The effects of a selective dopamine D2 receptor agonist on behavioral and pathological outcome in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys.
In this study, we investigated antiparkinsonian activity of the novel, highly selective dopamine D(2) receptor agonist sumanirole compared with two clinically effective dopaminergic therapies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. Squirrel monkeys were rendered parkinsonian by chronic administration of MPTP and subsequently dosed with vehicle, L-DOPA plus carbidopa (L-DOPA), ropinirole, or sumanirole over a duration of 8 weeks. Antiparkinsonian effects measured with a parkinsonian primate rating scale (PPRS) showed that sumanirole elicited improved functional outcome compared with vehicle. The dopamine D2/D3 agonist ropinirole improved behavioral outcome similar to sumanirole, whereas L-DOPA treatment yielded the most significant symptomatic improvement. The relative rank of therapies that elicited normalization of PPRS was L-DOPA > sumanirole; ropinirole did not normalize PPRS in any of the treated monkeys. Dyskinesias were present with L-DOPA treatment but were not observed in sumanirole-, ropinirole-, or placebo-treated primates. Pathologically, all MPTP-treated animals displayed neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and reactive astrocytosis. Neurons immunoreactive with antibodies to the nuclear transcription factor DeltaFosB were most significantly increased in the striatum of L-DOPA-treated monkeys. These results suggest that sumanirole can exert antiparkinsonian effects similar to L-DOPA without the behavioral and morphological consequences of the latter.
Stephenson
Diane T
DT
Pfizer Global Research and Development, Groton, CT 06340, USA. diane.t.stephenson@pfizer.com
Meglasson
Martin D
MD
Connell
Mark A
MA
Childs
Mary A
MA
Hajos-Korcsok
Eva
E
Emborg
Marina E
ME
D000818:Animals; D001479:Basal Ganglia / Q000473:pathology; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015306:Biogenic Monoamines / Q000134:cerebrospinal fluid; D018491:Dopamine Agonists / Q000627:therapeutic use*; D007980:Levodopa / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D012453:Saimiri; D013378:Substantia Nigra / Q000473:pathology
D001562:Benzimidazoles; D015306:Biogenic Monoamines; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; C108539:U 95666E; D007980:Levodopa