Cho Kyung-Ok, Kim Young Sun, Cho Young-Jin, Kim Seong Yun
Department of Pharmacology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, 137-701 Seoul, South Korea.
Exp Neurol. 2008 Jul;212(1):85-92. doi: 10.1016/j.expneurol.2008.03.017. Epub 2008 Apr 3.
Down syndrome candidate region 1 (DSCR1; also known as RCAN1 or Adapt78) has been shown to be induced by calcium overload and oxidative stress which are included in the pathogenic hallmarks of the ischemic diseases. After ischemic stroke, inflammatory responses play an important role in the exacerbation of neuronal loss. In this study, we investigated the expression pattern of DSCR1 in the mouse cortex after transient middle cerebral artery occlusion (MCAO). Then, in vitro studies were taken to address whether inflammatory mediators could induce DSCR1. Male C57BL/6 mice were subjected to transient MCAO for 35 min and sacrificed at 6, 24, and 72 h after the reperfusion. The expression of DSCR1 began to increase in layer VI of the peri-infarct cortex at 24 h and was prominently enhanced at 72h after transient MCAO. Moreover, real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry showed that the induction of the DSCR1 isoform 4 (DSCR1-4) mRNA preceded the expression of the DSCR1 protein. In in vitro studies, tumor necrosis factor alpha and interleukin-1beta (IL-1beta) were found to induce strong upregulation of DSCR1-4 mRNA. Furthermore, western blot analysis revealed that overexpression of DSCR1-4 in SK-N-SH neuroblastoma cells attenuated IL-1beta-induced cyclooxygenase 2 and intercellular adhesion molecule 1 expression. These results demonstrate upregulation of DSCR1 in the mouse peri-infarct cortex following transient MCAO. In addition, our results suggest that inflammatory mediators such as TNFalpha and IL-1beta can induce DSCR1-4 transcription, which may be associated with the alleviation of inflammatory processes.
唐氏综合征候选区域1（DSCR1；也称为RCAN1或Adapt78）已被证明可由钙超载和氧化应激诱导产生，而钙超载和氧化应激是缺血性疾病致病特征的一部分。缺血性中风后，炎症反应在神经元损失的加剧中起重要作用。在本研究中，我们调查了短暂性大脑中动脉闭塞（MCAO）后小鼠皮质中DSCR1的表达模式。然后，进行体外研究以探讨炎症介质是否能诱导DSCR1。雄性C57BL/6小鼠接受35分钟的短暂性MCAO，并在再灌注后6、24和72小时处死。短暂性MCAO后24小时，梗死周边皮质VI层中DSCR1的表达开始增加，并在72小时时显著增强。此外，实时逆转录聚合酶链反应和免疫组织化学显示，DSCR1亚型4（DSCR1-4）mRNA的诱导先于DSCR1蛋白的表达。在体外研究中，发现肿瘤坏死因子α和白细胞介素-1β（IL-1β）可诱导DSCR1-4 mRNA强烈上调。此外，蛋白质印迹分析显示，SK-N-SH神经母细胞瘤细胞中DSCR1-4的过表达减弱了IL-1β诱导的环氧化酶2和细胞间黏附分子1的表达。这些结果表明短暂性MCAO后小鼠梗死周边皮质中DSCR1上调。此外，我们的结果表明，肿瘤坏死因子α和IL-1β等炎症介质可诱导DSCR1-4转录，这可能与炎症过程的减轻有关。
