Increased Inflammatory Response in Old Mice is Associated with More Severe Neuronal Injury at the Acute Stage of Ischemic Stroke
Increased Inflammatory Response in Old Mice is Associated with More Severe Neuronal Injury at the Acute Stage of Ischemic Stroke
复制标题
老年小鼠炎症反应增加与缺血性中风急性期更严重的神经元损伤有关
DOI：
10.14336/ad.2018.0205
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发表时间：
2019-02-01
影响因子：
7.4
通讯作者：
Su, Hua
中科院分区：
文献类型：
--
作者：
Shen, Fanxia;Jiang, Lidan;Su, Hua
中风多发生于高龄患者。老年患者与年轻成人患者相比预后较差。为了了解潜在的机制，我们测试了我们的假设，即老年中风小鼠对急性缺血性损伤的炎症反应增加会导致更严重的脑损伤和行为功能障碍。通过永久性闭塞左侧远端大脑中动脉（dMCAO）在2月龄和12月龄的C57 BL/6小鼠中建立缺血性中风模型。通过用甲酚紫染色脑切片来定量脑萎缩/萎缩体积。感觉运动功能采用角试验和粘合剂去除试验进行评估。在dMCAO后1、3和14天对梗死周围区域中的CD 68+细胞进行定量。采用ELISA法检测缺血脑组织中白细胞介素-6（IL-6）、白细胞介素-1 β（IL-1β）和血管内皮生长因子（VEGF）的含量。Western blot检测紧密连接蛋白claudin-5和紧密连接蛋白ZO-1的表达水平。通过伊文思蓝（EB）外渗测定血脑屏障通透性。明胶酶B（MMP-9，IV型胶原酶）通过凝胶酶谱法测定。与2个月大的小鼠相比，12个月大的小鼠在中风的急性和慢性阶段都有更严重的行为缺陷。与2月龄小鼠相比，12月龄小鼠在dMCAO后1天和14天的梗死/萎缩体积更大，在dMCAO后1天和3天的IL-6和IL-1β水平更高，MMP 9活性更高，claudin-5和ZO-1水平更低。12月龄的小鼠在dMCAO后1、3和14天在梗死周围区域也有更多的CD 68+细胞，并且在dMCAO后3天有更多的EB渗漏。老年小鼠缺血性中风急性期较高的炎症反应与更严重的神经元损伤和长期行为功能障碍有关。
Stroke occurs mostly in patients with advanced age. Elderly patients have a less favorable prognosis compared with young adult patients. To understand the underlying mechanisms, we tested our hypothesis that an increased inflammatory response to acute ischemic injury in old stroke mice leads to more severe brain damage and behavioral dysfunction. An ischemic stroke model was created in 2- and 12-month-old C57BL/6 mice through permanent occlusion of the left distal middle cerebral artery (dMCAO). Infarct/atrophy volumes were quantified by staining the brain sections with Cresyl Violet. Sensorimotor function was assessed using the corner test and adhesive removal test. Quantification of CD68+ cells in the peri-infarct region was performed at 1, 3 and 14 days after dMCAO. Interleukin-6 (IL-6), interleukin-1 β (IL-1β) and vascular endothelial growth factor (VEGF) levels in the ischemic brain tissue were measured using ELISA. Western blot was used to determine the expression levels of tight junction proteins, claudin-5 and zonula occludens (ZO)-1. Blood-brain barrier permeability was measured by Evans blue (EB) extravasation. Gelatinase B (MMP-9, type IV collagenase) was measured by gel zymography. Compared to 2-month-old mice, 12-month-old mice had more severe behavioral deficits at both the acute and chronic stages of stroke. Compared with the 2-month-old mice, 12-month-old mice had larger infarct/atrophy volumes at 1 and 14 days after dMCAO, higher levels of IL-6 and IL-1β, higher MMP9 activity, and lower levels of claudin-5 and ZO-1 at 1 and 3 days after dMCAO. 12-month-old mice also had more CD68+ cells in the peri-infarct region at 1, 3 and 14 days after dMCAO and more EB leakage at 3 days after dMCAO. A higher inflammatory response at the acute stage of ischemic stroke in old mice is associated with more severe neuronal injury and long-term behavioral dysfunction.