Neurotrophic factors appear to be crucial for the survival and potential regeneration of injured neurons. Injury of the peripheral nervous system results in the induction of a number of neurotrophic molecules. Less is known about the response of central nervous tissue to injury. We have examined levels of mRNA for three trophic factors, basic and acidic fibroblast growth factor (bFGF, aFGF), and nerve growth factor (NGF), after an incomplete thoracic contusive spinal cord injury (SCI). RNase protection assays showed a rapid increase (three-fold) in the content of bF6F mRNA by 6 hours that persisted for at least 7 days after SCI. The induction of bFGF was specific, as no change in the levels of aFGF or NGF mRNA were seen. These data support a speculative hypothesis that bFGF may play a role in the partial recovery of function seen following incomplete contusive spinal cord injury. We propose to test this hypothesis. We will determine whether bFGF protein levels are also increased after SCI by immunohistochemistry, Western blot analysis and proliferation assays. Moreover, we will determine the location and cell types in which bFGF mRNA and protein are induced with respect to the injury epicenter, by in situ hybridization and immunohistochemistry. We will test specific hypotheses that the induction of bFGF after SCI is important for a) neovascularization, as well as b) neuronal survival and c) the glial reaction, following SCI. We will investigate the potential pharmacological manipulation of bFGF induction with corticosteroids, and glutamate receptor antagonists, classes of drugs that have been shown capable of enhancing functional recovery after traumatic SCI. These studies offer promise in understanding the mechanisms leading to the induction of bFGF in the CNS, as well as a potential new therapeutic approach to SCI. On the basis of experimental and/or pharmacological manipulation of bFGF levels, we will then rigorously test the hypothesis that bFGF plays a significant role in the observed partial recovery of sensori-motor function after SCI. Lastly, we will begin to place the induction of bFGF in the context of the overall neurotrophic environment in the spinal cord after injury. by initiating studies on the induction of Brain. Derived Neurotrophic Factor (BDNF) after SCI. We expect that the results from this project should provide important insights into natural, endogenous, recovery mechanisms in the CNS that can in the future be therapeutically manipulated.
