The parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP): a technical review of its utility and safety

Przedborski, Serge; Jackson‐Lewis, Vernice; Naini, Ali; Jakowec, Michael W.; Petzinger, Giselle M.; Miller, Renee M.; Akram, Muhammad

doi:10.1046/j.1471-4159.2001.00183.x

Cited by 447 publications

(288 citation statements)

References 31 publications

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“…The first group was perfused and brains were used for immunohistochemistry, whereas the second group of mice were killed, and brains were quickly removed, dissected (midbrain, striatum, cerebellum, and cortex), snap-frozen on dry ice, and stored at Ϫ80°C for Western blot, immunoprecipitation, and reverse transcriptase-PCR analysis. MPTP use and safety precautions were as described (19).…”

Section: Methodsmentioning

confidence: 99%

Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Vila

Jackson‐Lewis

Vukosavic

et al. 2001

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

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330

253

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons in the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Here, we show that the proapoptotic protein Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neuronal apoptosis. In adult mice, there is an up-regulation of Bax in the SNpc after MPTP administration and a decrease in Bcl-2. These changes parallel MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking Bax are significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that Bax plays a critical role in the MPTP neurotoxic process and suggests that targeting Bax may provide protective benefit in the treatment of Parkinson's disease. P arkinson's disease (PD) is a common neurodegenerative disorder whose cardinal clinical features include tremor, slowness of movement, stiffness, and postural instability (1). These disabling symptoms are primarily due to a profound deficit in striatal dopamine content that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the consequent loss of their projecting nerve fibers in the striatum (2, 3). Although several approved drugs do alleviate PD symptoms, their chronic use often is associated with debilitating side effects (4), and none seem to dampen the progression of the disease. Moreover, the development of effective neuroprotective therapies is impeded by our limited knowledge of the mechanism by which SNpc dopaminergic neurons die in PD. Thus far, however, significant insights into the pathogenesis of PD have been achieved by the use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which replicates in humans and nonhuman primates a severe and irreversible PD-like syndrome (5). In several mammalian species, MPTP reproduces most of the biochemical and pathological hallmarks of PD, including the dramatic degeneration of dopaminergic neurons (5).Mounting evidence indicates that highly regulated cell deathassociated molecular pathways could participate in the relentless demise of neurons in degenerative diseases (6, 7), including PD (8). In keeping with this, Bax (9) has emerged as a pro-cell death driving force within the central decision point constituted by the Bcl-2 family that modulates the activation of downstream effectors of cell death such as caspases (7). It is also clear that Bax is required for the death of several types of neurons in the peripheral and central nervous systems during both normal development and pathological situations (10-18). In light of its critical role within the programmed cell death machinery and its importance in neuronal death, Bax appears as a particularly appealing target for therapeutic interventions aimed at hampering neurodegeneration. Consistent with a potential pivotal role for Bax in SNpc neuronal death, here we show that Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neu...

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Section: Methodsmentioning

confidence: 99%

Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Vila

Jackson‐Lewis

Vukosavic

et al. 2001

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

Self Cite

330

253

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“…Control mice received saline according to the same time and dosage schedules. MPTP was handled in accordance with the guidelines reported by Przedborski et al (2001).…”

Section: Methodsmentioning

confidence: 99%

Caspase-11 Mediates Inflammatory Dopaminergic Cell Death in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson's Disease

Furuya¹,

Hayakawa²,

Yamada³

et al. 2004

J. Neurosci.

132

108

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The present study was designed to elucidate the inflammatory and apoptotic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a model of Parkinson's disease. Our results showed that mutant mice lacking the caspase-11 gene were significantly more resistant to the effects of acute treatment with MPTP than their wild-type mice. Thus, the neurotoxicity of MPTP seems to be mediated by the induction of both mitochondrial dysfunction and free radical generation. Previously, we showed that overexpression of the Apaf-1 dominant-negative inhibitor inhibited the mitochondrial apoptotic cascade in chronic MPTP treatment but not in acute MPTP treatment. The present results indicate that MPTP neurotoxicity may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade.

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“…Mice were pretreated with LBT-3627 (Longevity Biotech, Inc., Philadelphia, PA, USA), a VIPR2 agonist, at intraperitoneal dosages of 15 μg or 45 μg daily for 5 days prior to MPTP intoxication. On the sixth day, mice received 4 subcutaneous injections of vehicle [Dulbecco's phosphate-buffered saline (DPBS), 10 ml/kg body weight] or MPTP-HCl (SigmaAldrich, St. Louis, MO, USA) at 16 mg MPTP (free base)/ kg body weight in DPBS, with each injection given every 2 h. MPTP safety precautions were followed according to published safety and handling protocol [26,27]. All animal procedures used in this report were approved by the Institutional Animal Care and Use Committee of the University of Nebraska Medical Center and were in agreement with the guidelines set by the National Institutes of Health.…”

Section: Animals Drug Treatment and Mptp Intoxicationsmentioning

confidence: 99%

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

et al. 2016

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Neuroprotective immunity is defined by transformation of T-cell polarity for therapeutic gain. For neurodegenerative disorders and specifically for Parkinson's disease (PD), granulocyte-macrophage colony stimulating factor or vasoactive intestinal peptide receptor 2 (VIPR2) agonists elicit robust anti-inflammatory microglial responses leading to neuronal sparing in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. While neurotherapeutic potential was demonstrated for PD, there remain inherent limitations in translating these inventions from the laboratory to patients. One obstacle in translating such novel neurotherapeutics centers on the availability of suitable noninvasive methods to track disease progression and therapeutic efficacy. To this end, we developed manganese-enhanced magnetic resonance imaging (MEMRI) assays as a way to track a linkage between glial activation and VIPR2 agonist (LBT-3627)-induced neuroprotective immunity for MPTP-induced nigrostriatal degeneration. Notably, LBT-3627-treated, MPTP-intoxicated mice show reduced MEMRI brain signal intensities. These changes paralleled reduced astrogliosis and resulted in sparing of nigral tyrosine hydroxylase neurons. Most importantly, the data suggest that MEMRI can be developed as a biomarker tool to monitor neurotherapeutic responses that are relevant to common neurodegenerative disorders used to improve disease outcomes.

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The parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP): a technical review of its utility and safety

Cited by 447 publications

References 31 publications

Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

Caspase-11 Mediates Inflammatory Dopaminergic Cell Death in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson's Disease

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

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