The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety (original) (raw)
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Continuous MPTP intoxication in the Göttingen minipig results in chronic parkinsonian deficits
Acta neurobiologiae experimentalis, 2016
Parkinson's disease (PD) is a common neurodegenerative disorder, resulting from progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Neuroprotective therapies in PD are still not available, perhaps because animal models do not imitate the chronic and progressive nature of the clinical state of PD. To address this, we performed a feasibility study aimed at establishing a chronic non-primate large animal PD model in Göttingen minipigs based on continuous infusion of the neurotoxin 1-methyl-4-phenyl‑1,2,3,6-tetrahydropyridine (MPTP). Twelve female Göttingen minipigs were divided into groups of 2-4 animals and implanted with infusion pumps for continuous intramuscular MPTP delivery of 4-24 mg MPTP/day for 11 weeks. The animals showed parkinsonian symptoms with bradykinesia, rigidity, coordination and chewing difficulties. Symptoms were stable in the 12 and 18 mg MPTP/day groups, whereas the remaining groups showed partial or full behavioral recovery....
Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP
Cell and Tissue Research, 2004
Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinson’s disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common “classical” toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.g. rotenone, paraquat, maneb) are discussed elsewhere in this “special issue.”
Brain Research, 1992
Immunoassays sensitive to a broad range of compounds structurally related to 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP) and 1-methyl-4-phenylpyridine (MPP ÷) have been developed and used to test for the presence of possible chemically related neurotoxins in the brains of Parkinson's disease patients. The sensitivity and chemical reactivity of the polyclonal antibodies used in these assays have been characterized with a range of endogenous and chemically related materials. Two methods were developed and tested for extraction followed by chromatographic separation which would be applicable to stored or accumulated substances. The immunoassays were tested and applied to the assay of tissue extracts from MPTP or MPTP-analogue exposed animals, and indicated detectability of MPP+-immunoreactivity >8 weeks after exposure to MPTP in monkey brain. No difference in immunoactivity was measured in extracts from human brains of Parkinson's disease patients or controls, and particularly low levels of immunoactivity were found in the striatum relative to the levels measured in several cortical regions. From these studies, there is no evidence for the role of an environmental neurotoxin chemically related to MPTP in the pathogenesis of Parkinson's disease.
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...