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.
