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Cytosolic phospholipase A 2 protein as a novel therapeutic target for spinal cord injury
Author(s) -
Liu NaiKui,
Deng LingXiao,
Zhang Yi Ping,
Lu QingBo,
Wang XiaoFei,
Hu JianGuo,
Oakes Eddie,
Bonventre Joseph V.,
Shields Christopher B.,
Xu XiaoMing
Publication year - 2014
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24134
Subject(s) - spinal cord , spinal cord injury , phospholipase a2 , cytosol , pathogenesis , medicine , pharmacology , microbiology and biotechnology , biology , neuroscience , biochemistry , enzyme
Objective The objective of this study was to investigate whether cytosolic phospholipase A 2 (cPLA 2 ), 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 cPLA 2 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 cPLA 2 expression and activation. Activated cPLA 2 was localized mainly in neurons and oligodendrocytes. Notably, the SCI‐induced cPLA 2 activation was mediated by the extracellular signal‐regulated kinase signaling pathway. In vitro, activation of cPLA 2 by ceramide‐1‐phosphate or A23187 induced spinal neuronal death, which was substantially reversed by arachidonyl trifluoromethyl ketone, a cPLA 2 inhibitor. Remarkably, blocking cPLA 2 pharmacologically at 30 minutes postinjury or genetically deleting cPLA 2 in mice ameliorated motor deficits, and reduced cell loss and tissue damage after SCI. Interpretation cPLA 2 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. ANN NEUROL 2014;75:644–658