NEUROPROTECTION BY NOVEL ANTAGONISTS AT THE NMDA RECEPTOR-CHANNEL ANDGLYCINE(B) SITES

Glutamate may act via an N-methyl-D-Aspartate (NMDA)-sensitive recepto r site to destroy cholinergic neurons within the nucleus basalis magno cellularis in age-associated neurodegenerative diseases. Multiple inte resting properties of the NMDA receptor are relevant to its excitotoxi c actions, e.g., glutamate is ineffective unless a glycine (gly) modul atory site is also occupied. Thus, the antagonism of glutamate recepto r-related toxicity by blockade of either the NMDA-sensitive recognitio n site or the gly binding site may therefore have therapeutic applicat ions. The current study investigated the ability of four novel noncomp etitive antagonists at these two sites: one NMDA open channel antagoni st (MRZ 2/579: 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride ), and three gly(B) receptor antagonists (MRZ 2/570: 8-bromo-4-hydroxy -1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline sal t; MRZ 2/57: 8-fluoro-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta ] quinoline-5-oxide choline; MRZ 2/576: o-4-hydroxy-1-oxo-1,2-dihydrop yridaziono[4,5-beta] quinoline-5-oxide choline) administered acutely, to provide neuroprotection from a NMDA receptor agonist within the nuc leus basalis magnocellularis of young rats. Injection of NMDA into the nucleus basalis magnocellularis significantly decreased cortical chol ine acetyltransferase activity. Acute administration (i.p.) of MRZ 2/5 79, 2/570, 2/571 and 2/576 provided significant neuroprotection from N MDA. (C) 1998 Elsevier Science B.V.