Date on Master's Thesis/Doctoral Dissertation

7-2008

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Committee Chair

Xu, Xiao-Ming

Author's Keywords

Spinal cord injury; Tumor necrosis factor; Oligodendroglia; Phospholipase A2; Hydrogen peroxide

Subject

Spinal cord--Wounds and injuries--Treatment

Abstract

Spinal cord injury (SCI) can be divided into two distinct stages, an initial mechanical impact and a later "secondary injury" resulting from a cascade of cytokines triggering a spreading demyelination and apoptosis of neurons and glia within the spinal cord. It is believed that blockade of this "secondary injury" could improve functional and histological recovery following SCI. Here we propose that sPLA2 might be one of the crucial mediators of the secondary injury. To test this possibility we first elucidated that the mRNA and protein of several isozymes of sPLA2 are present in the rodent spinal cord and that the group II enzymes are upregulated following SCI with a peak expression at 4 hours. Next, we showed that injuring differentiated cultures of oligodendrocyte precursor cells with H2O2 or TNFa and IL-1ß induces sPLA2 expression and pharmacological inhibition with a sPLA2 inhibitor, S3319, creates partial reversal of this injury. We further showed that a nanogram injection of sPLA2 into the naÏve dorsolateral funiculus of the cervical spinal cord is sufficient to produce demyelination, axonopathy, and glial death as well as a dose dependent loss of function as measured by pellet retrieval. Finally we showed that inhibition of sPLA2 by either i.p. injections of S3319 or a frame shift mutation in the sPLA2-IIA gene creates functional improvements in overground locomotion and bladder function. The functional recovery correlates well with increased white matter sparing and oligodendrocyte numbers within in the spinal cord, increased axon numbers at the lesion epicenter, and decreased inflammation and lesion cavity volume. These findings suggest that sPLA2 may play an important role in secondary SCI and that its blockade could facilitate recovery following SCI.

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