MPTP neurotoxin

The neuroprotective property of green tea and EGCG in 7V-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mice model of Parkinson s disease has been described." MPTP neurotoxin caused dopamine neuron loss in substantia nigra concomitant with a depletion in striatal dopamine and tyrosine hydroxylase protein levels. These adverse effects could be suppressed by the green tea extract or EGCG. 

Herraiz T, Guillen H, Aran VJ, Idle JR, Gonzalez FJ (2006) Comparative aromatic hydroxylalion-and N-demethylation of MPTP neurotoxin and its analogs, N-methylatedj8-carboline and isoquinoline alkaloids, by human cytochrome P450 2D6. Toxicol Appl Pharmacol 216 387-398... 

Dopaminergic neurotoxin that causes parkinsonism via lesion of nigrostriatal dopamine neurons in rat, mice, monkeys. Unlike the dopaminergic neurotoxin MPTP (N-methy 1-4-phenyl-1,2,3,6-tetrahydropyridine) it does not cross the blood-brain barrier. 

A synthetic neurotoxin that causes parkinsonism in human and nonhuman primates, mice, gold fish, and dogs. MPTP is inert but metabolized by MAO-B to the neurotoxin MPP+ (1,2-dihydropyridine ion). This neurotoxin causes depletion of dopamine and degeneration of nigrostriatal dopamine neurons similar to what is observed in Parkinson s disease. 

In rats, lesions targeting presumptively wake-active dopaminergic neurons that extend dorsally from the VTA into the ventral periaqueductal gray have recently been shown to result in c. 20% reductions in wakefulness (Lu et al. 2006). Daytime sleepiness and SOREMs were reported in a non-human primate following systemic delivery of the dopamine neurotoxin MPTP (Daley et al. 1999), and this was subsequently confirmed in two additional animals (Daley... 

Figure 7.4 The chemical structure of meperidine, its analogue MPPP, and the closely related neurotoxin MPTP, are all shown here. Meperidine, an anesthetic, was also used as an alternative to morphine. It proved advantageous because it has a shorter length of duration and fewer side effects than morphine.

Fonne-Pfister R, Bargetzi MJ, Meyer UA. 1987. MPTP, the neurotoxin inducing Parkinson s disease, is a potent competitive inhibitor of human and rat cytochrome P450 isozymes (P450bufl, P450dbl) catalyzing debrisoquine 4-hydroxylation. Biochem Biophys Res Commun 148 1144-1150. 

Likewise, GDNF prevents dopaminergic loss (in animals) subsequent to the administration of the neurotoxin, MPTP, which induces parkinsonian symptoms in man. Even more encouragingly, administration of GDNF subsequent to MPTP-induced dopaminergic damage... 

FIGURE 13.3 Oxidation of MPTP to l-methyl-4-phenyl-2,3-dihydropyridium ion (MPDP+), and finally to MPP+ generates free radicals and causes parkinsonism in humans. A deficiency of NADK Co (complex I) also causes striatal cell death. A deficiency of complex I may signify that an MPTP-like neurotoxin is generated endogenously, enhancing the vulnerability of striatum to oxidative stress reactions. 

In addition to MPTP, other endogenously produced neurotoxins, namely, the monoamine-derived 1,2,3,4-tetrahydroisoquinolines and 6,7-dihydroxy-l,2,3,4-tetrahydroisoquinolines, have been proposed as factors accelerating dopamine cell death. A-methylated isoquinolines were found to be oxidized by MAO, and hydroxyl radicals were found to be produced by this reaction. In addition, by incubation with the A-methylated isoquinolines, ATP was depleted from a dopaminergic cell model. Pretreatment of the cells with MAO inhibitors such as selegiline could, however, protect against ATP depletion. These results suggest that oxidation of neurotoxic isoquinolines is directly involved in the oxidative stress to induce the cell death of dopamine neurons. On the other hand, 1 -methyl-1,2,3,4-tetrahydroisoquinoline and 1 -methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino-... 

The tetrahydropyridine l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) 288 is a well-known neurotoxin that induces symptoms like those for Parkinson s disease. The toxic effects of this compound have been attributed to its oxidation by monoamine oxidase (MAO) to form the pyridine MPP+ 289. MPP+ migrates into the mitochondria of neural cells inhibiting the production of ATP and results in cell death <2000MI1, 2001MI1>. Numerous compounds, such as 4-phenoxy- 290<1997BMC1519> and 4-pyrrole-tetrahydropyridines 291 <2002BMC3031>, have been modelled on MPTP in an attempt to inhibit MAO without exhibiting neurotoxic effects. 

Yang SC, Markey SP, Bankiewicz KS, London WT, Lunn G. Recommended safe practices for using the neurotoxin MPTP in animal experiments, Lab Animal Sci 1988 38 563-7. 

Fig. 9. Chemical structure of the synthetic neurotoxin l-methyl-4-phenyl-tetrahydro-pyridine (MPTP) and its metabolism, with monoamine oxidase B as substrate, via MPDP+ to the methyl-phenyl-pyridinium ion (MPP+), which is the active toxin. (For further details see Feldman (1997).)...

Environmental Toxins. Several substances have been shown to produce a Parkinson s-like syndrome. l-Methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a by-product of various meperidine derivatives, has received considerable attention since the report by Langston et al. (L4). This neurotoxin has been studied in animal models and found to selectively destroy the dopaminergic substantia nigra. Further studies showed the MPTP was converted by MAOb to the toxic 1-methyl-4-phenylpyridinium cation (MPP+). Following reduction by P450 reductase, the MPP free radical is formed, which reduces oxygen to 02 (A4). 

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