Severe acute neurotoxicity reflects absolute intra-carotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine dose in non-human primates.
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ABSTRACT:
SUBMITTER: Norris SA
PROVIDER: S-EPMC9673039 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Severe acute neurotoxicity reflects absolute intra-carotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine dose in non-human primates.
Norris S A SA White Hcb H Tanenbaum A A Williams E L EL Cruchaga C C Tian L L Schmidt R E RE Perlmutter J S JS
Journal of neuroscience methods 20211109
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Project description:BACKGROUND: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson's disease (PD)-like neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) via its oxidized product, 1-methyl-4-phenylpyridinium (MPP+), which is transported by the dopamine (DA) transporter into DA nerve terminals. DA receptor subtype 3 (D3 receptor) participates in neurotransmitter transport, gene regulation in the DA system, physiological accommodation via G protein-coupled superfamily receptors and other physiological processes in the nervous system. This study investigated the possible correlation between D3 receptors and MPTP-induced neurotoxicity. A series of behavioral experiments and histological analyses were conducted in D3 receptor-deficient mice, using an MPTP-induced model of PD. RESULTS: After the fourth MPTP injection, wild-type animals that received 15 mg/kg per day displayed significant neurotoxin-related bradykinesia. D3 receptor-deficient mice displayed attenuated MPTP-induced locomotor activity changes. Consistent with the behavioral observations, further neurohistological assessment showed that MPTP-induced neuronal damage in the SNpc was reduced in D3 receptor-deficient mice. CONCLUSIONS: Our study indicates that the D3 receptor might be an essential molecule in MPTP-induced PD and provides a new molecular mechanism for MPTP neurotoxicity.
| S-EPMC3734004 | biostudies-literature
Project description:Parkinson's disease pathogenesis proceeds through several phases, culminating in the loss of dopaminergic neurons of the substantia nigra (SN). Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of oxidative SN injury is frequently used to study degeneration of dopaminergic neurons in mice and non-human primates, an understanding of the temporal sequence of molecular events from inhibition of mitochondrial complex 1 to neuronal cell death is limited. Here, microarray analysis and integrative data mining were used to uncover pathways implicated in the progression of changes in dopaminergic neurons after MPTP administration. This approach enabled the identification of small, yet consistently significant, changes in gene expression within the SN of MPTP-treated animals. Such an analysis disclosed dysregulation of genes in three main areas related to neuronal function: cytoskeletal stability and maintenance, synaptic integrity, and cell cycle and apoptosis. The discovery and validation of these alterations provide molecular evidence for an evolving cascade of injury, dysfunction, and cell death. Keywords: Parkinson's disease; MPTP; gene expression; microarray; cytoskeleton; mouse
2006-05-12 | GSE4788 | GEO
Project description:Sirtuins are NAD-dependent protein deacetylases that were shown to have protective effects against different age-related diseases. SIRT2 is a strong deacetylase that is highly expressed in brain. It has been associated with neurodegenerative diseases. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a dopaminergic neurotoxin that displays clinical features of Parkinson's Disease (PD). MPTP leads to the degeneration of nigrostriatal dopaminergic pathway after its systemic administration. Chronic administration of MPTP induces lesion via apoptosis. We show here that SIRT2 deacetylates Foxo3a, increases RNA and protein levels of Bim, and as a result enhances apoptosis in the MPTP model of PD. We also show that neurodegeneration induced by chronic MPTP regimen is prevented by genetic deletion of SIRT2 in mouse. Deletion of SIRT2 leads to the reduction of apoptosis due to an increase in acetylation of Foxo3a and a decrease in Bim levels. We demonstrate that SIRT2 deacetylates Foxo3a, activates Bim, and induces apoptosis only in MPP(+)-treated cells. Therefore, designing SIRT2 inhibitors might be helpful in developing effective treatments for PD.
| S-EPMC4127494 | biostudies-literature
Project description:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of a meperidine-like narcotic used by drug abusers as a heroin substitute, produces Parkinsonian symptoms in humans and primates. The nigrostriatal toxicity is not due to MPTP itself but to one or more oxidation products resulting from the action of monoamine oxidase (MAO) on this tertiary allylamine. Both MAO A and B catalyse the oxidation of MPTP to the 1-methyl-4-phenyl-2,3-dihydropyridinium species (MPDP+), which undergoes further oxidation to the fully aromatic 1-methyl-4-phenylpyridinium species (MPP+). These bio-oxidations are blocked by selective inhibitors of MAO A and B. Additionally, MPTP, MPDP+ and MPP+ are competitive inhibitors of MAO A and B. The A form of the enzyme is particularly sensitive to this type of reversible inhibition. Both MAO A and B also are irreversibly inactivated by MPTP and MPDP+, but not by MPP+. This inactivation obeys the characteristics of a mechanism-based or 'suicide' process. The inactivation, which is accompanied by the incorporation of radioactivity from methyl-labelled MPTP, is likely to result from covalent modification of the enzyme.
| S-EPMC1146756 | biostudies-other
Project description:Mutations in the parkin gene are currently thought to be the most common cause of recessive familial Parkinsonism. Parkin functions as an E3 ligase to regulate protein turnover, and its function in mitochondrial quality control has been reported recently. Overexpression of parkin has been found to prevent neuronal degeneration under various conditions both in vivo and in vitro. Here, we generated a transgenic mouse model in which expression of wild type parkin was driven by neuron-specific enolase (NSE) promoter. We reported that both young and old parkin transgenic mice exhibited less reduction of striatal TH protein and number of TH positive neurons in the substantia nigra induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP), compared to wild type littermates. MPTP-induced mitochondrial impairment in the substantia nigra was improved in young parkin transgenic mice. Decreased striatal ?-synuclein was demonstrated in old parkin transgenic mice. These results provide reliable evidence from the transgenic mouse model for parkin that overexpression of parkin may attenuate dopaminergic neurodegeneration induced by MPTP through protection of mitochondria and reduction of ?-synuclein in the nigrostriatal pathway.
| S-EPMC3390003 | biostudies-literature
Project description:Acute intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal neurodegeneration that reflects Parkinson's disease (PD) pathobiology. The model is commonly used for rodent studies of PD pathogenesis and diagnostics and for developmental therapeutics. However, tests of motor function in MPTP-intoxicated mice have yielded mixed results. This unmet need reflects, in part, lesion severity, animal variability, and the overall test sensitivity and specificity. In attempts to standardize rodent motor function and behavioral tests, mice were trained on the rotarod or habituated in an open field test chamber, and baseline performance measurements were collected prior to MPTP intoxication. One week following MPTP intoxication, motor function and behavior were assessed and baseline measurements applied to post-MPTP measurements with normalization to PBS controls. Rotarod and open field tests assessed in this manner demonstrated significant differences between MPTP- and saline-treated mice, while tests of neuromuscular strength and endurance did not. We conclude that the rotarod and open field tests provide reliable measures of motor function for MPTP-intoxicated mice.
| S-EPMC3392900 | biostudies-literature
Project description:Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of protein inclusions and the loss of dopaminergic neurons. Transcranial direct current stimulation (tDCS) is a non-invasive brain-stimulating technique that has demonstrated promising results in clinical studies of PD. Despite accumulating evidence indicating that tDCS exerts a protective effect, the mechanism underlying its activity remains unknown. In the present study, we first investigated the neuroprotective effect of tDCS in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and then evaluated the effect of tDCS on the autophagy pathway. tDCS improved behavioral alterations, increased tyrosine hydroxylase protein levels and suppressed α-synuclein protein levels in MPTP-treated mice. MPTP-treated mice subjected to tDCS also had lower levels of autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 and AMP-activated protein kinase, and higher levels of mechanistic target of rapamycin and p62. In addition, the protein levels of phosphoinositide 3-kinase and brain-derived neurotrophic factor were higher, and the levels of unc-51-like kinase 1 were lower in MPTP-treated mice subjected to tDCS. Our findings suggest that tDCS protected against MPTP-induced PD in a mouse model by modulating autophagy.
| S-EPMC6181991 | biostudies-literature
Project description:Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both inflammatory processes and oxidative stress may contribute to MPTP- and PD-related neurodegeneration. However, whether inflammation may cause oxidative damage in MPTP and PD is unknown. Here we show that NADPH-oxidase, the main reactive oxygen species (ROS)-producing enzyme during inflammation, is up-regulated in SNpc of human PD and MPTP mice. These changes coincide with the local production of ROS, microglial activation, and DA neuronal loss seen after MPTP injections. Mutant mice defective in NADPH-oxidase exhibit less SNpc DA neuronal loss and protein oxidation than their WT littermates after MPTP injections. We show that extracellular ROS are a main determinant in inflammation-mediated DA neurotoxicity in the MPTP model of PD. This study supports a critical role for NADPH-oxidase in the pathogenesis of PD and suggests that targeting this enzyme or enhancing extracellular antioxidants may provide novel therapies for PD.
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Project description:Parkinson's disease (PD) is a chronic neurodegenerative disease. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for PD. Drugs originally developed for T2DM treatment such as liraglutide have shown neuroprotective effects in mouse models of PD. Cholecystokinin (CCK) is a peptide hormone with growth factor properties. Here, we demonstrate the neuroprotective effects of the (pGLu)-(Gln)-CCK8 analogue in an acute PD mouse model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of CCK analogue (50 nmol/kg ip.) for 14 days treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. The CCK analogue administration also restored tyrosine hydroxylase (TH) positive dopaminergic neurons number and synapse number (synaptophysin levels) in the substantia nigra pars compacta (SNpc). The CCK analogue decreased glia activation and neuroinflammation in the SNpc, and regulated autophagy dysfunction induced by MPTP. CCK analogue protected against mitochondrial damage and ER stress, and also decreased the ratio of apoptosis signaling molecules Bax/Bcl-2. Importantly, the CCK analogue improved the decrease of p-CREBS133 growth factor signaling in the SNpc. Therefore, the CCK analogue promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB pathway that also inhibits apoptosis and regulates autophagy impairment. The present results indicate that CCK analogue shows a promising potential for the treatment of PD.
| S-EPMC8964967 | biostudies-literature
Project description:Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's disease mouse model, we investigated protein expression changes associated with the action of electroacupuncture (EA) in the mouse striatum. Twelve-week-old male C57BL/6 mice were injected intraperitoneally with 30 mg/kg of MPTP at 24-h intervals for 5 days, and the 100-Hz EA stimulation was performed at GB34 and GB39 once a day for 12 days consecutively from the first injection. With the EA, the MPTP-induced dopaminergic neuronal destruction was reduced. Of the 13 proteins that were differentially expressed between control and MPTP treated mice, cytosolic malate dehydrogenase, munc18-1, and hydroxyacylglutathione hydrolase, which were increased by MPTP, and cytochrome c oxidase subunit Vb, which was decreased by MPTP, were restored to the level of the saline group after EA treatment. These proteins are likely related to cellular metabolism. Altogether, we propose that the EA may exert neuroprotective effects in mice striatum through reducing MPTP-induced toxicity such as oxidative stress.
| S-EPMC10717007 | biostudies-literature