Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury

Nai Kui Liu, Ling Xiao Deng, Yi Ping Zhang, Qing Bo Lu, Xiao Fei Wang, Jian Guo Hu, Eddie Oakes, Joseph V. Bonventre, Christopher B. Shields, Xiao Ming Xu

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39 Scopus citations

Abstract

Objective The objective of this study was to investigate whether cytosolic phospholipase A2 (cPLA2), an important isoform of PLA 2 that mediates the release of arachidonic acid, plays a role in the pathogenesis of spinal cord injury (SCI). Methods A combination of molecular, histological, immunohistochemical, and behavioral assessments were used to test whether blocking cPLA2 activation pharmacologically or genetically reduced cell death, protected spinal cord tissue, and improved behavioral recovery after a contusive SCI performed at the 10th thoracic level in adult mice. Results SCI significantly increased cPLA2 expression and activation. Activated cPLA2 was localized mainly in neurons and oligodendrocytes. Notably, the SCI-induced cPLA2 activation was mediated by the extracellular signal-regulated kinase signaling pathway. In vitro, activation of cPLA2 by ceramide-1-phosphate or A23187 induced spinal neuronal death, which was substantially reversed by arachidonyl trifluoromethyl ketone, a cPLA2 inhibitor. Remarkably, blocking cPLA2 pharmacologically at 30 minutes postinjury or genetically deleting cPLA2 in mice ameliorated motor deficits, and reduced cell loss and tissue damage after SCI. Interpretation cPLA2 may play a key role in the pathogenesis of SCI, at least in the C57BL/6 mouse, and as such could be an attractive therapeutic target for ameliorating secondary tissue damage and promoting recovery of function after SCI.

Original languageEnglish (US)
Pages (from-to)644-658
Number of pages15
JournalAnnals of Neurology
Volume75
Issue number5
DOIs
StatePublished - May 2014

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ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Liu, N. K., Deng, L. X., Zhang, Y. P., Lu, Q. B., Wang, X. F., Hu, J. G., Oakes, E., Bonventre, J. V., Shields, C. B., & Xu, X. M. (2014). Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury. Annals of Neurology, 75(5), 644-658. https://doi.org/10.1002/ana.24134