Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury
Copyright policy )Cytosolic phospholipase A2 protein as a novel therapeutic target for spinal cord injury
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. ANN NEUROL 2014;75:644–658
- Indiana University United States
- Brigham and Women's Faulkner Hospital United States
- Indiana University – Purdue University Indianapolis United States
- Harvard University United States
- Norton Healthcare United States
Enzymologic, Spinal Cord Injuries -- Enzymology, Male, Group IV Phospholipases A2 -- Deficiency, 610, Mice, Transgenic, Pilot Projects, Group IV Phospholipases A2 -- Antagonists & inhibitors, Inbred C57BL, Spinal Cord Injuries -- Genetics, Transgenic, Gene Expression Regulation, Enzymologic, Rats, Sprague-Dawley, Mice, Drug Delivery Systems -- Methods, Drug Delivery Systems, Nitriles, Butadienes, Animals, Enzyme Inhibitors, Research Articles, Injections, Spinal, Enzyme Activation -- Genetics, Mice, Knockout, Enzyme Inhibitors -- Administration & dosage, Group IV Phospholipases A2, Butadienes -- Administration & dosage, Rats, Enzyme Activation, Mice, Inbred C57BL, Gene Expression Regulation, Spinal Cord, Group IV Phospholipases A2 -- Genetics, Gene Targeting, Female
Enzymologic, Spinal Cord Injuries -- Enzymology, Male, Group IV Phospholipases A2 -- Deficiency, 610, Mice, Transgenic, Pilot Projects, Group IV Phospholipases A2 -- Antagonists & inhibitors, Inbred C57BL, Spinal Cord Injuries -- Genetics, Transgenic, Gene Expression Regulation, Enzymologic, Rats, Sprague-Dawley, Mice, Drug Delivery Systems -- Methods, Drug Delivery Systems, Nitriles, Butadienes, Animals, Enzyme Inhibitors, Research Articles, Injections, Spinal, Enzyme Activation -- Genetics, Mice, Knockout, Enzyme Inhibitors -- Administration & dosage, Group IV Phospholipases A2, Butadienes -- Administration & dosage, Rats, Enzyme Activation, Mice, Inbred C57BL, Gene Expression Regulation, Spinal Cord, Group IV Phospholipases A2 -- Genetics, Gene Targeting, Female
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