Cytosolic Phospholipase A(2) Protein as a Novel Therapeutic Target for Spinal Cord Injury

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.