MPTP produces a mosaic-like pattern of terminal degeneration in the caudate nucleus of dog

Wilson, James S.; Turner, Blair H.; Morrow, Gregory D.; Hartman, Paul J.

doi:10.1016/0006-8993(87)90857-2

Cited by 39 publications

(9 citation statements)

References 23 publications

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“…A compartmental pattern of nigrostriatal damage has been reported for MPTP-treated dogs, in which marked fiber degeneration was seen in the matrix but not in striosomes at 8-to 14-day survival times (22,23). Furthermore, after chronic MPTP treatment and extended (15-week) survival times, differential up-regulation of g opiate receptor ligand binding has been found in the striosomal system in monkeys (27).…”

Section: Discussionmentioning

confidence: 81%

“…We monitored monoamine uptake-site binding with [3H]mazindol as a postmortem marker for monoaminergic terminals (19). We looked for gradients of reduced [3H]mazindol binding, and we also used the binding distributions to determine whether dopaminecontaining fibers innervating the two main neurochemical compartments of the primate striatum, the striosomes and matrix (20,21), were differently affected as suggested for MPTP intoxication in dogs (22,23).…”

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confidence: 99%

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Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Moratalla

Quinn

DeLanney

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

134

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The meperidine analogue derivative l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal fiber damage and severe parkinsonism in humans and animals. MPTP-induced parkinsonism has been proposed as a model ofParkinson disease, but doubts have been raised about whether the patterns of nigrostriatal fiber loss in the two conditions are similar. We report here observations on [3H]mazindol monoamine (principally dopamine) uptake-site binding in the striatum of monkeys (Saimiri sciureus) exposed to low doses of MPTP. We show that this treatment can produce a pattern of nigrostriatal degeneration characteristic of that seen in Parkinson disease, in which there is greater depletion of dopaminergic markers in the putamen than in the caudate nucleus, especially posteriorly. Moreover, within the regions of diminished uptake-site binding in the MPTP-treated monkeys, there is differential preservation of binding in striosomes relative to the surrounding matrix. We suggest that both regional and striosome/matrix patterns of nigrostriatal depletion are key features of MPTP-induced neurodegeneration and that both patterns may provide dues to the mechanisms underlying neurodegeneration in Parkinson disease as well.Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a behavioral state in humans and other primates that strongly resembles idiopathic Parkinson disease (1, 2). MPTP-induced parkinsonism is highly responsive to L-dopa therapy, and in the brains of MPTP-treated primates (including one human) it has been shown that there is a concomitant loss of dopamine-containing neurons of the nigrostriatal tract, also a hallmark of pathology in Parkinson disease (3-8). These characteristics suggest that MPTPinduced parkinsonism may be similar to the idiopathic disease and have motivated a large body of work aimed at understanding the molecular mechanisms underlying MPTPinduced neurotoxicity (8-11).A key feature of the neurodegeneration in Parkinson disease is a characteristic gradient of dopamine loss in the striatum, with greater defects in the putamen than in the caudate nucleus and greater defects posteriorly than anteriorly in the putamen (4)(5)(6)(7)12). This pattern has not been found consistently in MPTP-treated monkeys (13-16). Instead, MPTP is capable of depleting dopaminergic markers from nearly the entire caudate nucleus as well as from the putamen, leaving only the ventral striatum (nucleus accumbens and olfactory tubercle) and the adjoining ventral caudoputamen relatively spared. This more global deficit has been interpreted as suggesting that MPTP-induced parkinsonism, for all its similarities to Parkinson disease, may not be a suitable model for the disease (14,15,17). This is a fundamentally important issue, because the MPTP model not only implicates environmental toxins as possible etiologic factors in Parkinson disease (11) but also, if correct, could greatly enhance efforts to understand the molecular basis of cell death in Parkinson disease (18).To address this issue ...

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Moratalla

Quinn

DeLanney

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

134

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“…MPTP has been shown to be a neurotoxin specific to dopaminergic neurons in the brain causing Parkinson's disease (PD) in humans [3]. It also caused parkinsonism in sub-human primates [4,5], cats [6], dogs [7], sheep [8] and mice [9,10]. Several species of mammals (such as rats and golden hamsters) have been shown to be resistant to the neurotoxin, which has been attributed to the inability of these animals to enzymatically convert MPTP into its active metabolite, 1-methyl-4-phenyl pyridinium ion (MPP + ) by the enzyme monoamine oxidase in the brain [11,12].…”

Section: Introductionmentioning

confidence: 99%

Apoptotic Mode of Cell Death in Substantia Nigra Following Intranigral Infusion of the Parkinsonian Neurotoxin, MPP+ in Sprague-Dawley Rats: Cellular, Molecular and Ultrastructural Evidences

et al. 2007

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The potent parkinsonian neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is known to cause dopaminergic neurodegeneration in nigrostriatal system. In the present study we investigated the nuclear morphology of cells in the substantia nigra pars compacta (SNpc) region of rats following unilateral intranigral infusion of the active metabolite, 1-methyl-4-phenyl pyridinium ion (MPP(+)), which resulted in a dose-dependent and prolonged dopamine depletion in the ipsilateral striatum. There appeared a substantial loss of tyrosine hydroxylase immunoreactive neurons in the SNpc that received the neurotoxin. Specific nuclear staining with Hoechst 33342 or acridine orange revealed bright pyknotic, shrunken, distorted nuclei and condensed chromatin with perinuclear nucleolus respectively following visualization with the former and latter dyes in the ipsilateral SNpc, as compared to the round, intact nuclei and centrally positioned nucleolus in the contralateral side. Ultrastructural details of the nucleus under transmission electron microscope confirmed distorted nuclear organization with shrunken or condensed nuclei and disrupted nuclear membrane. These features are typical of nucleus undergoing apoptosis, and suggest that MPP(+) causes dopaminergic neuronal death through an apoptotic mode. Typical laddering pattern of genomic DNA isolated from the ipsilateral SN in agarose gel electrophoresis conclusively established apoptosis following intranigral administration of MPP(+) in rats.

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“…Marshall (32) (34) and Turner et al (35) in dogs acutely exposed to MPITP. At 8-14 days after MPTP injection, these authors found intense degeneration of fibers in the extrastriosomal matrix with relative sparing of fibers in the striosomes.…”

Section: D2-selective Ligand Binding [Heightened In the Matrixmentioning

confidence: 99%

Dopamine uptake sites in the striatum are distributed differentially in striosome and matrix compartments.

Graybiel

Moratalla

1989

Proc. Natl. Acad. Sci. U.S.A.

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A major mechanism of neurotransmitter inactivation at catecholaminergic synapses is reuptake ofreleased transmitter at high-affinity uptake sites on presynaptic terminals. We have analyzed the anatomical distribution of siteselective ligand binding for dopamine uptake sites in the striatum of rat, cat, and monkey. We report here that desipramine-sensitive [31H]mazindol binding sites have highly heterogeneous distributions in the dorsal and the ventral striatum.

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MPTP produces a mosaic-like pattern of terminal degeneration in the caudate nucleus of dog

Cited by 39 publications

References 23 publications

Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Apoptotic Mode of Cell Death in Substantia Nigra Following Intranigral Infusion of the Parkinsonian Neurotoxin, MPP+ in Sprague-Dawley Rats: Cellular, Molecular and Ultrastructural Evidences

Dopamine uptake sites in the striatum are distributed differentially in striosome and matrix compartments.

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