MPTP , parkinsonism caused

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

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. 

The ability of MPTP to cause a lesion that parallels in many ways the characteristic lesion of idiopathic Parkinson s disease has stimulated efforts to identify possible enviromnental and endogenous compounds that may possess MPTP-type properties (Ikeda et al. 1992). Intracerebral microdialysis studies that estimate irreversible neuronal degeneration have provided evidence that a variety of pyridinium and related quaternized azaheteroaromatic systems are toxic to dopaminergic neurons (Rollema et al. 1990, 1994). Nevertheless, relatively few compounds meet all of the characteristics required for... 

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. 

Despite the misfortunes of these addicts, MPTP has proved an invaluable tool for studying the biology of Parkinson s disease. When MPTP is injected into experimental rats, mice, or monkeys, neurons in the substantia nigra of these animals start to die, and the animals develop motor problems that closely resemble the symptoms of Parkinson s disease. Researchers hope to use MPTP in animals to unravel the mystery of what causes Parkinson s disease in humans, in the hope that they can develop a cure for this devastating disease. 

Suitable animal models of the disease are available in both rodents and primates. A progressive dopaminergic degeneration of substantia nigra neurons is the result of intrastriatal 6-OH-dopamine injection in rats, and MPTP causes a Parkinson-like syndrome in monkeys [12]. The availability of transgenic mice [13] based on a-synuclein further expands the experimental options. 

Maret G, Testa B, Jenner P, et al. The MPTP story MAO activates tetrahydropyridine derivatives to toxins causing parkinsonism. Drug Metab Rev 1990 22 291. 

It therefore appears that neurons in the substantia nigra might ultimately be destroyed because genetic factors lead to neuronal protein accumulation and free radical-induced oxidative stress that causes the degeneration and death of these neurons. As indicated earlier, however, the influence of environmental factors should be considered.49,64 It has been theorized, for example, that environmental toxins (e.g., herbicides, insecticides, fungicides) accelerate the neuronal destruction in people with Parkinson disease.14 Much of this evidence is based on the finding that a compound known as l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) appears to be selectively toxic to these neurons and can invoke parkinsonism in primates.84... 

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. 

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