Balanced, polyvalent antiglutamatergic action as a novel approach to efficacious

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DESCRIPTION (provided by applicant): Excessively activated ionotropic glutamate receptors of both the N-methyl-D-aspartate (NMDA) and (RS)-amino-3-hydroxy-5-methyl-4-isoxazolepropioinic acid (AMPA)/kainate subtypes initiate numerous events leading to neuronal damage in a wide range of pathophysiological states, including acute hypoxic-ischemic brain injury, epilepsy and many chronic neurodegenerative diseases. Also, glutamate is a major excitatory neurotransmitter that plays a critical role in normal brain physiology. Therefore it is not surprising that many previous highly selective and potent glutamate receptor antagonists, usually specific to NMDARs, failed clinical trials, primarily because of side effects they produced. These adverse effects may occur because of: 1) impairment of essential physiological function of NMDARs by NMDA antagonists; 2) intact excitotoxicity mediated by AMPA/kainate receptors; 3) increase in glutamate release caused by NMDA antagonists. Current study tests the novel concept that antiglutamatergic agents with polyvalent actions at pre and postsynaptic sites and moderate potency have the potential to overcome these limitations by producing efficacious neuroprotection still enabling a level of balanced glutamate receptor activity required for physiological brain functions and thus avoiding significant side effects. 3, 5-dibromo-Dtyrosine (3,5-DBr-D-Tyr), by depressing NMDA and AMPA/kainate receptors and glutamate release in combination with its antioxidant properties, may represent such agents. We will investigate the cellular mechanisms of 3, 5-DBr-D-Tyr action in neuronal cultures using patch-clamp, liquid chromatography/tandem mass spectrometry and glutamate uptake measurements. The neuroprotective properties of 3, 5-DBr-D-Tyr will be studied in vivo using a rat model of stroke caused by transient middle cerebral artery occlusion (MCAO). Microdialysis with capillary electrophoresis and laser-induced fluorescence detection will be used to elucidate the antiglutamatergic and antioxidant properties of 3, 5-DBr-D-Tyr. In order to access safety of 3, 5-DBr-D-Tyr, cardiovascular parameters, processing of sensorimotor information, renal function and histopathological changes in the brain of treated animals will be evaluated. Aim #1: To characterize the cellular mechanisms of 3, 5-DBr-D-Tyr action in the brain. Aim #2: To determine efficacy and safety of the neuroprotective action of 3, 5-DBr-D-Tyr in vivo in the rat transient MCAO model of stroke and to elucidate underlying mechanisms. PUBLIC HEALTH RELEVANCE: Glutamate receptors represent an obvious target for potential pharmaceutical agents aiming at ameliorating symptoms of a wide range of CNS disorders. Many previous highly selective and potent glutamate receptor antagonists failed clinical trials, primarily because of side effects they produced. This study tests the novel concept that antiglutamatergic agents with polyvalent actions and moderate potency have the potential to overcome these limitations by producing efficacious neuroprotection and still enabling a level of balanced glutamate receptor activity required for physiological brain functions and thus avoiding significant side effects.