NEUROPROTECTIVE ANTAGONISTS OF KAINATE NEUROTOXICITY

PATHOLOGICAL OVERSTIMULATION OF RECEPTORS FOR THE NEUROTRANSMITTER L-GLUTAMATE IS BELIEVED TO CONTRIBUTE TO THE DEATH OR DEGENERATION OF NERVE CELLS THAT OCCURS IN MANYACUTE AND CHRONIC NEUROLOGICAL DISORDERS. THE GOAL OF THIS PROJECT IS TO DEVELOP A DRUG TREATMENT WHICH WILL LIMIT NEURONAL DAMAGE SUBSEQUENT TO EXCITOTOXIC STIMULATION OF THEKAINATE SUBCLASS OF GLUTAMATE RECEPTORS. EVIDENCE FROM ANIMAL STUDIES SUGGESTS THAT SUCH AGENTS MAY BE SINGULARLY EFFECTIVE IN PREVENTING THE DELAYED NEURONAL DEGENERATION THAT OCCURS FOLLOWING GLOBAL CEREBRAL ISCHEMIA. THE INTENT IS TO TEST A LARGE NUMBER OF COMPOUNDS FOR THEIR ABILITY TO INHIBIT SPECIFIC KAINATE-STIMULATED 45-CA++UPTAKE INTO CULTURED RAT CORTICAL NEURONS. RADIOLIGAND BINDING AND ELECTROPHYSIOLOGICAL STUDIES WILL BE USED TO DEFINE THE MECHANISM OF ACTION OF ACTIVE COMPOUNDS. PROMISING MOLECULES WILL BE TESTED IN AN IN VITRO MODEL OF KAINATE NEUROTOXICITY AND AN IN VIVO MODEL OF GLOBAL CEREBRAL ISCHEMIA. THE APPROACH IS DESIGNED TO IDENTIFY COMPOUNDS THAT ACT THROUGH A NUMBER OF MECHANISMS IN ADDITION TO COMPETITIVE INHIBITION AT THE KAINATE RECEPTOR'SGLUTAMATE RECOGNITION SITE. THE FOCUS WILL BE ON MOLECULES THAT MAY ACT BY BLOCKING THE ION CHANNEL ASSOCIATED WITH THEKAINATE RECEPTOR; THESE WOULD CONSTITUTE A COMPLETELY NOVEL CLASS OF PHARMACOLOGICAL AGENTS. PATHOLOGICAL OVERSTIMULATION OF RECEPTORS FOR THE NEUROTRANSMITTER L-GLUTAMATE IS BELIEVED TO CONTRIBUTE TO THE DEATH OR DEGENERATION OF NERVE CELLS THAT OCCURS IN MANYACUTE AND CHRONIC NEUROLOGICAL DISORDERS. THE GOAL OF THIS PROJECT IS TO DEVELOP A DRUG TREATMENT WHICH WILL LIMIT NEURONAL DAMAGE SUBSEQUENT TO EXCITOTOXIC STIMULATION OF THEKAINATE SUBCLASS OF GLUTAMATE RECEPTORS. EVIDENCE FROM ANIMAL STUDIES SUGGESTS THAT SUCH AGENTS MAY BE SINGULARLY EFFECTIVE IN PREVENTING THE DELAYED NEURONAL DEGENERATION THAT OCCURS FOLLOWING GLOBAL CEREBRAL ISCHEMIA. THE INTENT IS TO TEST A LARGE NUMBER OF COMPOUNDS FOR THEIR ABILITY TO INHIBIT SPECIFIC KAINATE-STIMULATED 45-CA++UPTAKE INTO CULTURED RAT CORTICAL NEURONS. RADIOLIGAND BINDING AND ELECTROPHYSIOLOGICAL STUDIES WILL BE USED TO DEFINE THE MECHANISM OF ACTION OF ACTIVE COMPOUNDS. PROMISING MOLECULES WILL BE TESTED IN AN IN VITRO MODEL OF KAINATE NEUROTOXICITY AND AN IN VIVO MODEL OF GLOBAL CEREBRAL ISCHEMIA. THE APPROACH IS DESIGNED TO IDENTIFY COMPOUNDS THAT ACT THROUGH A NUMBER OF MECHANISMS IN ADDITION TO COMPETITIVE INHIBITION AT THE KAINATE RECEPTOR'SGLUTAMATE RECOGNITION SITE. THE FOCUS WILL BE ON MOLECULES THAT MAY ACT BY BLOCKING THE ION CHANNEL ASSOCIATED WITH THEKAINATE RECEPTOR; THESE WOULD CONSTITUTE A COMPLETELY NOVEL CLASS OF PHARMACOLOGICAL AGENTS.