The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety (original) (raw)
MPTP-induced mouse model of Parkinson’s disease: A promising direction of therapeutic strategies
Bosnian Journal of Basic Medical Sciences, 2020
Amongst the popular animal models of Parkinson’s disease (PD) commonly used in researches are those that employ neurotoxins, especially the 1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). MPTP neurotoxin exerts its neurotoxicity by causing a barrage of insults such as oxidative stress, mitochondrial apoptosis, inflammation, excitotoxicity, and formation of inclusion bodies acting singly and in concert. All of this ultimately leads to dopaminergic neuron damage in substantia nigra pars compacta and striatum. The selective neurotoxicity induced by MPTP in the nigrostriatal dopaminergic neuron of the mouse brain brought a new dawn in our perspectives about PD. For decades now MPTP-induced mouse model of PD has become the gold standard in PD research despite its shortcoming in fully recapitulating PD symptomatology. It has the advantage of easy practicability, affordability, less ethical consideration, and more clinical correlation over the other toxin models of PD. The model h...
Toxin-induced models of Parkinson’s disease
NeuroRX, 2005
Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.
MPTP-induced mouse model of Parkinson’s disease: A promising direction for therapeutic strategies
Bosn J Basic Med Sci, 2020
Among the popular animal models of Parkinson’s disease (PD) commonly used in research are those that employ neurotoxins, especially 1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). This neurotoxin exerts it neurotoxicity by causing a barrage of insults, such as oxidative stress, mitochondrial apoptosis, inflammation, excitotoxicity, and formation of inclusion bodies acting singly and in concert, ultimately leading to dopaminergic neuronal damage in the substantia nigra pars compacta and striatum. The selective neurotoxicity induced by MPTP in the nigrostriatal dopaminergic neurons of the mouse brain has led to new perspectives on PD. For decades, the MPTP-induced mouse model of PD has been the gold standard in PD research even though it does not fully recapitulate PD symptomatology, but it does have the advantages of simplicity, practicability, affordability, and fewer ethical considerations and greater clinical correlation than those of other toxin models of PD. The model h...
Chemical Research in Toxicology, 2003
Reactive oxygen species (ROS) and reactive nitrogen species (RNS), particularly peroxynitrite, have been implicated as key participants in the dopaminergic neurotoxicity of 1-methyl-4phenylpyridinium (MPP +). However, on the basis of available information, it is not clear whether the MPP +-induced overproduction of ROS and RNS occurs in the intraneuronal and/ or extracellular compartment. Early steps in the neurotoxic mechanism evoked by MPP + include a profound dopaminergic energy impairment, which mediates a massive release of dopamine (DA), glutathione (GSH), and cysteine (CySH). In the event that MPP + mediates extracellular generation of ROS (such as superoxide and/or hydroxyl radicals) and/or peroxynitrite, released DA, GSH, and CySH should be oxidized forming thioethers of DA and disulfides. Using microdialysis experiments in which MPP + was perfused into the striatum of awake rats, the present study was unable to detect the presence of such biomarkers of extracellular ROS and/ or RNS generation. However, MPP + induced a transient, concentration-dependent rise of extracellular L-3,4-dihydroxyphenylalanine (L-DOPA), identified on the basis of dialysate analysis using several HPLC methods and its conversion to DA by purified L-DOPA decarboxylase (DDC). Methamphetamine (30 mg/kg, i.p.) similarly caused a significant but transient rise of L-DOPA in the rat striatum. Antioxidants such as salicylate and mannitol had no effect on the MPP +-mediated elevation of extracellular L-DOPA, suggesting that it is not formed by nonenzymatic hydroxylation of L-tyrosine by ROS or RNS. Rather, in vivo, but not in vitro, MPP + caused rapid inhibition of DDC, which appears to result in intraneuronal accumulation and subsequent release of L-DOPA. Because L-DOPA can mediate L-glutamate release, as well as be an excitotoxin, the possibility is raised that L-DOPA may play a role in the dopaminergic neurotoxicity of MPP + .
Neurotoxin models and treatments of Parkinson’s disease
International journal of health sciences
Parkinson’s disease (PD) is a prevalent neurological illness that manifests itself sporadically. The destruction of dopaminergic neuronal cells in the substantia nigra is the primary cause of PD. The cause of PD is unknown, while its pathogenesis is becoming to be recognized as a complex cascade of harmful elements. The majority of insights regarding PD pathogenesis reported evidence of experimental PD models, particularly those caused by neurotoxins. Although many natural and synthetic chemicals have negative effects on neuronal cells of the dopaminergic region, only a few are employed in living animal studies to mimic some of the symptoms of PD. Therefore, more studies are required to better understand the causes of PD and select better neurotoxin models in animals. In this review, we discussed the treatment drugs and animal induced model (neurotoxin model) including MPTP, rotenone,6-hydroxydopamine (6-OHDA), manganese, and paraquat for Parkinson’s disease. We also discussed the n...
Experimental Neurology, 2006
Many studies have shown that deficits in olfactory and cognitive functions precede the classical motor symptoms seen in Parkinson's disease (PD) and that olfactory testing may contribute to the early diagnosis of this disorder. Although the primary cause of PD is still unknown, epidemiological studies have revealed that its incidence is increased in consequence of exposure to certain environmental toxins. In the present study, we demonstrated that rats treated with intranasal infusion of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at low concentrations (0.1 mg/nostril) suffered progressive impairments in olfactory, cognitive and motor functions that were assessed with the olfactory discrimination, Morris water maze and open field tests, respectively. Moreover, intranasal administration of MPTP reduced the expression of the enzyme tyrosine hydroxylase in the olfactory bulb and substantia nigra of rats, resulting in a significant reduction of dopamine concentration in the olfactory bulb, prefrontal cortex and striatum, but not in the hippocampus. These results reinforce the notion that the olfactory system represents a particularly sensitive route for the transport of neurotoxins into the central nervous system that may be related to the etiology of PD. In addition, the time course of the olfactory, cognitive and motor impairments verified in rats treated intranasally with MPTP, which appears to be correlated with different stages of the human PD, suggest that the MPTP intranasal model in rats may provide new insights into the underlying mechanisms of PD pathogenesis.
Toxin-Induced Parkinson’s Disease Models
Neuro – Open Journal, 2017
The Topic "Toxin-Induced Parkinson's Disease Models' includes articles on experimental neurotoxic chemicals models of Parkinson's Disease (PD). The model toxicants with differing chemical structures recapitulate PD owning to their action on multiple molecular targets. These reports have provided with deeper understanding on the neurodegenerative events associated with the progressive disease. Several toxin-based models are developed in an attempt to experimentally mimic dopaminergic neurodegeneration, oxidative stress, cytoplasmic inclusions, proteasome dysfunction, altered protein trafficking, calcium overload and potentially mapping the events in the PD pathology. This spectrum includes research reports and reviews that discuss neurotoxin-based models (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-OHDA, rotenone, paraquat) that have greatly contributed to unravel the key mechanisms of neuronal cell death. In relevance to PD in humans, toxin-induced PD models have provided for observable behavioral deficits (motor and non-motor features). Moreover, the etiologic specific insights gained into the disease with the chemical modelling of PD has aided to screen/develop novel therapies.
Neuroscience, 1993
The progressive degeneration of dopamine neurons observed in idiopathic Parkinson's disease was mimicked by injecting low doses of I-methyl-4-phenyl-1,2,3,6_tetrahydropyridine (MPTP) to baboons, on a chronic basis. Five Papio papio baboons were treated on two different regimens (chronic intravenous administration at weekly intervals for 20-21 months or, daily MPTP treatment for five days followed five to six months later by chronic weekly injections for 5-21.5 months). All animals were assessed for motor symptoms during and after neurotoxic treatment. Both regimens invariably resulted in the appearance of a progressive and irreversible syndrome characterized by action and resting tremor, cogwheel rigidity, postural impairments, hypokinesia and bradykinesia. In some animals, symptoms of resting tremor and rigidity initially restricted to one side of the body became bilateral within a few months of treatment. Subtle abnormalities that may be found in idiopathic Parkinson's disease such as alterations of the blink reflex response were also noted. Neuropathological examination of caudate nucleus, putamen, substantia nigra and ventral @mental area in brain sections stained for tyrosine hydroxylase showed a typical uneven striatal dopamine fibre loss and a neuronal depletion in the dopaminergic mesencephalic cell groups that reproduce those observed in idiopathic Parkinson's disease. Immunocytochemical observations and behavioural data show that chronic rather than acute MPTP injection regimens can replicate most of the neuropathological and the clinical features typical of idiopathic Parkinson's disease, possibly by increasing the ability of this neurotoxin to target specific subpopulations of mesencephalic dopaminergic neurons.
Journal of Neurochemistry, 2012
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5 months were followed up to a maximum age of 21 months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21 months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14 months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In both ORIGINAL ARTICLE d JOURNAL OF NEUROCHEMISTRY | 2012 groups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process.
The Journal of biological chemistry, 2000
Uptake of the Parkinsonism-inducing toxin, 1-methyl-4-phenylpyridinium (MPP(+)), into dopaminergic terminals is thought to block Complex I activity leading to ATP loss and overproduction of reactive oxygen species (ROS). The present study indicates that MPP(+)-induced ROS formation is not mitochondrial in origin but results from intracellular dopamine (DA) oxidation. Although a mean lethal dose of MPP(+) led to ROS production in identified dopaminergic neurons, toxic doses of the Complex I inhibitor rotenone did not. Concurrent with ROS formation, MPP(+) redistributed vesicular DA to the cytoplasm prior to its extrusion from the cell by reverse transport via the DA transporter. MPP(+)-induced DA redistribution was also associated with cell death. Depleting cells of newly synthesized and/or stored DA significantly attenuated both superoxide production and cell death, whereas enhancing intracellular DA content exacerbated dopaminergic sensitivity to MPP(+). Lastly, depleting cells of ...