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 da...

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Published in:	Experimental neurology Vol. 203; no. 2; pp. 415 - 422
Main Authors:	Scheller, Dieter, Chan, Piu, Li, Qin, Wu, Tao, Zhang, Renling, Guan, Le, Ravenscroft, Paula, Guigoni, Celine, Crossman, Alan R., Hill, Michael, Bezard, Erwan
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Inc 01.02.2007 Elsevier
Subjects:	[125I]-nortropane [99mTc]-TRODAT Animals Autoradiography Biological and medical sciences Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Dopamine agonist Dopamine Agonists - therapeutic use Dopamine Plasma Membrane Transport Proteins - metabolism Dopamine transporter Female Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Immunohistochemistry Macaca Macaca fascicularis Medical sciences MPTP Poisoning - diagnostic imaging MPTP Poisoning - prevention & control Neostriatum - diagnostic imaging Neostriatum - metabolism Nervous system (semeiology, syndromes) Neurology Organotechnetium Compounds Parkinson Disease, Secondary - chemically induced Parkinson Disease, Secondary - diagnostic imaging Parkinson Disease, Secondary - prevention & control Radiopharmaceuticals SPECT Striatum Substantia nigra pars compacta Tetrahydronaphthalenes - therapeutic use Thiophenes - therapeutic use Tomography, Emission-Computed, Single-Photon Tropanes Tyrosine 3-Monooxygenase - metabolism ST SNc ROI SPECT [125I]-nortropane Striatum [99mTc]-TRODAT Autoradiography PD TH DAT Dopamine agonist l-DOPA Dopamine transporter MPTP Substantia nigra pars compacta DA PET CB Toxicity Central nervous system Monkey Parkinson disease D3 Dopamine receptor Prevention Ex vivo Primates Rotigotine Clinical trial Degenerative disease Degeneration Nervous system diseases Experimental data Dopamine Mimic D1 Dopamine receptor Single photon emission tomography Catecholamine Experimental study Photon Cerebral disorder Vertebrata Mammalia Locus niger D2 Dopamine receptor Treatment Animal Central nervous system disease Neurotransmitter Models Extrapyramidal syndrome
ISSN:	0014-4886
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Summary:	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.
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ISSN:	0014-4886
DOI:	10.1016/j.expneurol.2006.08.026