Phospholipase A2 superfamily members play divergent roles after spinal cord injury

FASEB J. 2011 Dec;25(12):4240-52. doi: 10.1096/fj.11-183186. Epub 2011 Aug 25.


Spinal cord injury (SCI) results in permanent loss of motor functions. A significant aspect of the tissue damage and functional loss may be preventable as it occurs, secondary to the trauma. We show that the phospholipase A(2) (PLA(2)) superfamily plays important roles in SCI. PLA(2) enzymes hydrolyze membrane glycerophospholipids to yield a free fatty acid and lysophospholipid. Some free fatty acids (arachidonic acid) give rise to eicosanoids that promote inflammation, while some lysophospholipids (lysophosphatidylcholine) cause demyelination. We show in a mouse model of SCI that two cytosolic forms [calcium-dependent PLA(2) group IVA (cPLA(2) GIVA) and calcium-independent PLA(2) group VIA (iPLA(2) GVIA)], and a secreted form [secreted PLA(2) group IIA (sPLA(2) GIIA)] are up-regulated. Using selective inhibitors and null mice, we show that these PLA(2)s play differing roles. cPLA(2) GIVA mediates protection, whereas sPLA(2) GIIA and, to a lesser extent, iPLA(2) GVIA are detrimental. Furthermore, completely blocking all three PLA(2)s worsens outcome, while the most beneficial effects are seen by partial inhibition of all three. The partial inhibitor enhances expression of cPLA(2) and mediates its beneficial effects via the prostaglandin EP1 receptor. These findings indicate that drugs that inhibit detrimental forms of PLA(2) (sPLA(2) and iPLA2) and up-regulate the protective form (cPLA2) may be useful for the treatment of SCI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Group II Phospholipases A2 / antagonists & inhibitors
  • Group II Phospholipases A2 / deficiency
  • Group II Phospholipases A2 / metabolism
  • Group IV Phospholipases A2 / antagonists & inhibitors
  • Group IV Phospholipases A2 / deficiency
  • Group IV Phospholipases A2 / genetics
  • Group IV Phospholipases A2 / metabolism
  • Group VI Phospholipases A2 / antagonists & inhibitors
  • Group VI Phospholipases A2 / deficiency
  • Group VI Phospholipases A2 / metabolism
  • Locomotion / drug effects
  • Locomotion / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Phospholipase A2 Inhibitors
  • Phospholipases A2 / classification
  • Phospholipases A2 / deficiency
  • Phospholipases A2 / metabolism*
  • Receptor Cross-Talk
  • Receptors, Prostaglandin E, EP1 Subtype / metabolism
  • Spinal Cord Injuries / drug therapy
  • Spinal Cord Injuries / enzymology*
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / physiopathology


  • Enzyme Inhibitors
  • Phospholipase A2 Inhibitors
  • Pla2g4a protein, mouse
  • Receptors, Prostaglandin E, EP1 Subtype
  • Group II Phospholipases A2
  • Group IV Phospholipases A2
  • Group VI Phospholipases A2
  • Phospholipases A2
  • Pla2g2a protein, mouse
  • Pla2g6 protein, mouse