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.
Spinal cord injury (SCI) is among the most disabling conditions affecting wounded members of the U.S. military. In this application, we will investigate whether a novel lipid signaling pathway, namely the cardiolipin (CL)- cytochrome c pathway, play a role in mediating cell death in vitro and tissue damage and functional impairment after SCI. Specifically, we will determine the treatment efficacy of a novel mitochondrial targeted antioxidant XJB, the molecular role of CL alteration in the signaling pathway of neuronal apoptosis, the abnormal mitochondria dynamics, and the optimal dose and therapeutic time window of XJB on neuroprotection and functional recovery after a clinically-relevant contusive SCI in adult rats.
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