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Journal ArticleDOI

Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase.

30 Apr 1984-Biochemical and Biophysical Research Communications (Biochem Biophys Res Commun)-Vol. 120, Iss: 2, pp 574-578
TL;DR: The neurotoxic chemical MPTP is metabolized by rat brain mitochondrial fractions at a rate of 0.91 +/- 0.02 nmoles/mg protein/min, and the major metabolite has been identified as the 1-methyl-4- phenylpyridinium species.
About: This article is published in Biochemical and Biophysical Research Communications.The article was published on 1984-04-30. It has received 1111 citations till now. The article focuses on the topics: MPTP & Tertiary amine.
Citations
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Journal ArticleDOI
TL;DR: Blockage of dopamine uptake by mazindol prevents MPTP-induced damage to nigrostriatal dopamine neurons, indicating that MPP+ concentration into dopamine neurons explains their selective destruction by MPTP.
Abstract: N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces neuropathological and clinical abnormalities in humans, monkeys, and mice that closely resemble idiopathic parkinsonism. N-Methyl-4-phenylpyridine (MPP+), a metabolite of MPTP formed by monoamine oxidase B, is accumulated into striatal and cerebral cortical synaptosomes by the dopamine and norepinephrine uptake systems, respectively, whereas MPTP itself is not accumulated. The potencies of drugs in inhibiting [3H]MPP+ or [3H]dopamine uptake into striatal synaptosomes are very similar, as are potencies in inhibiting [3H]MPP+ or [3H]norepinephrine uptake into cortical synaptosomes. The Km values for [3H]MPP+ uptake are 170 and 65 nM and the Vmax values are 2 and 0.1 nmol/g of tissue per min in rat striatum and cortex, respectively, similar to values for [3H]dopamine uptake, Autoradiography of accumulated [3H]MPP+ in slices of rat brain shows high densities in the caudate-putamen and nucleus accumbens. Furthermore, blockade of dopamine uptake by mazindol prevents MPTP-induced damage to nigrostriatal dopamine neurons, indicating that MPP+ concentration into dopamine neurons explains their selective destruction by MPTP.

1,262 citations

Journal ArticleDOI
TL;DR: Compromise of mitochondrial oxidative capacity by MPP+ could be an important factor in mechanisms underlying the toxicity of MPTP.

1,260 citations

Journal ArticleDOI
TL;DR: Recent data concerning the biochemical and molecular apoptotic mechanisms underlying the experimental models of PD are reported and correlates them to the phenomena occurring in human disease.

1,173 citations

Journal ArticleDOI
04 Oct 1984-Nature
TL;DR: It is reported that pargyline, nialamide and tranylcypromine, which inhibit both MAO-A andMAO-B, when administered to mice before MPTP, protect against MPTP-induced dopaminergic neurotoxicity.
Abstract: 1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) causes degeneration of the dopaminergic nigrostriatal pathway in several animal species, including humans1,2, monkeys3,4 and mice5–7. Changes observed after MPTP administration include marked decrements in the neostriatal content of dopamine and its major metabolites, dihydroxyphenylacetic acid and homovanillic acid, and a greatly diminished capacity of neostriatal synaptosomes to take up 3H-dopamine5,6. In contrast, there is no pronounced loss of serotonin in the neostriatum or of dopamine and its metabolites in other brain areas in MPTP-treated animals. The oxidative metabolism of MPTP to 1-methyl-4-phenyl pyridine, a positively charged species, has been suggested as a critical feature in the neurotoxic process8. Moreover, in rat brain preparations, the monoamine oxidase (MAO) inhibitor pargyline and the specific MAO-B inhibitor deprenil can prevent the formation of 1-methyl-4-phenyl-pyridine from MPTP, while the specific MAO-A inhibitor clorgyline has no such effect9, suggesting that MAO, and specifically MAO-B, is responsible for the oxidative metabolism of MPTP. We now report that pargyline, nialamide and tranylcypromine, which inhibit both MAO-A and MAO-B, when administered to mice before MPTP, protect against MPTP-induced dopaminergic neurotoxicity. Deprenil is also protective, but clorgyline is not. Our data are consistent with the premise that MAO-B has a crucial role in MPTP-induced degeneration of the nigrostriatal dopaminergic neuronal pathway.

1,010 citations

Journal ArticleDOI
TL;DR: Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case, suggesting that a time‐limited insult to the nigrostriatal system can set in motion a self‐perpetuating process of neurodegeneration.
Abstract: This report provides the first detailed neuropathological study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in humans. All 3 subjects self-administered the drug under the impression it was "synthetic heroin" and subsequently developed severe and unremitting parkinsonism, which was L-dopa responsive, at least in the earlier stages of illness. Survival times ranged from 3 to 16 years. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells. Patient 3 had a similar picture and also showed large amounts of extraneuronal melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time-limited insult to the nigrostriatal system can set in motion a self-perpetuating process of neurodegeneration. Although the mechanism by which this occurs is far from clear, the precedent set by the cases could have broad implications for human neurodegenerative disease.

972 citations

References
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Journal ArticleDOI
25 Feb 1983-Science
TL;DR: It is proposed that this chemical selectively damages cells in the substantia nigra in patients who developed marked parkinsonism after using an illicit drug intravenously.
Abstract: Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.

4,705 citations

Journal Article
TL;DR: 6-hydroxydopamine and 2,4,5-trihydroxyphenylalanine kill cells through the production of H2O2, O2[unknown], and OH·, while for dopamine and dopa the reaction of quinone oxidation products with nucleophiles probably also contributes to their cytotoxicity.
Abstract: The mechanism of cytotoxicity of 6-hydroxydopamine, 2,4,5-trihydroxyphenylalanine, dopa, dopamine, norepinephrine, and epinephrine was explored by asking whether cytotoxicity was a reflection of the potential for autoxidation of each polyphenol or of the sulfhydryl reactivity of its quinone products. The cytotoxicity of the polyphenols, as measured by inhibition of [3H]thymidine incorporation into DNA by C1300 neuroblastoma cells in tissue culture, correlated with the rate of autoxidation, as measured spectrophotometrically or by oxygen electrode studies. Polarographic determinations of the oxidation potentials of the polyphenols were also predictive of cytotoxicity; the most cytotoxic compounds had the most negative half-wave potentials and thus were the most readily oxidized. By contrast, the sulfhydryl reactivity of the quinone oxidation products of the polyphenols, as measured by inhibition of purified calf thymus DNA polymerase α, exhibited an inverse relationship to the cytotoxicity of the polyphenols; the most toxic compounds, 6-hydroxydopamine and 2,4,5-trihydroxyphenylalanine, were oxidized to the least reactive quinone products. An alternative mechanism of toxicity was observed with N -acetyldopamine, which was oxidized to 4-(2- N -acetylaminoethyl)-1,2-benzoquinone, a potent sulfhydryl reagent. N -Acetyldopamine was more toxic than predicted by its half-wave potential or its rate of autoxidation. Furthermore, while norepinephrine completely neutralized 6-hydroxydopamine and 2,4,5-trihydroxyphenylalanine as cytotoxic agents, the toxicity of N -acetyldopamine was minimally affected. Thus we conclude that 6-hydroxydopamine and 2,4,5-trihydroxyphenylalanine kill cells through the production of H2O2, O2[unknown], and OH·, while for dopamine and dopa the reaction of quinone oxidation products with nucleophiles probably also contributes to their cytotoxicity.

969 citations

Journal ArticleDOI
TL;DR: In this paper, a photoredox scheme to produce hydrogen gas was developed by utilizing ruthenium tris(bipyridyl) dication, Ru(bpy)/sub 3//sup 2 +/, as a photosensitizer.
Abstract: Many photoredox schemes to produce hydrogen gas have been developed by utilizing ruthenium tris(bipyridyl) dication, Ru(bpy)/sub 3//sup 2 +/, as a photosensitizer. Irradiation of an acetonitrile-water solution of Ru(bpy)/sub 3//sup 2 +/, triethylamine, and PtO/sub 2/ resulted in PHI/sub H/sub 2// = 0.37. The chemically active excited d..pi.. ..-->.. ..pi..* state of Ru(bpy)/sub 3//sup 2 +/ is relatively long lived (0.685 ..mu..s) and is capable of acting as either an oxidizing or a reducing agent. Low yields of oxygen and hydrogen at a pH of 4.7 have been observed when aqueous solutions of Ru(bpy)/sub 3//sup 2 +/, methyl viologen (MV/sup 2 +/), colloidal RuO/sub 2/ and colloidal Pt are illuminated. Charge-transfer emissions are characteristic of ruthenium complexes bonded to the ..cap alpha..-dimine (-N==C-C==N-) functionality which can be incorporated in either an aromatic or nonaromatic ligand. 1 figure. (DP)

142 citations