1 -Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , neurotoxicity

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... 

Cleren C, et al. Promethazine protects against l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Neurobiol. Dis. 2005 20 701-708. 

Kalaria RN, Mitchell MJ, Harik SI (1987) Correlation of l-methyl-4-phenyl-1,2,3,6- tetrahydropyridine neurotoxicity with blood-brain barrier monoamine oxidase activity. Proc Natl Acad Sci USA 84 3521-3525. 

Sershenn, H. Reithn, M.E.A., Hashim, A. and Lajtha, A. (1985) Protection against l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine neurotoxicity by the antioxidant ascorbic acid. Neuropharmacology 24 1257-1259. 

Behmand RA, Harik SI. Nicotine enhances 1-methyl-4-phenyl-1,2,36-tetrahydropyridine neurotoxicity. J Neurochem 1992 58 776-779. 

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... 

Sundstrom, E., and Jonsson, G. Pharmacological interference with the neurotoxic action of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse. Eur J Pharmacol 110 293-299, 1985. 

Ali, S.F., Martin, J.L., Black, M.D., Itzhak, Y. Neuroprotective role of melatonin in methamphetamine-and l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. Ann. N.Y. Acad. Sci. 890 119, 1999. 

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]. 

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. 

Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1984) Protection against the dopaminergic neurotoxicity of l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 311 467-469. 

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. 

Hallman H, Olson L, Jonsson G (1984) Neurotoxicity of the meperidine analogue N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on brain catecholamine neurons in the mouse. Eur J Pharmacol 97 133-136. 

Moratalla R, Quinn B, DeLanney LE, Irwin I, Langston JW, Graybiel AM (1992) Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 59 3859-3863. 

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

Similarly, a crucial role of DAT in the neurotoxic action of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been supported in mice lacking DAT (62,63). In numerous previous studies it had been demonstrated that MPTP neurotoxicity involves selective uptake of its active metabolite, l-methyl-4-phenylpyridinium (MPP+) into the DA neuron via the DAT (6,9). In DAT-KO mice treated with MPTP, markers of striatal neurotoxicity, such as depletion in DA levels and reactive astrogliosis, were virtually absent, whereas in DAT heterozygotes a partial sensitivity was observed (62). In another investigation, no apparent DA cell body loss was found in the substantia nigra of MPTP-treated DAT-KO mice (63). Thus, an absolute requirement of DAT for development of MPTP toxicity in vivo has been firmly established (9,62,63). 

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