JNK inhibition and inflammation after cerebral ischemia
JNK inhibition and inflammation after cerebral ischemia
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DOI：
10.1016/j.bbi.2009.11.001
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发表时间：
2010-07-01
影响因子：
15.1
通讯作者：
Hirt, Lorenz
中科院分区：
文献类型：
--
作者：
Benakis, Corinne;Bonny, Christophe;Hirt, Lorenz
c- jun - n-末端激酶信号通路（JNK）在缺血时高度激活，在细胞凋亡和炎症中起重要作用。我们之前已经证明，D-JNKI1，一种特定的JNK抑制剂，在中风动物模型中具有很强的神经保护作用。我们目前评估了D-JNKI1是否调节缺血后炎症，如小胶质细胞的激活和积累。杂种CD1小鼠进行45分钟大脑中动脉闭塞（MCAo）。在MCAo发病3小时后静脉给予D-JNKI1 （0.1 mg/kg）或对照物（生理盐水）。48 h时病灶大小明显减小，治疗组从28.2 +/- 8.5 mm(3) （n = 7）降至13.9 +/- 6.2 mm(3) （n = 6）。JNK通路的激活（c-Jun的磷酸化）在神经元和Isolectin B4阳性小胶质细胞中被观察到。我们通过测量缺血组织内CD11b标记（红外发射）的平均强度来量化活化的小胶质细胞（CD11b）。各组间无显著差异。将大鼠器官型海马切片培养物缺氧（5%）和葡萄糖剥夺30 min，建立脑缺血模型。在体外，D-JNKI1主要存在于CA1区的NeuN阳性神经元和少数Isolectin B4阳性小胶质细胞中。此外，OGD后48小时，小胶质细胞被激活，而在对照组和d - jnki1处理的切片中发现静息小胶质细胞。我们的研究表明，D-JNKI1在短暂性MCAo 48小时后减少梗死体积，并且在这个时间点对小胶质细胞的激活和积累不起作用。相反，体外数据显示D-JNKI1对小胶质细胞激活的调节具有间接作用。(C) 2009爱思唯尔公司版权所有。
The c-Jun-N-terminal kinase signaling pathway (JNK) is highly activated during ischemia and plays an important role in apoptosis and inflammation. We have previously demonstrated that D-JNKI1, a specific JNK inhibitor, is strongly neuroprotective in animal models of stroke. We presently evaluated if D-JNKI1 modulates post-ischemic inflammation such as the activation and accumulation of microglial cells.Outbred CD1 mice were subjected to 45 min middle cerebral artery occlusion (MCAo). D-JNKI1 (0.1 mg/kg) or vehicle (saline) was administered intravenously 3 h after MCAo onset. Lesion size at 48 h was significantly reduced, from 28.2 +/- 8.5 mm(3) (n = 7) to 13.9 +/- 6.2 mm(3) in the treated group (n = 6). Activation of the JNK pathway (phosphorylation of c-Jun) was observed in neurons as well as in Isolectin B4 positive microglia. We quantified activated microglia (CD11b) by measuring the average intensity of CD11 b labelling (infra-red emission) within the ischemic tissue. No significant difference was found between groups. Cerebral ischemia was modelled in vitro by subjecting rat organotypic hippocampal slice cultures to oxygen (5%) and glucose deprivation for 30 min. In vitro, D-JNKI1 was found predominantly in NeuN positive neurons of the CA1 region and in few Isolectin B4 positive microglia. Furthermore, 48 h after OGD, microglia were activated whereas resting microglia were found in controls and in D-JNKI1-treated slices. Our study shows that D-JNKI1 reduces the infarct volume 48 h after transient MCAo and does not act on the activation and accumulation of microglia at this time point. In contrast, in vitro data show an indirect effect of D-JNKI1 on the modulation of microglial activation. (C) 2009 Elsevier Inc. All rights reserved.