Cardiolipin as a Novel Target for Neuroprotection after Spinal Cord Injury

脊髓损伤（SCI）是影响美国军队受伤人员的最严重的致残性疾病之一。 不幸的是，SCI患者还没有有效的治疗方法。因此，这是一个紧迫的 医学需要开发新的修复策略，以减轻SCI的破坏性，并将其转化为 在临床上改善脊髓损伤退伍军人的生活质量。最近，一种新的脂质信号通路，即 已经鉴定了控制细胞死亡/凋亡的心磷脂（CL）-细胞色素c途径。CL是 结构独特的二聚体磷脂位于线粒体内膜，在那里它是必需的， 最佳线粒体功能CL是神经元损伤中的首选氧化底物，是唯一的磷脂 在细胞凋亡过程中经历早期氧化的线粒体中，是活性氧的早期靶点 物种（ROS）攻击。CL的改变与各种线粒体功能障碍有关， 病理条件。在SCI中首次使用基于质谱的脂质组学，我们生成了 初步数据显示SCI后CL过氧化和损失。值得注意的是，XJB-5-131（XJB），一本小说， 脊髓损伤后30分钟给予的靶向抗氧化剂显著减少了组织损伤， 改善成年大鼠的行为恢复。这些数据有力地表明，CL改变是一个关键机制， 介导损伤诱导的细胞死亡和组织损伤。然而，CL改变的作用和机制 在SCI中仍不清楚。在这里，我们假设CL的改变，包括过氧化和损失，是一个中心的， 过程介导脊髓继发性损伤，CL水平的恢复可能导致 脊髓损伤后的神经保护和功能恢复。利用大鼠脊髓神经元体外培养系统， 成年大鼠胸部挫伤性SCI模型，我们将确定1）CL改变是否诱导 线粒体功能障碍和神经元死亡，以及这种有害作用是否可以通过一种新的 线粒体靶向抗氧化剂XJB; 2）CL改变在线粒体靶向抗氧化剂XJB信号通路中的分子作用。 SCI后神经元凋亡以及这种CL改变是否足以介导继发性SCI; 3）是否 异常的线粒体动力学也在CL改变介导的细胞死亡中起作用;和4）最佳剂量 XJB对大鼠脊髓损伤后神经保护和功能恢复的治疗时间窗。

Spinal cord injury (SCI) is among the most disabling conditions affecting wounded members of the U.S. military. Unfortunately, there has been no effective treatment available for SCI patients. It is, therefore, an urgent medical need to develop novel repair strategies to mitigate the devastating nature of SCI and to translate them clinically to improve quality of life of our veterans with SCI. Recently, a novel lipid signaling pathway, namely the cardiolipin (CL)-cytochrome c pathway, that control cell death/apoptosis has been identified. CL is a structurally unique dimeric phospholipid localized in the inner mitochondrial membrane where it is required for optimal mitochondrial function. CL is a preferred oxidation substrate in neuronal injury, is the only phospholipid in the mitochondria that undergoes early oxidation during apoptosis, and is an early target of reactive oxygen species (ROS) attack. Alteration of CL has been associated with mitochondrial dysfunction in a variety of pathological conditions. Using mass spectrometry-based lipidomics for the first time in SCI, we have generated preliminary data showing CL peroxidation and loss after SCI. Remarkably, XJB-5-131 (XJB),  a novel mitochondria-targeted antioxidant, administered at 30 min post-SCI significantly reduces tissue damage and improves behavioral recovery in adult rats. These data strongly suggest that CL alteration is a key mechanism that mediates injury-induced cell death and tissue damage. However, the role and mechanism of CL alteration in SCI remain unclear. Here, we hypothesize that CL alteration, including peroxidation and loss, is a central process that mediates spinal cord secondary injury, and that restoration of CL level may lead to neuroprotection and recovery of function after SCI. Using a rat spinal cord neuronal culture system in vitro and an adult rat thoracic contusive SCI model in vivo, we will determine 1) whether CL alteration induces mitochondrial dysfunction and neuronal death and whether such detrimental effects can be reversed by a novel mitochondrial targeted antioxidant XJB; 2) the molecular role of CL alteration in the signaling pathway of neuronal apoptosis after SCI and whether such CL alteration is sufficient to mediate secondary SCI; 3) whether abnormal mitochondrial dynamics also play a role in CL alteration-mediated cell death; and 4) an optimal dose and therapeutic time window of XJB on neuroprotection and functional recovery after rat contusive SCI.