Synergism of the AMPA-antagonist NBQX and the NMDA-antagonist CPP with L-dopa in models of Parkinson's disease.
Degeneration of dopaminergic nigrostriatal neurons in Parkinson's disease results in an overactivity of excitatory glutamatergic projections from the subthalamic nucleus to the output nuclei of the basal ganglia resulting in rigidity and akinesia. In theory pharmacological blockade of these overactive systems should improve parkinsonian symptomatology. The selective AMPA-antagonist NBQX and the competitive NMDA-antagonist CPP are not effective in animal models of Parkinson's disease when given alone but ameliorate parkinsonian symptomatology and stimulate locomotor activity when co-administered with a threshold dose of L-Dopa. These synergistic effects are seen in the MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmoset and the rat with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra. Therefore competitive NMDA and non-NMDA antagonists may offer a new therapeutic strategy for the treatment of Parkinson's disease.
Löschmann
P A
PA
Parkinson's Disease Society Experimental Research Laboratories, King's College, London, United Kingdom.
Lange
K W
KW
Kunow
M
M
Rettig
K J
KJ
Jähnig
P
P
Honoré
T
T
Turski
L
L
Wachtel
H
H
Jenner
P
P
Marsden
C D
CD
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002144:Callithrix; D004195:Disease Models, Animal; D004357:Drug Synergism; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000188:drug therapy* / Q000209:etiology; D010879:Piperazines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013378:Substantia Nigra / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D010879:Piperazines; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D007051:Ibotenic Acid; D007980:Levodopa; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D016627:Oxidopamine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine