Small Molecule Treatments to Enhance Stroke Recovery

DESCRIPTION provided by applicant 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 FGF enhanced neurological recovery after experimental stroke in rats most likely through stimulation of neuronal sprouting and progenitor cell proliferation in brain However FGF is a charged protein that is difficult t administer systemically as a drug We have identified a family of small molecules that we believe bind to the FGF receptor FGFR complex in such a way as to increase FGF signal transduction In preliminary studies we showed that one of these molecules STMX increases neurological recovery in a rat stroke model when given intravenously at times starting up to days after stroke The proposed studies will further study the effects STMX 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 STMX binds to the FGF FGFR receptor complex and increases the effects of FGF in the predicted manner These studies will entail thermal stability assays FGFR phosphorylation assays and X ray crystallography We expect that these studies will ultimately pave the way for the development of STMX or a related compound as a drug to improve stroke recovery in humans PUBLIC HEALTH RELEVANCE 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 STMX that we believe may be useful in improving recovery after stroke The proposed studies will pave the way for the full development of STMX or a related molecule as a stroke recovery promoting drug