Modeling Parkinson's disease in monkeys for translational studies, a critical analysis

• Type of Material: Article
• Authors: Lisa F. Potts, Emory University; Hao Wu, Emory University; Arun Singh, Emory University; Irene Marcilla, University of Navarra; Maria R. Luquin, University of Navarra; Stella Papa, Emory University
• Language: English
• Date: 2014-06-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Elsevier Inc. CC BY NC ND 4.0
• Final Published Version (URL): http://dx.doi.org/10.1016/j.expneurol.2013.09.014
• Title of Journal or Parent Work: Experimental Neurology
• ISSN: 0014-4886
• Volume: 256
• Start Page: 133
• End Page: 143
• Grant/Funding Information: This work was supported by NIH grants NS045962 and NS073994 (S.M.P.); Fondo de Investigaciones Sanitarias (FIS 00/0321) and the agreement between Foundation for Applied Medical Research (FIMA) and the U.T.E. project CIMA (M.R.L.), NIH grants RR025008 and ACTSI award UL1TR000454 (H.W.); and NCRR RR000165 and ORIP/OD OD011132 (Yerkes National Primate Research Center).
• Keywords: Model; Neurosciences; Dyskinesia; DOPAMINERGIC-NEURONS; MPTP-TREATED MONKEYS; Parkinson's disease; NERVOUS-SYSTEM; DOPA-INDUCED DYSKINESIA; MOTOR COMPLICATIONS; MPTP; Life Sciences & Biomedicine; Science & Technology; Non-human primate; SUBSTANTIA-NIGRA; NONHUMAN-PRIMATES; PRIMATE MODELS; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-LESIONED MACAQUE MODEL; Neurosciences & Neurology; NIGROSTRIATAL DEGENERATION
• Research Categories: Biology, Neuroscience; Biology, Biostatistics

Abstract

The non-human primate MPTP model of Parkinson's disease is an essential tool for translational studies. However, the currently used methodologies to produce parkinsonian monkeys do not follow unified criteria, and the applied models may often fall short of reproducing the characteristics of patients in clinical trials. Pooling of data from the parkinsonian monkeys produced in our Centers provided the opportunity to evaluate thoroughly the behavioral outcomes that may be considered for appropriate modeling in preclinical studies. We reviewed records from 108 macaques including rhesus and cynomolgus species used to model moderate to advanced parkinsonism with systemic MPTP treatment. The attained motor disability and the development of levodopa-induced dyskinesias, as primary outcomes, and the occurrence of clinical complications and instability of symptoms were all analyzed for correlations with the parameters of MPTP administration and for estimation of sample sizes. Results showed that frequently the MPTP-treated macaque can recapitulate the phenotype of patients entering clinical trials, but to produce this model consistently it is important to adapt the MPTP exposure tightly according to individual animal responses. For studies of reduced animal numbers it is also important to produce stable models, and stability of parkinsonism in macaques critically depends on reaching "marked" motor disability. The analyzed data also led to put forward recommendations for successfully producing the primate MPTP model of Parkinson's disease for translational studies.