星形胶质细胞 N-Myc 下游调节基因-2 参与核转录因子 κB 介导的全脑缺血诱导的炎症反应。
Astrocytic N-Myc Downstream-regulated Gene-2 Is Involved in Nuclear Transcription Factor κB-mediated Inflammation Induced by Global Cerebral Ischemia.
机构信息
From the Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China (Y.D., Y.M., P.Q., Y.H., Z.G., W.H.); Anesthesia and Operation Center, People's Liberation Army of China General Hospital, Beijing, China (Y.M.); Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China (Z.Z.); First Affiliated Hospital to People's Liberation Army of China General Hospital, Beijing, China (L.Z.); and Department of Anesthesiology, People's Liberation Army of China General Hospital, Beijing, China (H.G.).
出版信息
Anesthesiology. 2018 Mar;128(3):574-586. doi: 10.1097/ALN.0000000000002044.
BACKGROUND
Inflammation is a key element in the pathophysiology of cerebral ischemia. This study investigated the role of N-Myc downstream-regulated gene-2 in nuclear transcription factor κB-mediated inflammation in ischemia models.
METHODS
Mice (n = 6 to 12) with or without nuclear transcription factor κB inhibitor pyrrolidinedithiocarbamate pretreatment were subjected to global cerebral ischemia for 20 min. Pure astrocyte cultures or astrocyte-neuron cocultures (n = 6) with or without pyrrolidinedithiocarbamate pretreatment were exposed to oxygen-glucose deprivation for 4 h or 2 h. Astrocytic nuclear transcription factor κB and N-Myc downstream-regulated gene-2 expression, proinflammatory cytokine secretion, neuronal apoptosis and survival, and memory function were analyzed at different time points after reperfusion or reoxygenation. Proinflammatory cytokine secretion was also studied in lentivirus-transfected astrocyte lines after reoxygenation.
RESULTS
Astrocytic nuclear transcription factor κB and N-Myc downstream-regulated gene-2 expression and proinflammatory cytokine secretion increased after reperfusion or reoxygenation. Pyrrolidinedithiocarbamate pretreatment significantly reduced N-Myc downstream-regulated gene-2 expression and proinflammatory cytokine secretion in vivo and in vitro, reduced neuronal apoptosis induced by global cerebral ischemia/reperfusion (from 65 ± 4% to 47 ± 4%, P = 0.0375) and oxygen-glucose deprivation/reoxygenation (from 45.6 ± 0.2% to 22.0 ± 4.0%, P < 0.001), and improved memory function in comparison to vehicle-treated control animals subjected to global cerebral ischemia/reperfusion. N-Myc downstream-regulated gene-2 lentiviral knockdown reduced the oxygen-glucose deprivation-induced secretion of proinflammatory cytokines.
CONCLUSIONS
Astrocytic N-Myc downstream-regulated gene-2 is up-regulated after cerebral ischemia and is involved in nuclear transcription factor κB-mediated inflammation. Pyrrolidinedithiocarbamate alleviates ischemia-induced neuronal injury and hippocampal-dependent cognitive impairment by inhibiting increases in N-Myc downstream-regulated gene-2 expression and N-Myc downstream-regulated gene-2-mediated inflammation.
背景
炎症是脑缺血病理生理学的一个关键因素。本研究探讨了 N-Myc 下游调节基因-2 在核转录因子 κB 介导的缺血模型炎症中的作用。
方法
给予核转录因子 κB 抑制剂吡咯烷二硫代氨基甲酸盐预处理的小鼠（n=6 至 12 只）行全脑缺血 20 分钟。给予或不给予吡咯烷二硫代氨基甲酸盐预处理的纯星形胶质细胞培养物或星形胶质细胞-神经元共培养物（n=6）行氧-葡萄糖剥夺 4 小时或 2 小时。在再灌注或再氧合后不同时间点分析再灌注或再氧合后星形胶质细胞核转录因子 κB 和 N-Myc 下游调节基因-2 的表达、促炎细胞因子的分泌、神经元凋亡和存活以及记忆功能。还在再氧合后研究了慢病毒转染的星形胶质细胞系中的促炎细胞因子分泌。
结果
再灌注或再氧合后，星形胶质细胞核转录因子 κB 和 N-Myc 下游调节基因-2 的表达和促炎细胞因子的分泌增加。吡咯烷二硫代氨基甲酸盐预处理可显著降低体内和体外 N-Myc 下游调节基因-2 的表达和促炎细胞因子的分泌，减少全脑缺血/再灌注（从 65±4%降至 47±4%，P=0.0375）和氧-葡萄糖剥夺/再氧合（从 45.6±0.2%降至 22.0±4.0%，P<0.001）引起的神经元凋亡，并改善全脑缺血/再灌注后动物的记忆功能。N-Myc 下游调节基因-2 慢病毒敲低可减少氧-葡萄糖剥夺诱导的促炎细胞因子分泌。
结论
脑缺血后星形胶质细胞 N-Myc 下游调节基因-2 上调，并参与核转录因子 κB 介导的炎症。吡咯烷二硫代氨基甲酸盐通过抑制 N-Myc 下游调节基因-2 表达和 N-Myc 下游调节基因-2 介导的炎症增加来减轻缺血引起的神经元损伤和海马依赖性认知障碍。
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