Dopaminergic Neurotoxicity of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine in Mice

Heikkila, Richard E.; Hess, Arthur; Duvoisin, Roger C.

doi:10.1126/science.6610213

Cited by 983 publications

(338 citation statements)

References 6 publications

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“…Furthermore, ten days after the insult, the absence of TH-positive cell bodies most likely represents a loss of cells, rather than a mere downregulation of tyrosine hydroxylase (Jackson-Lewis, et al, 1995). The finding of reduced TH-positive neurons in the myenteric ganglia in the absence of any effect on cholinergic or nitric oxide neurons confirms that MPTP is selectively toxic to dopamine neurons in the ENS, much as it is in the brain (Bove, et al, 2005, Heikkila, et al, 1984, Jackson-Lewis, et al, 1995). Our results suggest that nigral and enteric dopamine neurons exhibit grossly similar levels of sensitivity to parenteral MPTP, but the relative vulnerability between gut and brain dopamine neurons is difficult to assess.…”

Section: Discussionmentioning

confidence: 78%

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Anderson

Noorian

Taylor

et al. 2007

Experimental Neurology

205

196

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Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.

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Section: Discussionmentioning

confidence: 78%

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Anderson

Noorian

Taylor

et al. 2007

Experimental Neurology

205

196

View full text Add to dashboard Cite

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“…The dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP] is known to induce parkinsonism in hu-mans, primates, and mice ( [27,90,132,133]). MPTP is converted by astrocytes to the metabolite 1 methyl-4-phenylpyridinium [MPP + ], a substrate of the DA transporter ( [40,41]).…”

Section: Animal Models Of Parkinson's Diseasementioning

confidence: 99%

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Vegeto

Benedusi

Maggi

2008

Frontiers in Neuroendocrinology

273

206

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a b s t r a c tRecent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer's and Parkinson's Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia.

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“…review [1] we summarized how the sudden appearance of parkinsonism in relatively young patients in the San Francisco Bay Area in 1982 was traced to their use of a designer drug, 'new heroin', manufactured by a clandestine laboratory, and to the MPTP contained in defective batches of the street drug. Almost immediately following the reports that MPTP is neurotoxic to humans [2], subhuman primates md mice [3][4][5], eliciting damage to dopaminergic aeurons, it was shown that MPP + (1-methyl-4-phenylpyridinium) is the neurotoxic form and that it arises by 4-e oxidation of MPTP in brain mitochondria [6]. Proof that the enzyme responsible for processing MPTP is monoamine oxidase (MAO B) in the glial cells, of which it is an excellent substrate and that MAO A also oxidizes MPTP, albeit more slowly, was reported soon thereafter [7].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the neurotoxicity of MPTP

1990

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This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-l-l,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP + (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the Z-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP + and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP + and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP ÷, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.Monoamine oxidase; MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine); Neurotoxin; NADH dehydrogenase

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Dopaminergic Neurotoxicity of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine in Mice

Cited by 983 publications

References 6 publications

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

Mechanism of the neurotoxicity of MPTP

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