Protection Against N-methyl-D-aspartate Receptor-Mediated Neuronal Degeneration In Rat Brain by 7-chlorokynurenate and 3-amino-1-hydroxypyrrolid-2-one, Antagonists at The Allosteric Site for Glycine.
7-Chlorokynurenate (7-Cl KYNA) and 3-amino-1-hydroxypyrrolid-2-one (HA-966), two selective antagonists of the glycine site on the N-methyl-D-aspartate (NMDA) receptor, have been used to assess the involvement of this site in the neurodegeneration resulting from injection of excitotoxins in the rat brain. In the rat striatum, reductions in the enzymes choline acetyltransferase (CAT) and glutamate decarboxylase (GAD), occurring 7 days after a unilateral, intrastriatal injection of quinolinate (200 nmol), were prevented in a dose-dependent manner by intrastriatal administration of 7-Cl KYNA (10 - 50 nmol) and HA-966 (200 - 500 nmol) 1 h after the excitotoxin. In the rat hippocampus, degeneration of pyramidal and granule neurons caused by direct injection of quinolinate (60 nmol) was completely prevented by 7-Cl KYNA (50 nmol) and partially by HA-966 (500 nmol) injected intrahippocampally 1 h after the excitotoxin. In the rat striatum, 7-Cl KYNA (50 nmol) and HA-966 (500 nmol) also reduced neurotoxicity caused by intrastriatal injection of NMDA (200 nmol), but not that caused by the 'non-NMDA' receptor agonists DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate. The time course of protective effects of 7-Cl KYNA and HA-966 in the striatum was similar to that previously observed with the uncompetitive NMDA receptor antagonist MK-801, indicating that activation of the glycine site contributes to the delayed degeneration of neurons which occurs over the first 5 h following quinolinate injection. The neuroprotective effects of both 7-Cl KYNA and HA-966 in the rat striatum appear to be mediated via the glycine site on the NMDA receptor as they were completely reversed by D-serine, but not L-serine. These results indicate that activation of the glycine site is essential for the expression of the delayed degeneration of neurons resulting from intracerebral injection of an NMDA receptor agonist, a process which bears similarities to the delayed neurodegeneration which results from a period of cerebral ischaemia.
Foster
A. C.
AC
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK.
Willis
C. L.
CL
Tridgett
R.
R