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

Abstract

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 Ͼ 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 ⌬FosB 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.Degeneration of the dopaminergic cells in the substantia nigra (SN) in Parkinson's disease (PD) creates a dopamine (DA) deficiency state that is repleted by administering the DA precursor L-dihydroxyphenylalanine (L-DOPA). L-DOPA is effective in ameliorating the symptoms of bradykinesia, tremors, and muscular rigidity, but it suffers from complications such as induction of motor fluctuations and dyskinesias. As an alternative to L-DOPA, dopaminergic agonists have been developed. Agonists have several potential advantages over L-DOPA: 1) they do not require metabolism to an active form; 2) they do not compete with dietary amino acids for active transport across the intestinal epithelium; 3) agonists may have better reproducibility of the dose response and time action curves; and 4) unlike L-DOPA, agonists may not generate potentially toxic free radicals and may have antioxidant properties (Schapira and Olanow, 2003).DA receptors exist as five subtypes, each of which may have different functions based on dissimilar neuroanatomical expression and pharmacological properties. D 1 and D 2 receptors are abundant in the caudate and putamen, whereas D 3 receptors are expressed at lower levels in the basal ganglia (Emilien et al., 1999). The D 2 receptor may play a key role in the pathophysiology of motor function since it is up-regulated in the striatum in response to DA denervation (Gerfen et al., 1990;Gurevich and Joyce, 1999) as well as in human PD and

Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF

“…: Emborg et al, 2006; Kordower et al, 2000; Stephenson et al, 2005). Antibodies used include TH (1:20,000; Chemicon Inc., CA), GDNF (1:250; R&D Systems, Minneapolis, MN), lacZ (1:3,000; Novus Biologicals, Littleton, CO), GFAP (1:2,000; DakoCytomation, Glostrup, Denmark) and CD68 (1:3,000; DakoCytomation, Glostrup, Denmark).…”

Sumanirole, a Highly Dopamine D2-Selective Receptor Agonist: In Vitro and in Vivo Pharmacological Characterization and Efficacy in Animal Models of Parkinson's Disease

“…The studies in the MPTP-lesioned monkey suggest that sumanirole is efficacious in this model but are too limited to draw solid conclusions about the relative efficacy or the dyskinetic potential of this compound. The current issue of Journal of Pharmacology and Experimental Therapeutics reports results of a subsequent study in MPTP-treated monkeys in which sumanirole shows antiparkinsonian effects comparable with existing dopaminergic therapies without inducing dyskinesias using both behavioral and pathological assessments (Stephenson et al, 2005). Fig.…”

Autologous transplantation of GDNF-expressing mesenchymal stem cells protects against MPTP-induced damage in cynomolgus monkeys

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