Neuroprotective effects of the strychnine-insensitive glycine site NMDA antagonist (R)-HA-966 in an experimental model of Parkinson's disease.
The neuroprotective effects of (R)-HA-966 and (S)-HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) were examined in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced animal model of Parkinson's disease. Systemic pretreatment of C57 black mice with the strychnine-insensitive glycine site antagonist, (R)-HA-966 (3-30 mg/kg, i.p.), dose-dependently attenuated MPTP-induced depletion of striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC). Pretreatment with (R)-HA-966 also significantly protected the degeneration of tyrosine hydroxylase-positive neurons in the substantia nigra of mice treated with MPTP and alleviated the acute behavioral changes caused by the neurotoxin. In contrast, the other racemic form, (S)-HA-966, neither prevented the neurochemical depletions nor the neuronal injury caused by MPTP. These results indicate that excitatory mechanisms of neurodegeneration are involved in the pathophysiology of Parkinson's disease, and that strychnine-insensitive glycine site NMDA antagonists may serve as dopaminoprotective agents which intervene in the progressive neurodegeneration in Parkinson's disease.
Kanthasamy
A G
AG
Department of Neurology, College of Medicine, University of California Irvine, 92697, USA. akanthas@uci.edu
Kanthasamy
A
A
Matsumoto
R R
RR
Vu
T Q
TQ
Truong
D D
DD
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004351:Drug Resistance; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D018684:Glycine Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D011760:Pyrrolidinones / Q000627:therapeutic use*; D013237:Stereoisomerism; D013331:Strychnine / Q000494:pharmacology
D015259:Dopamine Agents; D018690:Excitatory Amino Acid Agonists; D018684:Glycine Agents; D018696:Neuroprotective Agents; D011760:Pyrrolidinones; D016202:N-Methylaspartate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C001369:1-hydroxy-3-amino-2-pyrrolidone; D013331:Strychnine; D004298:Dopamine