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The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine‐depleted rats and MPTP‐treated monkeys
Author(s) -
Klockgether Thomas,
Turski Lechoslaw,
Honoré Tage,
Zhang Zhiming,
Gash Don M.,
Kurlan Roger,
Greenamyre J. Timothy
Publication year - 1991
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410300513
Subject(s) - nbqx , ampa receptor , parkinsonism , pharmacology , neuroscience , glutamate receptor , monoamine neurotransmitter , chemistry , medicine , biology , receptor , serotonin , disease
Abstract Abnormally increased subthalamic nucleus output to the internal pallidal segment and the reticular part of the substantia nigra plays a critical pathophysiological role in the development of parkinsonism. Because synaptic transmission of subthalamic output is glutamatergic and mediated, in part, by the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA)subtype of glutamate receptor, AMPA receptor antagonists may posses antiparkinsonian properties. We report that in monoamine‐depleted rats, 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo(f)quinoxaline (NBQX) (Novo‐Nordisk, Copenhagen, Denmark)—a selective antagonist of the AMPA subtype of glutamate receptor—suppressed muscular rigidity but had no effect on akinesia. NBQX microinjected into the subthalamic nucleus, internal pallidal segment, and reticular part of the substantia nigra, but not into the laterodorsal neostriatum of the rats, stimulated locomotor activity and reduced muscular rigidity. In aged Rhesus monkeys with bilateral 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydrophyridine‐induced parkinsonism intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills. NBQX also potentiated the antiparkinsonian effects of L‐3,4‐dihydroxyphenylalanine in both rats and monkeys. Blockade of excitatory synaptic transmission by AMPA receptor antagonists may provide a new therapeutic strategy for Parkinson's disease (PD).