Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration
Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration
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DOI：
10.2119/molmed.2012.00020
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发表时间：
2012-06-01
影响因子：
5.7
通讯作者：
Fanelli, Roberto
中科院分区：
文献类型：
--
作者：
De Paola, Massimiliano;Mariani, Alessandro;Fanelli, Roberto
持续性炎症反应是神经退行性疾病中与神经元丢失相关的常见病理事件。已有证据表明，Toll样受体4(TLR4)在多种神经退行性疾病的神经炎症中起关键作用。然而，TLR4介导神经毒性信号的机制仍然知之甚少。我们研究了TLR4在运动神经元变性的体外和体内环境中的作用。利用小鼠脊髓原代培养物，我们研究了内毒素激活TLR4的促炎和神经毒性作用(激活小胶质细胞、释放促炎细胞因子和运动神经元死亡)以及蓝藻来源的TLR4拮抗剂(VB3323)的保护作用。随着TLR4缺陷细胞的使用，具有TLR4功能活性的小胶质成分在这种情况下出现了关键作用。体内实验是在自发运动神经元变性的小鼠模型Wobbler小鼠上进行的，我们初步证实了TLR4拮抗剂的保护作用。与赋形剂和利鲁唑治疗组相比，VB3323慢性治疗组小鼠脊髓神经元的小胶质细胞激活和形态改变减少，在爪子异常和握力测试中表现更好。综上所述，我们的数据增加了对TLR4在介导脊髓神经毒性中的作用的新的理解，并提示TLR4拮抗剂可以在未来的研究中被考虑作为退行性疾病运动神经元的候选保护剂。在线地址：http://www.molmed.org doi：10.2119/molmed.2012.00020
Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteria-derived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle- and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00020