Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease
Introduction
In contrast to other neurodegenerative conditions, symptomatic therapy exists for Parkinson's disease (PD). Unfortunately, there is no proven therapy to prevent or slow down the progressive neuronal cell death or to restore abnormally behaving neurons to a normal state (Fahn and Sulzer, 2004). There has been increasing interest in the development of drugs to modify the biochemical abnormalities that cause the neurodegeneration and thus alter the course of PD, either by retarding the rate of cell death or by restoring function to neurons that are likely to undergo degeneration (Dawson and Dawson, 2002). In this context, dopamine (DA) agonists have shown a particular promise. Not only do these drugs provide symptomatic relief of PD but they also appear to be associated with a significant decrease in the rate of motor complications and to be capable of protecting against some of the adverse consequences of levodopa use (for a review, see Olanow, 2004). Evidence based largely on experimental in vitro and in vivo rodent studies is emerging that DA agonists may have neuroprotective properties in addition to their symptomatic effects (for a review, see Le and Jankovic, 2001, Schapira, 2002). However, proof of neuroprotection in humans by DA agonists has been difficult. In ropinirole and pramipexole monotherapy studies positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively, have been used to assess the rate of progression of nigrostriatal dysfunction. Although the results suggested a beneficial effect (Marek et al., 2002, Whone et al., 2003), the methodologies and the results have been questioned (Morrish, 2003).
The present study aims at reconciling these experimental and clinical data by testing the protective property of the D3/D2/D1 receptor agonist rotigotine in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque model of PD that mimics the progression of the disease (Bezard et al., 2001, Bezard et al., 1997) using in vivo ([99mTc]-TRODAT-1 SPECT) and ex vivo (DA transporter (DAT) binding and tyrosine hydroxylase (TH) immunohistochemistry) endpoints.
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Housing and care
Experiments were carried out in accordance with European Communities Council Directive of 24 November 1986 (86/609/EEC) for care of laboratory animals. Experiments were conducted on seventeen drug naïve female cynomolgus monkeys (Macaca fascicularis, GuangXi Luxen Technology Co., Nanning, PR of China; mean ± SEM; 3.8 ± 0.1 years; 3.0 ± 0.2 kg). Animals were housed in individual primate cages (1.1 m × 0.8 m × 1 m) under controlled conditions of humidity (50 ± 5%), temperature (24 ± 1°C) and light (13 h
Evolution of symptoms
Rotigotine 2.5 mg/kg or vehicle (n = 4) was administered from day 8 of the intoxication protocol (Fig. 1A). The vehicle-treated animals displayed the classic progression of symptoms seen with this intoxication regimen (e.g., Bezard et al., 2001, Bezard et al., 2006, Meissner et al., 2003). Monkeys became increasingly bradykinetic adopting a flexed posture, with increased rigidity of the limbs and decreased vocalization. Their movements became less accurate, for example when reaching for fruit,
Discussion
The present results suggest that continuous administration the D3/D2/D1 receptor agonist rotigotine partially protects striatal DA terminals in a progressive MPTP-lesioned macaque model of PD that is supposed to recapitulate the progressive neurodegeneration of PD (Bezard et al., 2006, Meissner et al., 2004). The significant preservation of terminals as detectable by the autoradiography method is paralleled by the significant difference in parkinsonian disability scores, which persists after
Acknowledgments
We wish to thank L. Cardoit, R. Baishen, H. Li and J. Li for technical assistance and R. Jork for extensive discussions of the study protocol and carefully reading and commenting the manuscript. We also wish to thank especially P. Schwarz-Schuette, SCHWARZ PHARMA, for sponsoring this study.
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