Thrombin-induced delayed injury involves multiple and distinct signaling pathways in the cerebral cortex and the striatum in organotypic slice cultures
Thrombin-induced delayed injury involves multiple and distinct signaling pathways in the cerebral cortex and the striatum in organotypic slice cultures
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DOI：
10.1016/j.nbd.2005.10.008
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发表时间：
2006-04-01
影响因子：
6.1
通讯作者：
Akaike, A
中科院分区：
文献类型：
--
作者：
Fujimoto, S;Katsuki, H;Akaike, A
凝血酶是一种对血液凝固至关重要的丝氨酸蛋白酶，在与脑出血相关的细胞损伤中也发挥着重要作用。在这里，我们表明，在器官型皮质纹状体切片培养物中，凝血酶引起大脑皮层迟发性神经元损伤和纹状体收缩。这些作用可以被放线菌酮和放线菌素 D 阻止，但不能被 caspase-3 抑制剂阻止。凝血酶诱导的纹状体收缩可通过凝血酶抑制剂阿加曲班或预先热灭活凝血酶来消除，并通过蛋白酶激活受体 1 拮抗剂 FR171113 显着减弱。然而，热灭活或 FR171113 均不能阻止凝血酶诱导的皮质损伤，阿加曲班仅部分抑制该损伤。此外，抑制细胞外信号调节激酶（ERK）、Src酪氨酸激酶和蛋白激酶C可以防止皮质神经元损伤和纹状体收缩，而抑制p38丝裂原激活蛋白激酶和c-Jun N末端激酶只能防止纹状体收缩。凝血酶治疗迅速诱导 ERK 磷酸化，而抑制 Src 和蛋白激酶 C 并不能阻止这种磷酸化。因此，凝血酶通过以蛋白酶活性独立和依赖的方式募集多种不同的信号传导途径，从而诱导大脑皮层和纹状体的细胞损伤。 (c) 2005 Elsevier Inc. 保留所有权利。
Thrombin, a serine protease essential for blood coagulation, also plays an important role in cellular injury associated with intracerebral hemorrhage. Here, we show that, in organotypic cortico-striatal slice cultures, thrombin evoked delayed neuronal injury in the cerebral cortex and shrinkage of the striatum. These effects were prevented by cycloheximide and actinomycin D but not by a caspase-3 inhibitor. Thrombin-induced shrinkage of the striatum was abolished by a thrombin inhibitor argatroban or prior heat inactivation of thrombin, and significantly attenuated by a protease-activated receptor-1 antagonist FR171113. However, thrombin-induced cortical injury was not prevented either by heat inactivation or by FR171113, and was only partially inhibited by argatroban. In addition, inhibition of extra-celluar signal-regulated kinase (ERK), Src tyrosine kinase and protein kinase C prevented both neuronal injury in the cortex and shrinkage of the striatum, whereas inhibition of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase prevented shrinkage of the striatum only. Thrombin treatment promptly induced phosphorylation of ERK, which was not prevented by inhibition of Src and protein kinase C. Thus, thrombin induces cellular injury in the cerebral cortex and the striatum, by recruiting multiple and distinct signaling pathways in protease activity-independent as well as dependent manner. (c) 2005 Elsevier Inc. All rights reserved.