A new model to study compensatory mechanisms in MPTP-treated monkeys exhibiting recovery

Institut National de la Santé et de la Recherche Médicale, Unité 679, Paris F-75013, France.
Brain (Impact Factor: 9.2). 12/2007; 130(Pt 11):2898-914. DOI: 10.1093/brain/awm208
Source: PubMed


The cardinal symptoms in Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine is decreased by 60-80%. During the preclinical phase of PD, compensatory mechanisms are probably involved in delaying the appearance of motor symptoms. In a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of PD, a spontaneous recovery has been reported after initial intoxication suggesting that compensatory mechanisms are activated in this model as well. Assuming that mechanisms are similar in these phenomena, the study of recovery in monkeys following MPTP intoxication may enable identification of compensatory mechanisms involved in the preclinical phase of PD. In order to maximize the temporal similarity between PD and the MPTP model, we assessed a new progressive monkey model in which spontaneous recovery is expressed systematically and to characterize it based on (1) its behavioural features, and (2) the presence of compensatory mechanisms revealed by an immunohistological approach comparing dopaminergic and serotoninergic innervation between monkeys either exhibiting behavioural recovery or stable motor symptoms. This immunohistological study focused on the substantia nigra, striatum and pallidum, and their anatomical and functional subdivisions: sensorimotor, associative and limbic. The behavioural analysis revealed that with progressive MPTP intoxication motor symptoms were initially expressed in all monkeys. Observable recovery from these symptoms occurred in all monkeys (7/7) within 3-5 weeks after the last MPTP injection, and most exhibited a full recovery. In contrast, acute intoxication induced stable motor symptoms. Despite this obvious behavioural difference, immunohistological methods revealed that the loss of dopaminergic cell bodies in substantia nigra was substantial and similar in both MPTP-treated groups. However, quantification of fibres revealed that recovered monkeys displayed more dopaminergic and serotoninergic fibres than those with stable motor symptoms in sensorimotor and associative territories of striatum and more dopaminergic fibres in internal pallidum. This study provides a new model of PD where all monkeys expressed functional recovery from motor symptoms despite a large dopaminergic neuronal loss. The immunohistological results suggest that both dopamine and serotonin could be implicated in the compensatory mechanisms.

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Available from: Léon Tremblay, Oct 05, 2015
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    • " weekly by Kurlan motor scale which ranges from 0 to 29 ( Kurlan et al . , 1991 ) . 17 monkeys developed parkinsonian features with the first 1 – 2 MPTP injections . Five monkeys did not receive any further MPTP injection and exhibited progressive improvement until motor behavior had normalized ( score 0 – 1 ) and are labeled as recovered monkey ( Mounayar et al . , 2007 ) ."
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    ABSTRACT: Levodopa-induced dyskinesias (LIDs) are major complications in the pharmacological management of Parkinson's disease (PD). Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at: (i) characterizing N-methyl-D-aspartate (NMDA) receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs as well as in dyskinetic PD patients; and (ii) validating the potential therapeutic effect of a cell-permeable peptide (CPP) interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell-permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein postsynaptic density protein 95 (PSD-95) leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.
    Frontiers in Cellular Neuroscience 07/2015; 9:245. DOI:10.3389/fncel.2015.00245 · 4.29 Impact Factor
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    • "Concerning the late phase, following interruption of the MPTPtreatment , functional recovery has been characterized by increased TH protein-mRNA (in the ventral striatum and mecencephalon) and unchanged DAT protein-mRNA (in the striatum and ventral mecencephalon) (Rothblat et al., 2001). However, we identified higher in-vivo DAT values in the striatum of motor recovered compared to symptomatic cases, consistent with previous reports on post-mortem DAT levels (Blesa et al., 2012; Mounayar et al., 2007). "
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    ABSTRACT: The delayed appearance of motor symptoms in PD poses a crucial challenge for early detection of the disease. We measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [(11)C]PE2I in MPTP-treated macaque monkeys, thus establishing a detailed profile of the nigrostriatal DA status following MPTP intoxication and its relation to induced motor and non-motor symptoms. Clinical score and cognitive performance were followed throughout the study. We measured longitudinally in vivo the non-displaceable binding potential to DAT in premotor, motor-recovered (i.e. both non-symptomatic) and symptomatic MPTP-treated monkeys. Results show an unexpected and pronounced dissociation between clinical scores and [(11)C]PE2I-BPND during the premotor phase i.e. DAT binding in the striatum of premotor animals was increased around 20%. Importantly, this broad increase of DAT binding in the caudate, ventral striatum and anterior putamen was accompanied by i) deteriorated cognitive performance, showing a likely causal role of the observed hyperdopaminergic state (Cools, 2011; Cools and D'Esposito, 2011) and ii) an asymmetric decrease of DAT binding at a focal point of the posterior putamen, suggesting that increased DAT is one of the earliest, intrinsic compensatory mechanism. Following spontaneous recovery from motor deficits, DAT binding was greatly reduced as recently shown in-vivo with other radiotracers (Blesa et al., 2010, 2012). Finally, high clinical scores were correlated to considerably low levels of DAT only after the induction of a stable parkinsonian state. We additionally show that the only striatal region which was significantly correlated to the degree of motor impairments is the ventral striatum. Further research on this period should allow better understanding of DA compensation at premature stages of PD and potentially identify new diagnosis and therapeutic index.
    NeuroImage 08/2014; 102. DOI:10.1016/j.neuroimage.2014.07.059 · 6.36 Impact Factor
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    • "This supports previous reports of discordant changes in terminal fields versus nigral cell bodies in the nigrostriatal pathway in PD patients (Burke and O'Malley, 2013; Fuente-Fernandez et al., 2011; Kordower et al., 2013) and MPTP treated animals (German et al., 1996; Lavoie and Parent, 1991). Yet, these findings seem to differ from previous non-human primate PD studies that suggest terminal regeneration commences within 4 or 5 weeks in animals with partial lesions induced by MPTP as revealed by increased branching and diameter of some TH-ir fiber types (Song and Haber, 2000) or increased optical density measures of immunostaining and visual quantification of individual fibers (Mounayar et al., 2007). The differences between our findings and those from other groups may be due to the difference in monkey species, MPTP administration method, as well as the quantification method. "
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    ABSTRACT: A single unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into non-human primates causes injury to the nigrostriatal pathway including nigral cell bodies, axons and striatal terminal fields. In this model, motor parkinsonism correlates well with the loss of nigral dopaminergic cell bodies but only correlates with in vitro measures of nigrostriatal terminal fields when nigral cell loss does not exceed 50%. The goals of this study are to determine the relationship of motor parkinsonism with the degree of injury to nigrostriatal axons, as reflected by in vitro fiber length density measures, and compare in vivo with in vitro measures of striatal terminal fields. We determined axon integrity by measuring fiber length density with tyrosine hydroxylase (TH) immunohistology and dopamine transporter (DAT) density with DAT immunohistology. We then calculated the terminal arbor size and compared these measures with previously published data of quantified in vivo positron emission tomography (PET) measures of presynaptic dopaminergic neurons, autoradiographic measures of DAT and vesicular monoamine transporter type 2 (VMAT2), striatal dopamine, nigral cell counts, and parkinsonian motor ratings in the same animals. Our data demonstrate that in vivo and in vitro measures of striatal terminal fields correlate with each other regardless of the method of measurement. PET-based in vivo striatal measures accurately reflect in vitro measures of DAT and VMAT2. Terminal arbor size and other terminal field measures correlate with nigral TH immunoreactive (TH-ir) cell counts only when nigral TH-ir cell loss does not exceed 50%. Fiber length density was the only striatal measure that linearly correlated with motor ratings (Spearman: r=-0.81, p<0.001, n=16).
    Brain Research 05/2014; 1571. DOI:10.1016/j.brainres.2014.05.009 · 2.84 Impact Factor
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