Small Molecule Treatments to Enhance Neurological Recovery After Stroke

PROJECT SUMMARYStroke is a major public health problem in the U Sand worldwideIt is defined as an area of brain damagegenerally due to the sudden occlusion of an artery in or leading to the brainStroke can cause weaknessnumbnessvisual disturbancespeech difficultybalance problemsand memory lossamong other symptomsWhile good treatments exist to limit stroke in the first few hours after occurrencefew treatments exist to improve neurological recovery from deficits remaining after such acute treatmentsAlthough physicaloccupationaland speech therapy are usefulno new drugs have been approved that promote stroke recoveryWe showed in previous studies that the intracerebral administration of fibroblast growth factorFGFenhances neurological recovery after experimental stroke in ratsmost likely through stimulation of neuronal sprouting and progenitor cell proliferation in brainHoweverFGFis a charged protein that is difficult to administer systemically as a drugMore recentlywe have identified a small moleculeSTMXwhich binds to FGFcomplexed to its major receptor FGFRand increases biological signaling of this complexLike FGFSTMXenhances stroke recovery in ratsincluding adult males and femalesas well as aged ratsHoweverSTMXitself is not suitable as a drug candidatebecause of poor solubility and other factorsThe current proposal seeks to identify one or more druglike analogs of STMXand to subject the most promising of these to further detailed characterizationAnalogs of STMXwill be chemically generated and run through a complex eight stage in vitro and in vivo vetting process designed to select and characterize the most promising drug candidatesWe expect that the proposed studies will generate a singleleadcompound as well as backups that are suitable for further development as stroke recovery promoting drugs in humans NARRATIVEStroke is a major public health problem in the U Sand worldwideAlthough effective treatments are available to prevent stroke and to treat acute strokethere are no approved drug treatments that can be given to patients days to weeks after stroke to improve neurological recoveryWe have identified a small moleculeSTMXthat improves neurological recovery when given starting a day after stroke in ratsThe proposed studies seek to chemically optimize this molecule and to further develop the optimized compound toward an effective treatment that improves post stroke recovery in humans