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.

Public Health Relevance

This application will test a central hypothesis that phospholipase A2 (PLA2) is a convergence molecule that mediates multiple injury mechanisms associated with secondary spinal cord injury (SCI). To test this hypothesis, we have proposed three specific aims to determine 1) whether cPLA2 serves as a convergence molecule that mediates 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. We hope that, by completion of this application, we will identify a novel target for therapeutic intervention aimed at promoting greater anatomical and functional recoveries after SCI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059622-05
Application #
8494696
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Jakeman, Lyn B
Project Start
2009-09-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$318,583
Indirect Cost
$111,711
Name
Indiana University-Purdue University at Indianapolis
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Deng, Ling-Xiao; Walker, Chandler; Xu, Xiao-Ming (2015) Schwann cell transplantation and descending propriospinal regeneration after spinal cord injury. Brain Res 1619:104-14
Walker, Chandler L; Wang, Xiaofei; Bullis, Carli et al. (2015) Biphasic bisperoxovanadium administration and Schwann cell transplantation for repair after cervical contusive spinal cord injury. Exp Neurol 264:163-72
Wang, Xiaofei; Xu, Xiao-Ming (2014) Long-term survival, axonal growth-promotion, and myelination of Schwann cells grafted into contused spinal cord in adult rats. Exp Neurol 261:308-19
Liu, Nai-Kui; Deng, Ling-Xiao; Zhang, Yi Ping et al. (2014) Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury. Ann Neurol 75:644-58
Li, Yiping; Walker, Chandler L; Zhang, Yi Ping et al. (2014) Surgical decompression in acute spinal cord injury: A review of clinical evidence, animal model studies, and potential future directions of investigation. Front Biol (Beijing) 9:127-136
Wu, Wei; Lee, Seung-Young; Wu, Xiangbing et al. (2014) Neuroprotective ferulic acid (FA)-glycol chitosan (GC) nanoparticles for functional restoration of traumatically injured spinal cord. Biomaterials 35:2355-64
Walker, Chandler L; Xu, Xiao-Ming (2014) PTEN inhibitor bisperoxovanadium protects oligodendrocytes and myelin and prevents neuronal atrophy in adult rats following cervical hemicontusive spinal cord injury. Neurosci Lett 573:64-8
Walker, Chandler L; Liu, Nai-Kui; Xu, Xiao-Ming (2013) PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries. Front Biol (Beijing) 8:
Zhang, Yi Ping; Walker, Melissa J; Shields, Lisa B E et al. (2013) Controlled cervical laceration injury in mice. J Vis Exp :e50030
Deng, Ling-Xiao; Deng, Ping; Ruan, Yiwen et al. (2013) A novel growth-promoting pathway formed by GDNF-overexpressing Schwann cells promotes propriospinal axonal regeneration, synapse formation, and partial recovery of function after spinal cord injury. J Neurosci 33:5655-67

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