title: Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death.
abstract: After the initial mechanical insult of spinal cord injury (SCI), secondary mediators propagate a massive loss of oligodendrocytes. We previously showed that following SCI both the total phospholipase activity and cytosolic PLA(2)-IV alpha protein expression increased. However, the expression of secreted isoforms of PLA(2) (sPLA(2)) and their possible roles in oligodendrocyte death following SCI remained unclear. Here we report that mRNAs extracted 15 min, 4 h, 1 day, or 1 month after cervical SCI show marked upregulation of sPLA(2)-IIA and IIE at 4 h after injury. In contrast, SCI induced down regulation of sPLA(2)-X, and no change in sPLA(2)-IB, IIC, V, and XIIA expression. At the lesion site, sPLA(2)-IIA and IIE expression were localized to oligodendrocytes. Recombinant human sPLA(2)-IIA (0.01, 0.1, or 2 microM) induced a dose-dependent cytotoxicity in differentiated adult oligodendrocyte precursor cells but not primary astrocytes or Schwann cells in vitro. Most importantly, pretreatment with S3319, a sPLA(2)-IIA inhibitor, before a 30 min H(2)O(2) injury (1 or 10 mM) significantly reduced oligodendrocyte cell death at 48 h. Similarly, pretreatment with S3319 before injury with IL-1 beta and TNFalpha prevented cell death and loss of oligodendrocyte processes at 72 h. Collectively, these findings suggest that sPLA(2)-IIA and IIE are increased following SCI, that increased sPLA(2)-IIA can be cytotoxic to oligodendrocytes, and that in vitro blockade of sPLA(2) can create sparing of oligodendrocytes in two distinct injury models. Therefore, sPLA(2)-IIA may be an important mediator of oligodendrocyte death and a novel target for therapeutic intervention following SCI.
authors.affiliation: Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors.forename: W Lee
authors.initials: WL
authors.lastname: Titsworth
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Cheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Ke
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Deng
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Burckardt
authors.forename: Chris
authors.initials: C
authors.lastname: Pendleton
authors.forename: Nai-Kui
authors.initials: NK
authors.lastname: Liu
authors.forename: Hui
authors.initials: H
authors.lastname: Shao
authors.forename: Qi-Lin
authors.initials: QL
authors.lastname: Cao
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Xu
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002574:Cervical Vertebrae; D005260:Female; D054501:Group II Phospholipases A2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D016877:Oxidants / Q000633:toxicity; D054497:Phospholipases A2, Secretory / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000502:physiology; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D016877:Oxidants; D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; D006861:Hydrogen Peroxide; D054501:Group II Phospholipases A2; D054497:Phospholipases A2, Secretory