Several drugs have been shown to reduce neurologic damage in a variety of stroke models by the critical pharmacologic actions of the therapies have not been detailed in most instances. The search for therapies to prevent or minimize ischemic central nervous system injury has been hindered by inadequate fundamental understanding of the mechanisms of damage. This has been caused, in part, by models that are not well designed for correlating biochemical, pharmacological, and neurological function studies. There have been substantial recent advances in identification of trophic factors. These are proteins that have many actions including involvement in repair of injuries to various parts of the body. They are also present in the central nervous system. Some appear necessary for survival of neuronal populations, and there is reason to suspect they are involved in the responses to central nervous system injury. Several of these factors stimulate protein kinases, which are families of enzymes that function as second messengers in this chain of events. Protein kinases have been the focus of numerous important investigations over the past few years because their actions seem responsible for the primary activities of many cell types, especially in the nervous system. We hypothesize that disturbances of protein phosphorylation are a major cause of the onset of irreversible ischemic neurologic damage. Furthermore, we think that trophic factors can modify central nervous system damage, at least partly by their actions on protein phosphorylation. For these studies, we will use a rabbit spinal cord ischemia model which produces highly reproducible lesions that are particularly valuable for biochemical studies. This model can also be used as a very sensitive bioassay system to allow us to test whether a form of therapy improves neurologic function. The proposed studies are intended to further define the molecular mechanisms causing ischemia induced loss of neurologic function, and techniques that may be useful for developing new ways to prevent such losses or restore function.
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