Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease.
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.
Scheller
Dieter
D
SCHWARZ BIOSCIENCES GmbH, Alfred-Nobel Strasse 10, Monheim, Germany. dieter.scheller@schwarzpharma.com
Chan
Piu
P
Li
Qin
Q
Wu
Tao
T
Zhang
Renling
R
Guan
Le
L
Ravenscroft
Paula
P
Guigoni
Celine
C
Crossman
Alan R
AR
Hill
Michael
M
Bezard
Erwan
E
D000818:Animals; D001345:Autoradiography; D018491:Dopamine Agonists / Q000627:therapeutic use*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D020267:MPTP Poisoning / Q000000981:diagnostic imaging / Q000517:prevention & control*; D008252:Macaca fascicularis; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism; D015609:Organotechnetium Compounds; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000517:prevention & control*; D019275:Radiopharmaceuticals; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D015899:Tomography, Emission-Computed, Single-Photon; D014326:Tropanes; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D014326:Tropanes; C104196:technetium Tc 99m TRODAT-1; C047508:rotigotine; D014446:Tyrosine 3-Monooxygenase