AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression
AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression
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DOI：
10.1016/j.nbd.2012.11.008
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发表时间：
2013-03-01
影响因子：
6.1
通讯作者：
Steckelings, U. Muscha
中科院分区：
文献类型：
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作者：
Namsolleck, Pawel;Boato, Francesco;Steckelings, U. Muscha
血管紧张素at2受体（AT2R）具有神经保护作用已被广泛接受。在本研究中，我们使用新型非肽at2r激动剂化合物21 （C21）测试了at2r刺激作为治疗脊髓压迫损伤（SCI）小鼠模型的药物治疗方法。在初级神经元和器官型培养中进行的互补实验有助于确定潜在的机制。应用C21 （0.3 mg/kg/d i.p）或载药4周后，监测脊髓损伤后皮质脊髓束（CST）纤维的功能恢复和可塑性。用gfp阳性的内嗅皮质与海马靶组织共培养，评价C21对神经再生的影响。研究了小鼠原代星形胶质细胞和神经细胞中神经元的分化、凋亡和神经营养因子的表达。与对照组相比，C21显著改善了脊髓损伤后的功能恢复，这与损伤部位尾侧CST纤维数量的增加显著相关。在体外，C21显著促进器官型脑切片共培养的神经再生（+50%）和原代神经元的神经突生长（+25%）。AT2R-KO小鼠的神经元中没有c21诱导的神经突生长。在原代神经元中，C21进一步诱导抗凋亡Bcl-2（+75.7%）、脑源性神经营养因子（BDNF）（+53.7%）、神经营养因子受体TrkA（+57.4%）和TrkB（+67.9%）以及神经突生长标志物GAP43（+103%）的RNA表达，但不诱导TrkC表达。我们的数据表明，选择性at2r刺激通过促进轴突可塑性以及通过神经保护和抗凋亡机制改善实验性脊髓损伤的功能恢复。因此，at2r刺激可能被认为是一种治疗脊髓损伤的新方法。(C) 2012爱思唯尔公司版权所有。
It is widely accepted that the angiotensin AT2-receptor (AT2R) has neuroprotective features. In the present study we tested pharmacological AT2R-stimulation as a therapeutic approach in a model of spinal cord compression injury (SCI) in mice using the novel non-peptide AT2R-agonist, Compound 21 (C21). Complementary experiments in primary neurons and organotypic cultures served to identify underlying mechanisms. Functional recovery and plasticity of corticospinal tract (CST) fibers following SCI were monitored after application of C21 (0.3 mg/kg/day i.p.) or vehicle for 4 weeks. Organotypic co-culture of GFP-positive entorhinal cortices with hippocampal target tissue served to evaluate the impact of C21 on reinnervation. Neuronal differentiation, apoptosis and expression of neurotrophins were investigated in primary murine astrocytes and neuronal cells.C21 significantly improved functional recovery after SCI compared to controls, and this significantly correlated with the increased number of CST fibers caudal to the lesion site. In vitro, C21 significantly promoted reinnervation in organotypic brain slice co-cultures (+50%) and neurite outgrowth of primary neurons (+25%). C21-induced neurite outgrowth was absent in neurons derived from AT2R-KO mice. In primary neurons, treatment with C21 further induced RNA expression of anti-apoptotic Bcl-2 (+75.7%), brain-derived neurotrophic factor (BDNF) (+53.7%), the neurotrophin receptors TrkA (+57.4%) and TrkB (+67.9%) and a marker for neurite growth, GAP43 (+103%), but not TrkC.Our data suggest that selective AT2R-stimulation improves functional recovery in experimental spinal cord injury through promotion of axonal plasticity and through neuroprotective and anti-apoptotic mechanisms. Thus, AT2R-stimulation may be considered for the development of a novel therapeutic approach for the treatment of spinal cord injury. (C) 2012 Elsevier Inc. All rights reserved.