Mechanisms of Secondary Damage After Spinal Cord Injury

炎症和兴奋性毒性似乎是中枢神经系统创伤的关键，但针对继发性损伤的这些方面的有效策略一直难以捉摸。促炎性细胞因子在中枢神经系统损伤和修复中似乎具有复杂且有时相互矛盾的作用。类似地，谷氨酸受体负责损伤中神经元和神经胶质的兴奋性毒性死亡，但也是正常CNS功能所必需的，并且与损伤后的恢复有关。促炎细胞因子肿瘤坏死因子-α（TNF α）最近已显示在正常神经元谷氨酸突触传递的调节中具有独特且关键的作用（Beattie等人，2002; Stellwagen和Malenka，2006; Aizenman和Pratt，2008），并且还加剧兴奋毒性细胞死亡（Hermann等人，2001; Beattie，2004）。我们已经确定TNFa介导的缺乏GluR 2的、Ca++可渗透的AMPA受体（CP-AMPAR）的运输是损伤诱导的炎症和兴奋性毒性之间的新的并且可能是“节点”联系。TNFa在体外增加兴奋性毒性细胞死亡，并增强脊髓损伤（SCI）后的神经元死亡。此外，在SCI的颈损伤模型中，通过在SCI后阻断TNF α来减少缺乏GluR 2的AMPAR插入到神经元膜中，导致神经元死亡减少、白色损伤减少和更好的结果。

Inflammation and excitoxicity appear to be pivotal in CNS trauma, but effective strategies for targeting these aspects of secondary injury have been elusive. Proinflammatory cytokines appear to have complex and sometimes contradictory roles in CNS injury and repair. Similarly, glutamate receptors are responsible for excitotoxic death of neurons and glia in injury, but are also essential for normal CNS function, and have been implicated in recovery after injury. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNFa) has recently been shown to have a unique and critical role in the modulation of normal neuronal glutamate synaptic transmission (Beattie et ai, 2002; Stellwagen and Malenka, 2006; Aizenman and Pratt, 2008), and also to exacerbate excitotoxic cell death (Hermann et ai, 2001; Beattie, 2004). We have identified TN Fa-mediated trafficking of GluR2-lacking, Ca++-permeable AMPA receptors (CP-AMPARs) as a novel and perhaps 'nodal' link between injury-induced inflammation and excitotoxicity. TN Fa increases excitotoxic cell death in vitro, and enhances neuronal death after spinal cord injury (SCI). Further, reducing GluR2- lacking AMPAR-insertion into neuronal membranes by blocking TNFa after SCI, results in reduced neuronal death, reduced white matter damage, and better outcomes in a cervical injury model of SCI.