MPTP-induced parkinsonism in primates: pattern of striatal dopamine loss following acute and chronic administration

doi:10.1016/0304-3940(94)91094-4

Neuroscience Letters

Volume 175, Issues 1–2, 4 July 1994, Pages 121-125

https://doi.org/10.1016/0304-3940(94)91094-4 Get rights and content

Abstract

We analyzed the effect of two different schedules of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment on dopaminergic systems in the striatum of cynomolgus monkeys. Acute MPTP treatment produced a marked dopamine (DA) depletion, more severe in the caudate nucleus than in the putamen. Chronic MPTP induced a more pronounced reduction in DA levels, the putamen being slightly more affected than the caudate nucleus, in accord with immunohistochemical findings that showed a higher loss of tyrosine-hydroxylase positive neurons in ventral subpopulations of the substantia nigra pars compacta. A striking increment in the quotient DOPAC + HVA/DA was also observed in chronically but not in acutely treated monkeys, especially in the putamen. In chronically treated animals there was a nearly complete loss of DA in all subdivisions of the putamen. In the caudate nucleus, a rostrocaudal gradient of DA depletion was found, with a greater decrease in DA concentration in the rostral parts, especially in the dorsolateral portions The pattern of striatal DA loss characteristic of Parkinson's disease can be reproduced to a certain extent in MPTP-intoxicated primates.

References (19)

G.M. Alexander et al.
Changes in brain catechocalines and dopamine uptake sites at different stages of MPTP parkinsonism in monkeys
Brain Res.
(1992)
A.Y. Deutch et al.
Preferential vulnerability of A8 dopamine neurons in the primate to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Neurosci. Lett.
(1986)
J.D. Elsworth et al.
Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on catecholamines and metabolites in primate brain and CSF
Brain Res.
(1987)
J.D. Elsworth et al.
Symptomatic and asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates: biochemical changes in striatal regions
Neuroscience
(1989)
D.C. German et al.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian syndrome in macacca fascicularis: which midbrain dopaminergic neurons are lost?
Neuroscience
(1988)
P. Hantraye et al.
Stable parkinsonian syndrome and uneven loss of striatal dopamine fibres following chronic MPTP administration in baboons
Neuroscience
(1993)
M.T. Herrero et al.
GM-1 ganglioside promotes the recovery of surviving midbrain dopaminergic neurons in MPTP-treated monkeys
Neuroscience
(1993)
I. Pérez-Otaño et al.
Extensive loss of brain dopamine and serotonin induced by chronic administration of MPTP in the marmoset
Brain Res.
(1991)
Ch. Pifl et al.
The neurotoxin MPTP does not reproduce in the rhesus monkey the interregional pattern of striatal dopamine loss typical of human idiopathic Parkinson's disease
Neurosci. Lett.
(1988)

There are more references available in the full text version of this article.

Cited by (47)

Primate Models of Complications Related to Parkinson Disease Treatment
2015, Movement Disorders: Genetics and Models: Second Edition
More than 30 years since its introduction, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–lesioned nonhuman primate (MPTP-NHP), albeit refined and developed, remains the gold standard model of Parkinson disease (PD). Not only does the MPTP-NHP exhibit the core clinical features of PD, but long-term levodopa therapy results in the development of stable, reproducible involuntary movements (dyskinesia) that closely resemble the phenomenology of human dyskinesia. In particular, the model can differentiate between types of dyskinesia (chorea vs. dystonia). In addition, the duration of response to levodopa is shortened, resembling the wearing-off process. Certain nonmotor symptoms have been described more recently in MPTP-NHP models treated with levodopa, including neuropsychiatric symptoms and sleep disturbances. However, because of a lack of progression and clear modeling of the molecular pathology of idiopathic PD, shortcomings remain in the value of understanding the pathophysiology of chronic PD. The strength of the MPTP-NHP model lies in the face and predictive validity. Many therapeutics and surgical strategies for PD have been developed directly as a consequence of studies using this model. Future translational studies may be improved with homogenization of rating scales between MPTP-NHP and phase II studies and the development of its use in nonmotor aspects of PD.
Increased DAT binding in the early stage of the dopaminergic lesion: A longitudinal [<sup>11</sup>C]PE2I binding study in the MPTP-monkey
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Striatal [11C]PE2I-BPND values were decreased by 71.5 ± 9.7% once maximum recovery was reached (Supplementary Table 3). The ventral striatum was the most preserved structure (Fig. 4B, Supplementary Table 3), consistently with previous reports on pattern of nigrostriatal denervation both following chronic MPTP intoxication e.g. (Perez-Otano et al., 1994) and in PD patients (Gibb and Lees, 1991), but still showing 60.1 ± 14.2% decrease in DAT binding. After maximal motor recovery, the decrease of [11C]PE2I-BPND was large (Fig. 4D).
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 [¹¹C]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 [¹¹C]PE2I-BP_ND 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 mechanisms. 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.
Parkinson's disease-related modulation of functional connectivity associated with the striatum in the resting state in a nonhuman primate model
2014, Brain Research
Citation Excerpt :
This is inconsistent with idiopathic PD, in which there is greater depletion of dopamine markers in the posterior striatum than in the anterior sector (Kish et al., 1988). Some studies (Hantraye et al., 1993; Perez-Otano et al., 1994) found that chronic low doses of MPTP administration can replicate the neuropathological features typical of idiopathic PD, whereas other studies (Pifl et al., 1991; Snow et al., 2000; Ueki et al., 1989) also failed to detect such a phenomenon, which is consistent with our findings. Differences in dose and the total length of MPTP treatment as well as in the route of administration (intramuscular versus intravenous) may account for the discrepant results.
The goal of this study was to describe Parkinson׳s disease (PD)-related modulation of functional connectivity (FC) associated with the striatum in the resting state in a nonhuman primate model of early-stage PD. Weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (0.5 mg/kg body weight) were performed until parkinsonian motor symptoms developed in four macaques. After 13 weeks of MPTP treatment, all monkeys displayed parkinsonian symptoms. During the course of the experiment, each animal underwent four magnetic resonance imaging scans and four positron emission tomography (PET) scans with the vesicular monoamine transporter 2 (VMAT2)-selective ligand 9-[¹⁸F] fluoropropyl-(+)-dihydrotetrabenazine, performed prior to the beginning of MPTP administration as well as after 4, 9, and 13 MPTP injections. The FC profile of the striatum was evaluated using a seed voxel correlation approach and post hoc region of interest analysis on resting-state functional magnetic resonance imaging data. The PET images were subjected to region of interest analysis to examine brain regional reductions in VMAT2 density in the PD model. Significant reductions in the connectivity pattern of the striatal regions were observed: limbic striatum and left hippocampus; caudate nucleus/associative and brain regions, including the right pre-supplementary motor area and bilateral dorsolateral prefrontal cortex; putamen/associative region and left inferior temporal gyrus or right orbital and medial prefrontal cortex; and putamen/motor and cortical structures, including the right superior temporal gyrus and bilateral postcentral gyrus. Subsequent PET studies showed the progressive loss of striatal VMAT2 in the striatum with the presentation of parkinsonism. Significant differences between the specific uptake ratio reductions in each striatal subdivision were not found. By using a long-term, low-dose MPTP-lesioned nonhuman primate model, this study demonstrated PD-related decreased corticostriatal FC in a resting state; moreover, altered sensorimotor integration was also found in early-stage PD.
Mechanical stretch exacerbates the cell death in SH-SY5Y cells exposed to paraquat: Mitochondrial dysfunction and oxidative stress
2014, NeuroToxicology
Citation Excerpt :
Various environmental agents, especially pesticides, and factors leading to increased exposure to these chemicals (e.g. farming, well-water drinking and rural living) have been proposed as potential risk factors for PD (Freire and Koifman, 2012). In the 1980s, it was discovered that exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a substance structurally similar to the herbicide paraquat, caused chronic and severe parkinsonism in humans resulting in the degeneration of dopaminergic neurons (Perez-Otano et al., 1994). Paraquat is frequently used as a neurotoxicant in experimental PD studies and an increasing body of evidence supports the strong correlation between herbicide exposure and PD (Abdulwahid Arif and Ahmad Khan, 2010; Allen and Levy, 2013; Tanner et al., 2011).
Recent studies suggest that traumatic brain injury (TBI) and pesticide exposure increase the risk of Parkinson's disease (PD), but the molecular mechanisms involved remain unclear. Using an in vitro model of TBI, we evaluated the role of mitochondrial membrane potential (ΔΨm) and mitochondrial reactive oxygen species (ROS) induced by stretch on dopaminergic cell death upon paraquat exposure. Human dopaminergic neuroblastoma SH-SY5Y cells grown on silicone membrane were stretched at mild (25%) and moderate (50%) strain prior to paraquat exposure. We observed that moderate stretch (50% strain) increased the vulnerability of cells to paraquat demonstrated by the loss of plasma membrane integrity (propidium iodide-uptake) and decreased mitochondrial activity (MTT assay). Mitochondrial depolarization occurred immediately after stretch, while mitochondrial ROS increased rapidly and remained elevated for up to 4 h after the stretch injury. Intracellular glutathione (GSH) stores were also transiently decreased immediately after moderate stretch. Cells treated with paraquat, or moderate stretch exhibited negligible mitochondrial depolarization at 48 h post treatment, whereas in cells stretched prior to paraquat exposure, a significant mitochondrial depolarization occurred compared to samples exposed to either paraquat or stretch. Moderate stretch also increased mitochondrial ROS formation, as well as exacerbated intracellular GSH loss induced by paraquat. Overexpression of manganese superoxide dismutase (MnSOD) markedly diminished the deleterious effects of stretch in paraquat neurotoxicity. Our findings demonstrate that oxidative stress induced by mitochondrial dysfunction plays a critical role in the synergistic toxic effects of stretch (TBI) and pesticide exposure. Mitigation of oxidative stress via mitochondria-targeted antioxidants appears an attractive route for treatment of neurodegeneration mediated by TBI.
Interaction of caudate dopamine depletion and brain metabolic changes with cognitive dysfunction in early Parkinson's disease
2012, Neurobiology of Aging
Citation Excerpt :
Moreover, contralateral CN BP was strongly correlated with contralateral putaminal BP. These findings suggest that, at early disease stages, the CN is already involved in the disease process, as demonstrated by previous SPECT findings (Winogrodzka et al., 2003) and by PD animal models (Pérez-Otaño et al., 1994), in which a parallel loss of DA terminals in putamen and CN was observed, although initially and to a greater extent in the putamen. In this PD sample mild to moderate deficits in EF, STM, and LTM were observed.
Damage to nonmotor dopamine (DA)-mediated frontostriatal circuits has been proposed as the main pathophysiological basis of cognitive dysfunction in Parkinson's disease (PD). In the present study, 18 early nondemented drug naive PD patients were investigated, by dual-tracer N-ω-fluoropropyl-2β-carbomethoxy-3β-4-[123I]iodophenyl-nortropane ([123I]FP-CIT) single-photon emission computed tomography (SPECT)/[18F] fluoro-deoxyglucose (FDG) positron emission tomography (PET) imaging, to test whether an early and not yet treatment-modulated relation exists between cognitive functions, caudate nucleus (CN) DA impairment and brain metabolism (CMRglc) in associative frontostriatal circuits. Verbal fluency performance correlated with DA impairment in CN, and with CMRglc in dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Further, CMRglc in orbitofrontal cortex, DLPFC, and ACC was shown to be early modulated by the level of DA impairment in CN. The present study demonstrates in vivo the early functional disruption of nonmotor frontostriatal circuits in PD. The effect of CN DA impairment on DLPFC and ACC metabolism is proposed as a possible early pathophysiological and functional substrate for executive dysfunction in PD.
The MPTP-lesioned non-human primate models of Parkinson's disease. Past, present, and future
2010, Progress in Brain Research
Citation Excerpt :
Thus cortical and limbic dopamine (Perez-Otano et al., 1991) and VTA cell loss may occur (Mitchell et al., 1985; Rose et al., 1989), although to a much lesser extent than in the SNC. In contrast to human PD, the pattern of dopamine loss in the striatum is usually more uniform, rather than the preferential loss in the putamen (Perez-Otano et al., 1994; Pertwee and Wickens, 1991). A secondary effect of loss of striatal dopamine is a reduction in spine density, with up to 50% reduction in spines in both the caudate nucleus and putamen, with the sensorimotor post-commissural putamen being the most severely affected region for both dopamine depletion and spine loss (Villalba et al., 2009).
Non-human primate (NHP) models of Parkinson’s disease (PD) have been essential in understanding the pathophysiology and neural mechanisms underlying PD. The most common toxin employed, MPTP, produces a parkinsonian phenotype in NHPs that is very similar to human PD with excellent response to dopaminergic drugs and development of long-term motor complications. Over the past 25 years, MPTP-lesioned NHP models, using several species and a variety of MPTP administration regimens, have been used to understand disease pathophysiology, investigate several stages of the disease progression, from pre-symptomatic to advanced with motor complications, and apply knowledge gained to develop potential therapeutics. Many treatments in common use in PD patients were developed on the basis of studies in the MPTP model, in particular dopamine agonists, amantadine, and targeting the subthalamic nucleus for surgical treatment of PD. Continued development of novel therapies for PD will require improving methods of evaluating symptoms in NHPs to ease translation from NHP to patients with homogenized scales and endpoints. In addition, recent studies into non-motor symptoms of PD, especially in response to chronic treatment, is expanding the usefulness and impact of MPTP-lesioned NHP models. Despite these obvious successes, limitations still exist in the model, particularly when considering underlying mechanisms of disease progression; thus, it appears difficult to reliably use acute toxin administration to replicate a chronic progressive disorder and provide consistent evidence of Lewy-like bodies.

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^☆: This study was supported in part by a grant from Fundacion JALS (Bilbao, Spain).

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MPTP-induced parkinsonism in primates: pattern of striatal dopamine loss following acute and chronic administration☆

Abstract

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