• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of neuroinflammation >TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation
【24h】

TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation

机译：TNF-α蛋白合成抑制剂可恢复神经元功能并逆转由慢性神经炎症引起的认知功能障碍

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Background Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF)-α are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT), an agent with anti-TNF-α activity, in a model of chronic neuroinflammation. Methods Lipopolysaccharide or artificial cerebrospinal fluid was infused into the fourth ventricle of three-month-old rats for 28 days. Starting on day 29, animals received daily intraperitoneal injections of DT (56 mg/kg/day) or vehicle for 14 days. Thereafter, cognitive function was assessed by novel object recognition, novel place recognition and Morris water maze, and animals were euthanized 25 min following water maze probe test evaluation. Results Chronic LPS-infusion was characterized by increased gene expression of the proinflammatory cytokines TNF-α and IL-1β in the hippocampus. Treatment with DT normalized TNF-α levels back to control levels but not IL-1β. Treatment with DT attenuated the expression of TLR2, TLR4, IRAK1 and Hmgb1, all genes involved in the TLR-mediated signaling pathway associated with classical microglia activation. However DT did not impact the numbers of MHC Class II immunoreactive cells. Chronic neuroinflammation impaired novel place recognition, spatial learning and memory function; but it did not impact novel object recognition. Importantly, treatment with DT restored cognitive function in LPS-infused animals and normalized the fraction of hippocampal neurons expressing the plasticity-related immediate-early gene Arc. Conclusion Our data demonstrate that the TNF-α synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-α is a critical mediator of chronic neuroinflammation-induced neuronal dysfunction and cognitive impairment and targeting its synthesis could provide an effective therapeutic approach to several human neurodegenerative diseases.
机译：背景慢性神经炎症是与认知丧失相关的几种神经系统疾病的标志。活化的小胶质细胞和诸如肿瘤坏死因子（TNF）-α之类的分泌因子是神经炎症的关键介质，可能导致神经元功能障碍。我们的研究旨在评估一种新型沙利度胺类似物3,6'-二硫代沙利度胺（DT）（一种具有抗TNF-α活性的药物）在慢性神经炎症模型中的治疗潜力。方法将脂多糖或人工脑脊液注入三个月大的大鼠的第四脑室，持续28天。从第29天开始，每天接受腹膜内注射DT（56 mg / kg /天）或赋形剂的动物持续14天。此后，通过新物体识别，新地点识别和莫里斯水迷宫评估认知功能，并在水迷宫探针测试评估后25分钟对动物实施安乐死。结果长期LPS输注的特征在于海马中促炎细胞因子TNF-α和IL-1β的基因表达增加。用DT处理可将TNF-α水平恢复至正常对照水平，但不能恢复IL-1β。 DT处理减弱了TLR2，TLR4，IRAK1和Hmgb1的表达，TLR2，TLR4，IRAK1和Hmgb1的所有基因均参与了与经典小胶质细胞激活相关的TLR介导的信号通路。然而，DT不影响II类MHC免疫反应细胞的数量。慢性神经炎症会损害新颖的位置识别，空间学习和记忆功能;但这并没有影响新颖的物体识别。重要的是，用DT处理可恢复注入LPS的动物的认知功能，并使表达可塑性相关的即早基因Arc的海马神经元比例正常化。结论我们的数据表明TNF-α合成抑制剂DT可以显着逆转慢性神经炎症引起的海马依赖性认知功能障碍。这些结果表明，TNF-α是慢性神经炎症引起的神经元功能障碍和认知障碍的关键介质，靶向其合成可以为几种人类神经退行性疾病提供有效的治疗方法。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号