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

Abstract:

OBJECTIVE:The objective of this study was to investigate whether cytosolic phospholipase A2 (cPLA2 ), an important isoform of PLA2 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.

journal_name

Ann Neurol

journal_title

Annals of neurology

authors

Liu NK,Deng LX,Zhang YP,Lu QB,Wang XF,Hu JG,Oakes E,Bonventre JV,Shields CB,Xu XM

doi

10.1002/ana.24134

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

644-58

issue

5

eissn

0364-5134

issn

1531-8249

journal_volume

75

pub_type

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