Role of phospholipase A2 in spinal cord secondary injury

磷脂酶A2在脊髓继发性损伤中的作用 脊髓损伤有两种机制：一种是原发的机械性损伤，另一种是 多种损伤机制介导的继发性损伤。到目前为止，有三种伤害机制，即 脊髓损伤后的炎症、氧化和兴奋性神经毒性被广泛研究。 (SCI)。由于涉及多个机制，因此阻止一个特定的机制不太可能 显著预防继发性脊髓损伤的病程。然而，这些不同的机制可能 可能共享一条中枢或汇聚途径来发挥其有害影响。如果是这样，则阻止这种 汇聚途径应该比阻断单一的 路径。一个可以作为收敛媒介的候选分子是酶磷脂酶。 A2(PLA2)。磷脂酶A2是一个不同的酶家族，它能分解sn-2位的酯键。 产生游离脂肪酸的磷脂，如花生四烯酸(AA)和溶血磷脂。这些 产品是众所周知的具有生物活性的二十烷基类化合物和血小板激活因子(PAF)的前体。 炎症、氧化和细胞毒性的介体。此外，PLA2可以直接攻击细胞膜 以诱导神经元和神经胶质细胞死亡。虽然PLA2的下游产品，如AA，已经被 令我们惊讶的是，人们对PLA2本身的作用和机制知之甚少。 创伤性脊髓损伤。最近，我们第一次证明，总PLA2和 急性心肌梗死后胞浆PLA2(cPLA2；PLA2亚型)的表达显著增加。 挫伤性脊髓损伤(Liu等人，Ann Neurol 59：606-619,2006)。值得注意的是，cPLA2抑制剂AACOCF3， 小鼠脊髓损伤后30min给药显著减少组织损伤并改善行为学 恢复。在这里，我们提出了一个中心假设，即PLA2是一种汇聚分子，它介导 与继发性脊髓损伤相关的多条损伤途径。如果我们的假设是正确的，阻止 PLA2的激活应能抑制多种损伤途径，从而促进 脊髓损伤后更好的神经保护和功能恢复。因为cPLA2是最重要的 PLA2同工酶在受体介导的AA释放中的作用，这一应用将着重于其作用和 CplA2在脊髓损伤中的作用机制。因此，提出了以下三个具体目标： 确定1)cPLA2是否作为一种聚合分子介导FREE的细胞毒作用 自由基、兴奋性氨基酸和炎性细胞因子，2)cPLA2激活是否都是必需的 3)cPLA2介导继发性脊髓损伤的机制。 重点是线粒体功能障碍。完成这项申请可能会导致 开发新的和有效的战略，旨在促进更大的解剖和功能 脊髓损伤后的康复。

Role of phospholipase A2 in spinal cord secondary injury There are two mechanisms of damage to the spinal cord after injury: a primary mechanical injury and a secondary injury mediated by multiple injury mechanisms. To date, three injury mechanisms, i.e., inflammation, oxidation and excitatory neurotoxicity, are extensively studied following spinal cord injury (SCI). Since multiple mechanisms are involved, it is unlikely that blocking one particular mechanism would significantly prevent the course of secondary SCI. However, it is possible that these different mechanisms may share a central or convergence pathway to exert their detrimental effects. If so, blocking such a convergence pathway should result in greater anatomical and functional recovery than blocking a single pathway. A candidate molecule that could serve as a convergence mediator is the enzyme phospholipase A2 (PLA2). PLA2 is a diverse family of enzymes that hydrolyze the ester bond at the sn-2 position of phospholipids to produce a free fatty acid such as arachidonic acid (AA) and a lysophospholipid. These products are precursors of bioactive eicosanoids and platelet activating factor (PAF) that are well-known mediators of inflammation, oxidation and cytotoxicity. Additionally, PLA2 can attack cell membranes directly to induce neuronal and glial death. Although the downstream products of PLA2, such as AA, have been extensively studied, to our surprise, little is known concerning the role and mechanism of the PLA2 itself in traumatic SCI. Recently, we demonstrated, for the first time, that both the activity of total PLA2 and expression of cytosolic PLA2 (cPLA2; a subtype of PLA2) increased significantly following an acute contusive SCI (Liu et al., Ann Neurol 59:606-619, 2006). Remarkably, AACOCF3, a cPLA2 inhibitor, administered at 30 min post-SCI in mice significantly reduced tissue damage and improved behavioral recovery. Here, we propose a central hypothesis that PLA2 is a convergence molecule that mediates multiple injury pathways associated with the secondary SCI. If our hypothesis is correct, blocking PLA2 activation should induce inhibition of multiple injury pathways and, therefore, promotion of greater neuroprotection and functional recovery following SCI. Since cPLA2 is the most important PLA2 isozyme implicated in receptor-mediated release of AA, this application will focus on the role and mechanisms of cPLA2 action in mediating SCI. As such, the following three specific aims are proposed to determine 1) whether cPLA2 serves as a convergence molecule mediating the cytotoxic effects of free radicals, excitatory amino acids and inflammatory cytokines, 2) whether cPLA2 activation is both necessary and sufficient to mediate secondary SCI, and 3) the mechanism by which cPLA2 mediates secondary SCI with an emphasis being placed on the mitochondria dysfunction. Completion of this application may lead to the development of novel and effective strategies aimed at promoting greater anatomical and functional recoveries after SCI.