The MPTP model: versatile contributions to the treatment of idiopathic Parkinson's disease

Bloem, Bastiaan R.; Irwin, Ian; Buruma, O. J. S.; Haan, J. A. Bierens de; Roos, Raymund A.C.; Tetrud, James W.; Langston, J. W.

doi:10.1016/0022-510x(90)90225-c

Cited by 150 publications

(72 citation statements)

References 90 publications

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“…30,31) MPTP causes a partial lesion of the substantia nigra and a significant reduction in striatal dopamine levels. 23.32) Drugs that are able to ameliorate MPTP-induced neuronal damage are considered to be neuroprotective.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Kaempferol against a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Mouse Model of Parkinson's Disease

Shen

2011

Biological & Pharmaceutical Bulletin

136

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Parkinson's disease (PD) is a progressive, age-related, neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor and gait disturbance 1) ; it occurs in 1-2% of the population over the age of 60 years.2) Typical neuropathologic features of the disease are dopaminergic neuron degeneration in the substantia nigra and the presence of eosinophilic intracytoplasmic inclusions (Lewy bodies) in the residual dopaminergic neurons. The most widely used mouse model of PD is produced by systemically administering the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).3) MPTP is converted by monoamine oxidase B (MAO-B) to 1-methyl-4-phenylpyridinium (MPP ϩ ), which is a neurotoxic metabolite and could block cellular respiration, promote reactive oxygen species (ROS) formation, and cause neuronal death. 4,5) Oxidative stress has been implicated either as the cause or as a consequence of the pathogenetic mechanisms responsible for neurodegenerative disease, including PD. Indeed, the brain is prone to producing ROS and oxidative stress, due to its high metabolic rate, combined with the high content of oxidizable molecules, such as dopamine and neuromelanin, whose metabolism generates ROS. [6][7][8] Superoxide dismutase (SOD) is one of the key enzymes that provide the first line of defense against pro-oxidants. Glutathione peroxidase (GSH-PX) is thought to play an important role in protecting membranes from damage due to lipid peroxidation. The major detoxification function of GSH-PX is the termination of radical chain propagation by quick reduction to yield further radicals.9) The levels of SOD and GSH-PX activity reflect the ability of organism to eliminate free radicals. Malondialdehyde (MDA) is the end product of lipid peroxidation, and its level could indirectly reflect the metabolic degree of oxygen radicals, thus serving as an index of oxidative damage. 10)Kaempferol is a prototype member of the flavonol subclass of flavonoids, which is widely found in tea, broccoli, grapefruit, brussel sprouts and apple and is claimed to have strong antioxidant and anti-inflammatory properties. 11)Kaempferol, can be given orally, is absorbed well and the bioavailability is proportionate to its dose.12) Kaempferol had earlier been shown to afford efficient neuroprotection against several apoptosis and necrosis-inducing insults, such as oxidized low-density lipoproteins 13,14) and L-glutamate. 15,16)Ishige et al. 15) demonstrated that kaempferol efficiently blocked the increase in ROS associated with the oxidative stress caused by glutamate in the mouse hippocampal cell line demonstrated that kaempferol exerted a strong and prolonged protective effect against rotenone toxicity, which was a classical toxin inducing PD. Striatal glutamatergic response of rat brain slices was also preserved by kaempferol, posing a more general protection of kaempferol in PD.Preliminary studies in our laboratory have shown that kaempferol derivatives prevent oxidative stress-induced cell death in a DJ-1-dependent manner in...

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Kaempferol against a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Mouse Model of Parkinson's Disease

Shen

2011

Biological & Pharmaceutical Bulletin

136

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“…MPTP is a causative agent for the Parkinson's disease model (1,2). Because MPP ϩ is an active metabolite of MPTP (3), it is important to understand the molecular mechanism of MPP ϩ in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…MG63 and HeLa S3 were maintained in DMEM (Invitrogen) supplemented with 10% heat-inactivated fetal calf serum (FCS) and antibiotics (100 IU/ml penicillin and 100 g/ml streptomycin) at 37°C in a humid atmosphere containing 5% CO 2 . PC12 cells were maintained in RPMI (Invitrogen) supplemented with 10% heat-inactivated fetal horse serum and 5% FCS antibiotics (100 IU/ml penicillin and 100 g/ml streptomycin) at 37°C in a humid atmosphere containing 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Proteasome-dependent Degradation of Cyclin D1 in 1-Methyl-4-phenylpyridinium Ion (MPP+)-induced Cell Cycle Arrest

Bai

Nakamura

Ueda

et al. 2004

Journal of Biological Chemistry

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1-Methyl-4-phenylpyridinium ion (MPP ؉), an active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, induces cell death and inhibition of cell proliferation in various cells. However, the mechanism whereby MPP ؉ inhibits cell proliferation is still unclear. In this study, we found that MPP ؉ suppressed the proliferation with accumulation in G 1 phase without inducing cell death in p53-deficient MG63 osteosarcoma cells. MPP ؉ induced hypophosphorylation of retinoblastoma protein and rapidly down-regulated the protein but not mRNA levels of cyclin D1 in MG63 cells. The down-regulation of cyclin D1 protein was suppressed by a proteasome inhibitor, MG132. The cyclin D1 down-regulation by MPP ؉ was also observed in p53-positive PC12, HeLa S3, and HeLa 0 cells, which are a subclone of HeLa S3 lacking mitochondrial DNA. Moreover, MPP ؉ dephosphorylated Akt in PC12 cells, which was rescued by the pretreatment with nerve growth factor. In addition, the pretreatment with nerve growth factor or lithium chloride, a glycogen synthase kinase-3␤ inhibitor, suppressed the cyclin D1 down-regulation caused by MPP ؉ . Our results demonstrate that MPP ؉ induces cell cycle arrest independently of its mitochondrial toxicity or the p53 status of the target cells, but rather through the proteasome-and phosphatidylinositol 3-Akt-glycogen synthase kinase-3␤-dependent cyclin D1 degradation.1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 1 is commonly used in animals to produce an experimental model of Parkinson's disease (1, 2). 1-Methyl-4-phenylpyridinium ion (MPP ϩ ) (3), an active metabolite of MPTP, induces cell death and inhibition of proliferation not only in neuronal cells but also in other types of cell (4 -7). The mechanisms whereby MPP ϩ induces the inhibition of membrane-bound NADH dehydrogenase in mitochondrial complex I (8 -10), ATP depletion (11), and production of the superoxide radicals (12, 13) have been studied extensively. However, the mechanisms involved in the inhibition of cell proliferation by MPP ϩ have rarely been examined.Progression and transition in the cell cycle of mammalian cells are governed by cyclin-dependent kinases (Cdks) whose activities are regulated by the binding of their regulatory subunits (called cyclins) or Cdk inhibitors (14). p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6, which have a direct role in the G 1 /S transition, but it is a poor inhibitor of other known Cdks (15-17). Cyclin proteolysis is essential for cell cycle progression (18,19). Cyclin D1 regulates G 1 arrest and the phosphorylation status of retinoblastoma protein (Rb). Cyclin D1 degradation is mediated by phosphorylation-triggered, ubiquitin-dependent proteolysis (20). Cyclin D1 proteolysis is regulated by glycogen synthase kinase-3␤ (GSK-3␤) (21), which is inactivated by a pathway that sequentially involves Ras, phosphatidylinositol 3-kinase (PI3K), and Akt (22).The aim of this study was to examine the mechanisms whereby MPP ϩ inhibits cell proliferation. We show here that MPP ϩ initiates an efficient p53-...

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“…In addition, the etiology of PD remains unknown, and this has impeded the development of effective therapies. However, insights into the pathogenesis of PD have been achieved experimentally by using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Bloem et al, 1990;Grunblatt et al, 2000). MPTP produces irreversible clinical, biochemical, and neuropathological effects that mimic those observed in idiopathic PD, including the dramatic neurodegeneration of the nigrostriatal dopaminergic pathway (Bloem et al, 1990;Grunblatt et al, 2000;Przedborski et al, 2000).…”

Section: Parkinson's Diseasementioning

confidence: 99%

The Significance of Vasoactive Intestinal Peptide in Immunomodulation

Delgado

Pozo²,

Ganea³

2004

Pharmacol Rev

372

319

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The MPTP model: versatile contributions to the treatment of idiopathic Parkinson's disease

Cited by 150 publications

References 90 publications

Neuroprotective Effect of Kaempferol against a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Mouse Model of Parkinson's Disease

Neuroprotective Effect of Kaempferol against a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Mouse Model of Parkinson's Disease

Proteasome-dependent Degradation of Cyclin D1 in 1-Methyl-4-phenylpyridinium Ion (MPP+)-induced Cell Cycle Arrest

The Significance of Vasoactive Intestinal Peptide in Immunomodulation

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