NEUROTROPHIC ACTIONS OF FATTY ALCOHOL ANALOGS

NEURODEGENERATION OCCURS IN BRAIN TISSUE DURING THE COURSE OF SEVERAL NEUROLOGICAL DISORDERS, INCLUDING ALZHEIMER'S DISEASE AND HUNTINGTON'S DISEASE, AND FOLLOWING STROKE OR CARDIAC ARREST. PHARMACOLOGICAL INTERVENTION MAY REDUCE SUCH NEURODEGENERATION. HEXACOSANOL, A FATTY ALCOHOL, HAS BEEN SHOWN TO BE EFFECTIVE TOWARD CULTURED CEREBRAL CORTICAL NEURONS IN STIMULATING NEURITE OUTGROWTH AND INCREASING LEVELS OF NEURON-SPECIFIC ENZYMES. SIMILAR EFFECTS ELICITED IN VIVO COULD ENHANCE THE SURVIVAL OF BRAIN NEURONS OR STIMULATE THEIR GROWTH. THIS PROJECT WILL IDENTIFY FATTY ALCOHOL ANALOGS WITH NEUROTROPHIC ACTIVITIES FOR BRAIN NEURONS TOWARD THE ULTIMATE GOAL OF DEVELOPING THERAPEUTIC MODALITIES. PHASE I EFFORTS WILL IDENTIFY WHICH BRAIN NEURONS ARE SUPPORTED BY FATTY ALCOHOL ANALOGS AND DETERMINE IF THESE ANALOGS PROTECT CULTURED NEURONS FROM THE TOXIC EFFECTS OF EXCITATORY AMINO ACIDS AND HYPOXIA. THE ABILITY OF BIOLOGICALLY ACTIVE ANALOGS TO EXERT SIMILAR PROTECTIVE EFFECTS IN VIVO WILL THEN BE EXAMINED USING RODENT MODELS OF BRAIN NEURODEGENERATION. DURING PHASE II, ANALOGS THAT CAN CROSS THE BLOOD-BRAIN BARRIER WILL BE IDENTIFIED AND STRUCTURE-ACTIVITY STUDIES WILL BE COMPLETED THAT WILL ALLOW THE DESIGN AND SYNTHESIS OF MORE EFFECTIVE ANALOGS. THESE WILL BE TESTED IN RODENTS BEFORE BEING TESTED CLINICALLY IN HUMANS.