Disease relevance of C04599

• Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a syndrome that resembles Parkinson's disease [1].
• Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [2].
• MPTP toxicity: implications for research in Parkinson's disease [3].
• Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS) [4].
• The MPTP monkey is a well-characterized animal model of parkinsonism and provides an exceptional tool for the study of dyskinesias induced by dopamine-like agents [5].

Psychiatry related information on C04599

• We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease [6].
• In aged Rhesus monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills [7].
• In the course of MPTP intoxication (0.3-0.4 mg/kg every 4-5 days) and before parkinsonian motor symptoms appeared, the reaction time (RT), movement time (MT) and variability of reaching trajectories increased in all monkeys [8].
• In humans, positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam) [9].
• Behavioral manifestations in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, such as changes in general locomotor activity and rotorod performance, require large doses of MPTP and are often transient [10].

High impact information on C04599

• PGC-1alpha null mice are much more sensitive to the neurodegenerative effects of MPTP and kainic acid, oxidative stressors affecting the substantia nigra and hippocampus, respectively [11].
• In addition, mutant mice were resistant to the neurodegenerative effects of MPTP, a toxin that induces a condition reminiscent of Parkinson's disease [12].
• We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates [4].
• MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease [4].
• This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease [4].

Chemical compound and disease context of C04599

• The production by the pyridine MPTP of a parkinsonian syndrome strikingly similar to the 'idiopathic' disorder, and the paucity of evidence supporting a hereditary or infectious etiology for Parkinson's disease (PD), have stimulated a search for environmental chemicals resembling MPTP that might cause PD [13].
• In this issue of Neuron, Kaur et al. demonstrate that iron chelation by ferritin transgene or the metal chelator clioquinol prevent oxidative damage and MPTP toxicity in mice [14].
• Benztropine inhibits toxicity of MPTP in mice [15].
• Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity [16].
• GPI-1046 also induced regenerative sprouting from spared nigrostriatal dopaminergic neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice or 6-hydroxydopamine (6-OHDA) toxicity in rats [17].

Biological context of C04599

• Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons [18].
• Budipine and the MPTP binding site [19].
• NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease [20].
• VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity [21].
• Finally, the MPTP delta locus was tightly linked to the brown (b) locus on mouse chromosome 4 [22].

Anatomical context of C04599

• To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [23].
• Hydroxylated derivatives of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a nigrostriatal neurotoxin in humans and primates, noncompetitively inhibited dihydropteridine reductase from human liver and rat striatal synaptosomes in vitro at micromolar concentrations [24].
• We have studied the effect of unilateral autografts of carotid body cell aggregates into the putamen of MPTP-treated monkeys with chronic parkinsonism [25].
• We conducted a preclinical study of electrical interference in the primary motor cortex using a chronic MPTP primate model in which dopamine depletion was progressive and regularly documented using 18F-DOPA positron tomography [26].
• Unilateral implantation of murine NSCs into the midbrains of aged mice, in which the presence of stably impaired but nonapoptotic DA neurons was increased by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was associated with bilateral reconstitution of the mesostriatal system [27].

Associations of C04599 with other chemical compounds

• We have used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF might exert protective or regenerative effects in vivo in the adult nigrostriatal dopamine system in C57/B1 mice [28].
• Timing of levodopa therapy: evidence from MPTP-treated primates [29].
• In this study, we produced nigral degeneration by infusing 1-methyl-4-phenylpyridinium (MPP+), a mitochondrial complex I inhibitor and the active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), into the rat striatum [30].
• Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [31].
• Monoamine oxidases A and B [MAOA and MAOB; amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4] play important roles in the metabolism of neuroactive, vasoactive amines and the Parkinsonism-producing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [32].

Gene context of C04599

• Here we extend the rodent studies to an animal closer to the human in brain organization and function, by evaluating the effects of GDNF injected intracerebrally in rhesus monkeys that have had the symptomatology and pathophysiological features of Parkinson's disease induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [33].
• Monoamine oxidase B (MAO-B) is implicated in the cause of Parkinson's disease (PD) because of its role in metabolizing the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and forming H2O2 during dopamine metabolism [34].
• Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo [35]?
• Effects of systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to mice on tyrosine hydroxylase, L-3,4-dihydroxyphenylalanine decarboxylase, dopamine beta-hydroxylase, and monoamine oxidase activities in the striatum and hypothalamus [36].
• In the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, inducible NO synthase (iNOS) derived nitric oxide (NO) is an important mediator of dopaminergic cell death [37].

Analytical, diagnostic and therapeutic context of C04599

• Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation [2].
• A syndrome similar to idiopathic parkinsonism developed after intravenous self-administration of an illicit drug preparation in which N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) might have been responsible for the toxicity [38].
• In situ hybridization of brain samples revealed that MPTP delta mRNA is present in the hippocampus, thalamic reticular nucleus, and piriform cortex, where some Src family PTKs have been also demonstrated to exist [22].
• Striatal 18F-6-fluorodopa (FD) uptake constants were measured by positron emission tomography in (1) normal cynomolgus monkeys and (2) a series of cynomolgus and rhesus monkeys that had received intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [39].
• Quantitative 2-[14C]deoxyglucose autoradiography was used to map the pattern of alterations in local cerebral glucose utilization associated with unilateral lesions of the substantia nigra pars compacta produced by the infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into one internal carotid artery of rhesus monkeys [40].

References