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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    • "P ) toxicity . MPTP is a neurotoxin that causes the selective death of dopaminergic neurons and as a result , a decrease in the level of DA through the inhibition of mitochondrial energy metabolism ( Morfini et al . , 2007 ) . Humans and monkeys receiving MPTP produce the entire triad of Parkinsonian symptoms : bradykinesia , tremor and rigidity ( Mounayar et al . , 2007 ) . Monkeys in this study were assigned into different groups to develop mild or severe Parkinsonian symptoms by receiving two different MPTP intoxication protocols . The monkeys ' Parkinsonian symptoms were graded to estimate the degrees of impairment to the DA systems in the brain . Then they were tested for morphine CPP . The prefere"
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    ABSTRACT: It is well known that dopamine (DA) is critical for reward, but the precise role of DA in reward remains uncertain. The aim of this study was to determine what percentage of dopaminergic neurons in the primate brain is required for the expression of conditioned reward by measuring the performance of DA-deficient rhesus monkeys in a morphine-induced conditioned place preference (CPP) paradigm. Animals with mild Parkinsonian symptoms successfully developed and retained a morphine preference that was equivalent to control monkeys. However, these monkeys could not maintain the preference as well as controls when they retained severe Parkinsonian symptoms. On the other hand, monkeys initially in a severe Parkinsonian state developed a preference for morphine, but this preference was weaker than that of the controls. Histological results showed that the loss of dopaminergic neurons in monkeys that had severe Parkinsonian symptoms was about 80% in comparison to the control monkeys. All these data suggest that a severely impaired DA system alters rewarding-seeking behavior in non-human primates.
    Frontiers in Behavioral Neuroscience 11/2015; 9:273. DOI:10.3389/fnbeh.2015.00273 · 3.27 Impact Factor
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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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