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首页> 外文期刊>Life sciences >ERK1/2 and p38 mitogen-activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury
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ERK1/2 and p38 mitogen-activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury

机译：ERK1 / 2和p38丝裂原激活的蛋白激酶介导iNOS诱导的急性脊髓损伤后的脊髓神经元变性

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The enhanced production of nitric oxide (NO) via inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of neuronal apoptosis after acute traumatic spinal cord injury (SCI). In the present study, to further characterize the pathways mediating the synthesis and release of NO, we examined activation of extracellular signal regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinases (p38 MAPK) in microglia/macrophages in the injured area of adult rats subjected to a complete transection at the T 10 vertebrae level and assessed their role in NO production and survival of neurons by using immunohistochemistry, Western blot, RT-PCR and pharmacological interventions. Results showed activation of microglia/macrophages featured by morphological changes, as visualized immunohistochemically with the marker OX-42, in the areas adjacent to the lesion epicenter 1 h after surgery. Concomitantly, iNOS mRNA and its protein in the activated microglia/macrophages were also significantly upregulated at early hours after surgery. Their levels were maximal at 6 It, persisted for at least 24 It, and returned to basal level 72 h after SCI. Furthermore, phosphorylated ERK 1/2 and p38 MAPK were activated as well in microglia/macrophages in injured area with a similar time course as iNOS. With administration Of L-NAME, a NOS inhibitor, the number of apoptotic neurons was clearly decreased, as assessed with TUNEL method at 24 h after SCI. In parallel, loss of neurons induced by SCI, assessed with NeuN immumohistochemistry, was also diminished. Moreover, the effect of inhibition of phosphorylation ERK1/2 and p38 MAPK by corresponding inhibitors PD98059 and SB203580 administered before and after SCI was also investigated. Inhibition of p38 effectively reduced iNOS mRNA expression and rescued neurons from apoptosis and death in the area adjacent to the lesion epicenter; whereas the inhibition of ERK 1/2 had a smaller effect on decrease of iNOS mRNA and no long-term protective effect on cell loss. These results indicate the ERK1/2 and p38 MAPK signaling pathway, especially the latter, play an important role in NO-mediated degeneration of neuron in the spinal cord following SCI. Strategies directed to blocking the initiation of this cascade prove to be beneficial for the treatment of acute SCI. (c) 2006 Elsevier Inc. All rights reserved.
机译：通过诱导型一氧化氮合酶（iNOS）提高一氧化氮（NO）的产生已牵涉急性创伤性脊髓损伤（SCI）后神经元凋亡的发病机理。在本研究中，为进一步表征介导NO合成和释放的途径，我们研究了小胶质细胞/巨噬细胞中细胞外信号调节激酶1/2（ERK1 / 2）和p38丝裂原活化蛋白激酶（p38 MAPK）的激活。通过免疫组织化学，蛋白质印迹，RT-PCR和药理学干预评估成年大鼠在T 10椎骨水平完全横断的受损区域，并评估其在NO产生和神经元存活中的作用。结果显示，术后1 h，在靠近病灶震中的区域中，用标记OX-42免疫组化观察到的形态改变所致的小胶质细胞/巨噬细胞的活化。同时，在手术后的早期，活化的小胶质细胞/巨噬细胞中的iNOS mRNA及其蛋白也显着上调。它们的水平在6 It时最大，持续至少24 It，并在SCI后72小时恢复至基础水平。此外，在受损区域的小胶质细胞/巨噬细胞中，磷酸化的ERK 1/2和p38 MAPK也被激活，其时间过程与iNOS相似。如在SCI后24小时用TUNEL方法评估，通过使用NOS抑制剂L-NAME可以明显减少凋亡神经元的数量。同时，用NeuN免疫组织化学评估的SCI诱导的神经元丢失也减少了。而且，还研究了在SCI之前和之后施用的相应抑制剂PD98059和SB203580对ERK1 / 2和p38 MAPK磷酸化的抑制作用。抑制p38可有效降低iNOS mRNA的表达，并使神经元免受损伤中心附近区域的细胞凋亡和死亡的影响; ERK 1/2的抑制作用对iNOS mRNA的降低作用较小，对细胞丢失没有长期的保护作用。这些结果表明ERK1 / 2和p38 MAPK信号通路，尤其是后者，在脊髓损伤后NO介导的脊髓神经元变性中起重要作用。证明了阻止这种级联反应启动的策略对治疗急性SCI有益。 （c）2006 Elsevier Inc.保留所有权利。

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