Signaling proteins in spinal parenchyma and dorsal root ganglion in rat with spinal injury-induced spasticity.
Signaling proteins in spinal parenchyma and dorsal root ganglion in rat with spinal injury-induced spasticity.
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DOI：
10.1016/j.jprot.2013.06.028
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发表时间：
2013-10
影响因子：
3.3
通讯作者：
H. Kupcová Skalníková;Roman Navarro;S. Marsala;Rita Hrabakova;P. Vodička;S. Gadher;H. Kovářová;M. Marsala
中科院分区：
文献类型：
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作者：
H. Kupcová Skalníková;Roman Navarro;S. Marsala;Rita Hrabakova;P. Vodička;S. Gadher;H. Kovářová;M. Marsala
脊髓创伤性损伤导致的进行性肌肉痉挛的发展可以通过局部节段抑制的丧失和/或感觉传入驱动的增加从而导致α-运动神经元活动加剧来介导。为了确定神经活性物质在这种痉挛状态发展中的潜在贡献，我们采用了明确的脊髓损伤诱发的痉挛大鼠模型。使用 Kinex™ 抗体微阵列对脊髓损伤水平以下的脊髓实质和相应的背根神经节细胞中的信号分子进行分析。结果揭示了血管生成和神经变性途径的参与以及由具有 SH-2 结构域的几种中枢蛋白介导的直接串扰。横断后 2 周和 5 周，在脊髓腹角中观察到多种蛋白质的上调，包括 CaMKIV、RONα 和 PKCδ 以及 MAPK3/ERK1 磷酸化。我们的结果表明，这些信号分子及其神经元效应系统不仅在脊柱创伤后痉挛状态的启动和维持中发挥重要作用。在腰椎实质而非背根神经节中观察到的特定蛋白质变化的排他性表明，新的治疗策略应主要针对特定的脊柱节段，以预防或减轻痉挛状态。生物学意义进行性肌肉痉挛和强直的发展代表与脊髓缺血或创伤性损伤相关的严重并发症。使用 Kinex™ 抗体微阵列对脊髓损伤水平以下的脊髓实质和脊髓损伤大鼠模型中相应的背根神经节细胞中的信号蛋白（包括其磷酸化状态）进行分析。结果揭示了直接蛋白质相互作用介导的血管生成和神经变性途径之间的串扰，这可能对受损区域的愈合过程有显着贡献。重要的是，我们鉴定了几种专门在脊柱腰椎腹角中观察到的靶蛋白，这些蛋白不仅在脊柱创伤后痉挛状态的启动中发挥重要作用，而且在痉挛状态的维持中也发挥着重要作用。因此，潜在的新治疗策略，例如基因沉默或药物治疗，应主要针对损伤中心及其周围的脊髓实质部位，并且最有可能采用鞘内或靶向脊髓节段特异性载体或药物递送。我们相信这项工作将刺激未来的转化研究，最终改善脊柱创伤性损伤患者的生活质量。
Development of progressive muscle spasticity resulting from spinal traumatic injury can be mediated by loss of local segmental inhibition and/or by an increased sensory afferent drive with resulting exacerbated α-motoneuron activity. To identify potential contributions of neuroactive substances in the development of such spasticity state, we employed a well-defined spinal injury-evoked spasticity rat model. Signaling molecules were analyzed in the spinal parenchyma below the level of spinal injury and in the corresponding dorsal root ganglion cells using Kinex™ antibody microarrays. The results uncovered the involvement of angiogenesis and neurodegeneration pathways together with direct cross-talk mediated by several hub proteins with SH-2 domains. At 2 and 5 weeks after transection, up-regulation of several proteins including CaMKIV, RONα and PKCδ as well as MAPK3/ERK1 phosphorylation was observed in the spinal ventral horns. Our results indicate that these signaling molecules and their neuronal effector systems cannot only play an important role in the initiation but also in the maintenance of spasticity states after spinal trauma. The exclusivity of specific protein changes observed in lumbar spinal parenchyma but not in dorsal root ganglia indicates that new treatment strategies should primarily target specific spinal segments to prevent or attenuate spasticity states.Biological significanceDevelopment of progressive muscle spasticity and rigidity represents a serious complication associated with spinal ischemic or traumatic injury. Signaling proteins, including their phosphorylation status, were analyzed in the spinal parenchyma below the level of spinal injury and in the corresponding dorsal root ganglion cells in a rat model of spinal injury using Kinex™ antibody microarrays. The results uncovered direct protein interaction mediated cross-talk between angiogenesis and neurodegeneration pathways, which may significantly contribute to the healing process in the damaged region. Importantly, we identified several target proteins exclusively observed in the spinal lumbar ventral horns, where such proteins may not only play an important role in the initiation but also in the maintenance of spasticity states after spinal trauma. Hence, potential new treatment strategies such as gene silencing or drug treatment should primarily target spinal parenchymal sites at and around the injury epicenter and most likely employ intrathecal or targeted spinal segment-specific vector or drug delivery. We believe that this work will stimulate future translational research, ultimately leading to the improvement of quality of life of patients with spinal traumatic injury.