1- Methyl-4-phenyl-tetrahydropyridine MPTP

Another synthetic heroin-like compound was sold to heroin-dependent individuals in California in 1982 as "new heroin", which was soon recognized to cause severe Parkinsonian symptoms in young people. Eventually it was discovered that "new heroin" contained pethidine together with an N-methyl-phenyl-tetrahydropyridine (MPTP) contaminant. It is now established that MPTP is converted to a neurotoxic... 

Recently much interest has centred on a very specific toxin for DA neurons. This is 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). It was discovered when a student, who was addicted to pethidine, tried to manufacture l-methyl-4-phenyl-4-propionoxy-piperidine (MPPP) but took a short-cut in synthesis and produced MPTP. When he administered this to himself he developed Parkinsonism. MPTP destroys DA neurons. Again this process depends on the neuronal uptake mechanism, since MPTP itself is not the active material. It needs to be deaminated to MPP+ which is then taken up by DA nerve terminals. 

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... 

Cohen, G., and Mytilineou. C. Studies on the mechanism of action of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). Life Sci 35 237-242, 1985. 

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

Unaware of it at the time, the college student s sloppy chemistry had, in addition to synthesizing MPPP, inadvertently created some additional by-products that were very toxic. It turns out that one of the by-products, called l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is very toxic to neurons in... 

Of the two analogs, MPPP poses a somewhat more serious threat to users because a highly toxic by-product, l-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), is sometimes formed during its synthesis. MPTP forms during the synthesis of MPPP if the pH of the reaction solution is too low or the reaction temperature is too high. Thus, errors that might appear relatively minor to an inexperienced chemist can result in a contaminated product (MPPP + MPTP) that is highly toxic to users. 

Nicotine was examined as a treatment for PD as early as the 1920s (Moll 1926). A number of studies have shown that smokers have a lower than expected incidence of PD, suggesting a protective effect of nicotine (J. A. Baron 1986, 1994 R. J. Baumann et al. 1980). Nicotine has also been shown to counteract the locomotor effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-induced lesions in mice, a putative model for PD (Sershen et al. 1987). 

Przedborski, S., Jackson-Lewis, V., Yokoyama, R., Shibata, T., Dawson, V.L., Dawson, T. M. Role of neuronal nitric oxide in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, Proc. Natl. Acad. Sci. USA 1996, 93, 4565-4571. 

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