞（UCAO）。手术后，将大鼠置于日本允许饮食（JPD）并接受含1% NaCl的饮用水。MRI、组织学、生物化学和ELISA表征白色病变和Morris水迷宫（MWM）检测认知障碍。观察UCAO/JPD后4-5周的白色损害。免疫印迹显示髓鞘碱性蛋白（MBP）的显着减少和未成熟OIs的上调。成熟Ols经历caspase-3介导的凋亡。MWM显示认知功能障碍。观察到异常出现的血管，并被炎性样细胞包围。IgG外渗和出血，表明血脑屏障（BBB）的破坏，与MMP-9的表达密切相关。白色病变表现为反应性星形胶质细胞增多和表达肿瘤坏死因子-α（TNF-α）的活化小胶质细胞。MMP-3和MMP-9在星形胶质细胞和Ol中显著升高，MMP-2降低。我们发现成熟Ols的凋亡与未成熟Ols的增加。MMP-3、MMP-9和TNF-α的增加与髓鞘破坏和BBB破坏有关。神经炎症是白色物质损伤和Ol死亡的重要因素，并且可以进行使用这种新模型的研究以评估阻断炎症的药剂。
Small vessel disease is the major cause of white matter injury in patients with vascular cognitive impairment. Matrix metalloproteinase (MMP)-mediated inflammation may be involved in the white matter damage with oligodendrocyte (Ol) death. Therefore, we used spontaneously hypertensive stroke-prone rats (SHR-SP) to study the role of neuroinflammation in white matter damage. Permanent unilateral carotid artery occlusion (UCAO) was performed at 12-weeks of age in SHR-SP. Following surgery, rats were placed on a Japanese permissive diet (JPD) and received 1 % NaCl in drinking water. MRI, histology, biochemistry, and ELISA characterized white matter lesions and cognitive impairment was tested by Morris water maze (MWM). white matter damage was observed 4-5 weeks following UCAO/JPD. Immunoblotting showed marked reduction in myelin basic protein (MBP) and up regulation of immature Ols. Mature Ols underwent caspase-3-mediated apoptosis. MWM showed cognitive impairment. Abnormally appearing vessels were observed and surrounded by inflammatory-like cells. IgG extravasation and hemorrhage, indicating blood-brain barrier (BBB) disruption, was closely associated with MMP-9 expression. Lesions in white matter showed reactive astrocytosis and activated microglia that expressed tumor necrosis factor-α (TNF-α). MMP-3 and MMP-9 were significantly increased and MMP-2 reduced in astrocytes and Ol. We found apoptosis of mature Ols with an increase in immature Ols. Increased MMP-3, MMP-9 and TNF-α were associated with myelin breakdown and BBB disruption. Neuroinflammation is an important factor in white matter damage and Ol death, and studies using this new model can be done to assess agents to block inflammation.