The final functional outcome of spinal cord injury (SCI) is the result of an interplay between secondary degenerative events and endogenous mechanisms of repair. We now know that the secondary injury process includes the induction of programmed cell death in both glia and neurons. We also know that there are substantial reparative events in the cord after injury that involve growth and trophic factors. Exciting new information on the stimulation of proliferating progenitor cells after injury to the CNS suggest that more repair may be possible than previously imagined. We have developed models of contusion spinal cord injury in rats that mimic some of the clinical features of SCI in man. Recovery occurs over time in the face of continuing apoptotic cell death. At the same time, ependymal zone cells as well as cells in the white proliferate and appear to contribute to repair at the lesion margins. In addition, new axonal growth can be seen entering the lesion area. Using these observations as a background, we will examine the effects of methylprednisolone (MP) and basic fibroblast growth factor (bFGF) on these cellular events after SCI. MP is the current Agold standard@ of clinical treatment of acute SCI, but its mechanisms of action are not fully understood. BFGF is a promising treatment for brain and spinal trauma that is likely to retard apoptosis and drive cellular proliferation of CNS progenitor cells. We will study recovery of function and the effects of MP and bFGF after both contusion and dorsal hemisection SCI using established behavior methods. We will examine the effect of these agents on apoptotic cell death of neurons and glia, and on cell proliferation and phenotypic expression. We will examine the effects of combination treatments on behavior and the regeneration of the corticospinal tract, which will be used a barometer of axonal growth in these two lesion types. The results are expected to provide further information on the biology of SCI as well as an assessment of potential therapies that could reach the clinic in a short time.
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