The overall aim of this study is to determine the beneficial effects of several therapeutic strategies to the histopathological and functional consequences of spinal cord injury (SCI) in rats, with a secondary goal of determining treatment effects on apoptotic pathways. There is a great need in the clinical arena to develop new therapeutic strategies to treat the acute injury. The proposed studies, therefore, will test whether the neurotrophic factor, fibroblast growth factor 2 (FGF-2), and significantly improve outcome following mild, moderate or severe levels of SCI. Special attention will be directed toward death processes in the pathogenesis. To this end, we will first define and characterize mechanisms of cell death following SCI using histopathological and molecular approaches to assess the characteristics features of apoptosis and necrosis. Once these studies are completed, therapeutic strategies directed toward this important pathophysiological process will be undertaken. FGF-2 treatment that has previously been shown to neuroprotective in models of stroke and brain trauma will then be conducted following SCI. Intraspinal infusion, a procedure that has been demonstrated to reduce contusion volume following SCI, will be used to determine whether FGF-2 leads to an improvement in functional outcome. Because FGF-2 may be improving outcome by apoptosis as well as hemodynamic processes, mechanistic experiments are proposed to determine the role of these important events in terms of neuroprotective approaches. Finally, the use of an anti-inflammatory cytokine and caspase inhibitors that inhibit inflammation will be attempted as a second distinctive therapeutic approach. IL-10 which has been shown in preliminary studies to provide a significant degree of neuroprotection will be tested. Mechanistic questions regarding how these cytokines improve outcome will involve clarifying whether this therapy targets the synthesis of pro-inflammatory cytokines and other mediators of inflammation. Taken together, these studies should provide new approaches to the therapeutic treatment of acute SCI, as well as clarifying mechanisms by which these agents provide their neuroprotective effects.
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