Phospholipase A<sub>2</sub>superfamily members play divergent roles after spinal cord injury

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  • Rubèn López‐Vales
    Center for Research in NeuroscienceResearch Institute of the McGill University Health Center Montreal Quebec Canada
  • Nader Ghasemlou
    Center for Research in NeuroscienceResearch Institute of the McGill University Health Center Montreal Quebec Canada
  • Adriana Redensek
    Center for Research in NeuroscienceResearch Institute of the McGill University Health Center Montreal Quebec Canada
  • Bradley J. Kerr
    Center for Research in NeuroscienceResearch Institute of the McGill University Health Center Montreal Quebec Canada
  • Efrosini Barbayianni
    Department of ChemistryUniversity of Athens, Panepistimiopolis Athens Greece
  • Georgia Antonopoulou
    Department of ChemistryUniversity of Athens, Panepistimiopolis Athens Greece
  • Constantinos Baskakis
    Department of ChemistryUniversity of Athens, Panepistimiopolis Athens Greece
  • Khizr I. Rathore
    Center for Research in NeuroscienceResearch Institute of the McGill University Health Center Montreal Quebec Canada
  • Violetta Constantinou‐Kokotou
    Chemical LaboratoriesAgricultural University of Athens Athens Greece
  • Daren Stephens
    Department of Chemistry and BiochemistrySchool of Medicine, University of California–San Diego La Jolla CA USA
  • Takao Shimizu
    Department of Biochemistry and Molecular BiologyFaculty of Medicine, University of Tokyo Tokyo Japan
  • Edward A. Dennis
    Department of Chemistry and BiochemistrySchool of Medicine, University of California–San Diego La Jolla CA USA
  • George Kokotos
    Department of ChemistryUniversity of Athens, Panepistimiopolis Athens Greece
  • Samuel David
    Center for Research in NeuroscienceResearch Institute of the McGill University Health Center Montreal Quebec Canada

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説明

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.

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