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 #
5R01NS059622-04
Application #
8305087
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Hicks, Ramona R
Project Start
2009-09-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$330,138
Indirect Cost
$115,763
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
Wang, Ying; Wu, Wei; Wu, Xiangbing et al. (2018) Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery. Elife 7:
Ordaz, Josue D; Wu, Wei; Xu, Xiao-Ming (2017) Optogenetics and its application in neural degeneration and regeneration. Neural Regen Res 12:1197-1209
Al-Ali, Hassan; Ding, Ying; Slepak, Tatiana et al. (2017) The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury. J Neurosci 37:7079-7095
Chen, Chen; Zhang, Yi Ping; Sun, Yan et al. (2017) An In Vivo Duo-color Method for Imaging Vascular Dynamics Following Contusive Spinal Cord Injury. J Vis Exp :
Wu, Xiangbing; Zhang, Yi Ping; Qu, Wenrui et al. (2017) A Tissue Displacement-based Contusive Spinal Cord Injury Model in Mice. J Vis Exp :
Wu, Xiangbing; Walker, Chandler L; Lu, Qingbo et al. (2017) RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation. Mol Neurobiol 54:6885-6895
Wu, Xiangbing; Xu, Xiao-Ming (2016) RhoA/Rho kinase in spinal cord injury. Neural Regen Res 11:23-7
Gianaris, Alexander; Liu, Nai-Kui; Wang, Xiao-Fei et al. (2016) Unilateral microinjection of acrolein into thoracic spinal cord produces acute and chronic injury and functional deficits. Neuroscience 326:84-94
Qu, Wenrui; Liu, Nai-Kui; Xie, Xin-Min Simon et al. (2016) Automated monitoring of early neurobehavioral changes in mice following traumatic brain injury. Neural Regen Res 11:248-56
Deng, Lingxiao; Ruan, Yiwen; Chen, Chen et al. (2016) Characterization of dendritic morphology and neurotransmitter phenotype of thoracic descending propriospinal neurons after complete spinal cord transection and GDNF treatment. Exp Neurol 277:103-114

Showing the most recent 10 out of 34 publications