NEUROPROTECTIVE EFFECTS OF THE STRYCHNINE-INSENSITIVE GLYCINE SITE NMDA ANTAGONIST (R)-HA-966 IN AN EXPERIMENTAL-MODEL OF PARKINSONS-DISEASE

The neuroprotective effects of (R)-HA-966 and (S)-HA-966 (3-amino-1-hy droxy-2-pyrrolidinone) were examined in an MPTP ethyl-4-phenyl-1,2,3,6 -tetrahydropyridine)-induced animal model of Parkinson's disease. Syst emic pretreatment of C57 black mice with the strychnine-insensitive gl ycine site antagonist, (R)-HA-966 (3-30 mg/kg, i.p.), dose-dependently attenuated MPTP-induced depletion of striatal dopamine and 3,4-dihydr oxyphenylacetic acid (DOPAC). Pretreatment with (R)-HA-966 also signif icantly protected the degeneration of tyrosine hydroxylase-positive ne urons in the substantia nigra of mice treated with MPTP and alleviated the acute behavioral changes caused by the neurotoxin. In contrast, t he other racemic form, (S)-HA-966, neither prevented the neurochemical depletions nor the neuronal injury caused by MPTP. These results indi cate that excitatory mechanisms of neurodegeneration are involved in t he pathophysiology of Parkinson's disease, and that strychnine-insensi tive glycine site NMDA antagonists may serve as dopamino-protective ag ents which intervene in the progressive neurodegeneration in Parkinson 's disease. (C) 1997 Elsevier Science B.V.