LY503430,a Novel alpha-Amino-3-hydroxy-5-methylisozazole-4-propionic Acid Receptor Potentiator with Functional,Neuroprotective and Neurotrophic Effects in Rodent Models of Parkinson's Disease

摘要

Glutamate is the major excitatory transmitter in the brain Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisozazole-4-propionic acid (AMPA)subtype of glutanate redeptors have led to the discovery of selective potent and systemicallyi active AMPA receptor ptoentiators These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes In the present study we first characterized a novel AMPA receptor potentiator (R)'-4[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-crboxylic acid native preparations in vitro and then evaluated the potential neuroprotec-tive efedts of the olecule in rodent models of Parkinson's disease Results indicated that submicromolar concentrations of LY503430 selective enhane dglutamate-induce calcium influx into human embryonic kiney 293 cells transfected with human GLU_A1 GLU_A2,or GLU_A4 AMPA receptors the molecule also potentaiate Ampa-mediated resoponses in native cortical hippocampla and substantia nigra neurone We also report here that LY503430 provided dose-dependent fuctional and histlogical protection in aminal mosels of Parkinson's disease THe neurotoxicity after nilateral infusin of 6-hydroxy-dopamine into either the substanita nigra or the triatum of rats and that after systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in micr were reduce Interestingly LY503430 also produced some increase in brain-derved neurotrophic factor in the substanitia nigra and a dose-dependent increases in growth associated protein-43 (GAP-43) expression in the stratum Therfore we ropose that AMPA receptor poteniators ofter the ptoential of a new disease modifying therapy for Parkinsonis sidsease.