Elsevier

Experimental Neurology

Volume 203, Issue 2, February 2007, Pages 415-422
Experimental Neurology

Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease

https://doi.org/10.1016/j.expneurol.2006.08.026Get rights and content

Abstract

Clinical DA agonist monotherapy trials, which used in vivo imaging of the DA transporter (DAT) to assess the rate of progression of nigrostriatal degeneration, have failed to demonstrate consistent evidence for neuroprotection. The present study aims at reconciling these experimental and clinical data by testing the protective property of the continuously delivered D3/D2/D1 dopamine receptor agonist rotigotine. Using a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned (MPTP) macaque model that mimics the progression of Parkinson's disease in vivo ([99mTc]-TRODAT-1 single photon emission computed tomography (SPECT)) and ex vivo ([125I]-nortropane DAT labelling) endpoints were evaluated. After 38 days of treatment followed by two weeks of washout, rotigotine-treated animals were significantly less parkinsonian than the vehicle-treated ones. Such behavioural difference is the consequence of a partial protection of the DA terminals as could be confirmed by ex vivo DAT labelling. However, the protection of nerve terminals was not detected using SPECT. The data suggest that rotigotine exerts partial protection but that conventional imaging would not be able to identify such protection.

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.

Section snippets

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.

References (47)

  • W. Meissner et al.

    Neuroprotective strategies for Parkinson's disease: conceptual limits of clinical trials and animal models

    Trends Pharmacol. Sci.

    (2004)
  • C. Prunier et al.

    Presymptomatic diagnosis of experimental parkinsonism with 123I-PE2I SPECT

    NeuroImage

    (2003)
  • M. Abercrombie

    Estimation of nuclear population from microtome sections

    Anat. Rec.

    (1946)
  • E.J. Benner et al.

    Therapeutic immunization protects dopaminergic neurons in a mouse model of Parkinson's disease

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • E. Bezard et al.

    Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of Parkinson's disease

    J. Neurosci.

    (2001)
  • E. Bezard et al.

    Enriched environment confers resistance to MPTP and cocaine: involvement of dopamine transporter and neurotrophic factors

    J. Neurosci.

    (2003)
  • E. Bezard et al.

    Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function

    Nat. Med.

    (2003)
  • J.M. Brotchie et al.

    Quantitative assessment of dyskinesias in subhuman primates

    Mov. Disord.

    (1999)
  • B. Connor et al.

    Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat

    Gene Ther.

    (1999)
  • P. Damier et al.

    Temporospatial progression of the loss of dopaminergic neurons in the substantia nigra in Parkinson's disease

    Mov. Disord.

    (1997)
  • P. Damier et al.

    The substantia nigra of the human brain—I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D-28K immunohistochemistry

    Brain

    (1999)
  • P. Damier et al.

    The substantia nigra of the human brain—II. Patterns of loss of dopamine-containing neurons in Parkinson's disease

    Brain

    (1999)
  • T.M. Dawson et al.

    Neuroprotective and neurorestorative strategies for Parkinson's disease

    Nat. Neurosci.

    (2002)
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