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

Abstract

ObjectiveThe 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).MethodsA 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.ResultsSCI 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.InterpretationcPLA2 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.

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

“…cPLA 2 is an 85kDa protein enzyme that preferentially produces arachidonic acid (AA) by hydrolyzing the sn-2 position of glycerophospholipids [49]. Our lab has previously shown that cPLA 2 activation increased as early as 8 hours and peaked at 7 days post-SCI [22,21]. Activation of cPLA 2 by its activator, ceramide-1-phosphate or A23187, is sufficient to induce neuronal death, whereas cPLA 2 inhibition reduces cell loss in vitro [22].…”

“…Our lab has previously shown that cPLA 2 activation increased as early as 8 hours and peaked at 7 days post-SCI [22,21]. Activation of cPLA 2 by its activator, ceramide-1-phosphate or A23187, is sufficient to induce neuronal death, whereas cPLA 2 inhibition reduces cell loss in vitro [22]. Following acute SCI, cPLA 2 inhibition reduces inflammation, cell death, tissue damage and improves functional recovery [22].…”

“…Activation of cPLA 2 by its activator, ceramide-1-phosphate or A23187, is sufficient to induce neuronal death, whereas cPLA 2 inhibition reduces cell loss in vitro [22]. Following acute SCI, cPLA 2 inhibition reduces inflammation, cell death, tissue damage and improves functional recovery [22]. TNF-α or glutamate have also been shown to activate cPLA 2 in several nonneuronal cell types [50,51].…”

“…A main product of cPLA 2 is arachidonic acid (AA) [19], which can give rise to eicosanoids that mediate inflammation, necrosis and apoptosis [19,20]. Our prior research has demonstrated significant increases of PLA 2 activity and cPLA 2 expression following SCI [21,22]. cPLA 2 is highly expressed in neurons, axons and glial cells and peaked at day 1 in axons, day 3 in glial cells, and day 7 in neurons after SCI [21].…”

“…Activation of cPLA 2 is sufficient to induce spinal cord neuronal death in vitro. Genetic ablation of cPLA 2 reduces cell loss and tissue damage, and improves behavioral recovery after SCI [22].…”