Stroke is a major public health problem in the U.S. and worldwide. It is defined as an area of brain damage, generally due to the sudden occlusion of an artery in or leading to the brain. Stroke can cause weakness, numbness, visual disturbance, speech difficulty, balance problems, and memory loss, among other symptoms. While good treatments exist to limit stroke in the first few hours after occurrence, few treatments exist to improve neurological recovery from deficits remaining after such acute treatments. Although physical, occupational, and speech therapy are useful, few drugs or other treatments have been identified that improve stroke recovery. We showed in previous studies that the intracerebral administration of fibroblast growth factor-2 (FGF- 2) enhanced neurological recovery after experimental stroke in rats, most likely through stimulation of neuronal sprouting and progenitor cell proliferation in brain. However, FGF-2 is a charged protein that is difficult t administer systemically as a drug. We have identified a family of 200 small molecules that we believe bind to the FGF-2/receptor (FGFR1) complex in such a way as to increase FGF-2 signal transduction. In preliminary studies, we showed that one of these molecules, STMX110, increases neurological recovery in a rat stroke model, when given intravenously at times starting up to 21 days after stroke. The proposed studies will further study the effects STMX110 after stroke in rats. Specifically, we will perform detailed dose-finding and time-window studies in mature male rats. In addition, proof of concept studies will be done in mature female rats, and aged male rats. We will also seek direct evidence that STMX110 binds to the FGF-2/FGFR1 receptor complex, and increases the effects of FGF-2 in the predicted manner. These studies will entail thermal stability assays, FGFR1 phosphorylation assays, and X-ray crystallography. We expect that these studies will ultimately pave the way for the development of STMX110 (or a related compound) as a drug to improve stroke recovery in humans.
Stroke is a leading public health problem in the U.S. and worldwide. Few treatments exist that can be given weeks or months after stroke to improve neurological recovery. We have identified a molecule, STMX110, that we believe may be useful in improving recovery after stroke. The proposed studies will pave the way for the full development of STMX110 (or a related molecule) as a stroke recovery-promoting drug.
