Biochemical Events in the Development of Parkinsonism Induced by 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine

Singer, Thomas P.; Castagnoli, Neal; Ramsay, Rona R.; Trevor, Anthony J.

doi:10.1111/j.1471-4159.1987.tb03384.x

Cited by 238 publications

(92 citation statements)

References 40 publications

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“…With respect to the subtypes of the enzyme, it was shown that MPP+ potently and competitively inhibits MAO-A, which therefore does not significantly contribute to the conversion of MPTP to MPP +. The B form of the enzyme which appears to be only slightly inhibited by MPP + (Fritz et al, 1985), plays the predominant role in the bioactivation of MPTP (Singer et al, 1987). However, in the light of the present findings, i.e.…”

Section: Discussioncontrasting

confidence: 54%

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An in vitro model of 1‐methyl‐4‐phenyl‐pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis

Feuerstein

Hedler

Jackisch

et al. 1988

British J Pharmacology

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1 Slices of rabbit caudate nucleus were preincubated for up to 24h in vitro in the presence of the neurotoxic compound 1-methyl-4-phenyl-pyridinium (MPP+). Subsequently the levels of endogenous monoamines in the slices were determined by h.p.l.c. with electrochemical detection. MPP +, in concentrations higher than 32 nm significantly diminished the dopamine levels within the slices in a concentration-and time-dependent manner; at 32yM the depletion was more than 95%. The concentration of the major metabolite of dopamine, dihydroxyphenyl acetic acid (DOPAC) was decreased at concentrations of MPP+ that did not alter dopamine levels. Thus, MPP+ increased the dopamine/DOPAC ratio. 2 In contrast, both 5-hydroxytryptamine (5-HT) levels and 5-HT/5-hydroxyindolacetic acid (5-HIAA) ratios were increased at nanomolar concentrations of MPP +. 5-HT was significantly reduced only at 32 pM.3 The dopamine uptake inhibitor nomifensine reduced the depletory effect of MPP + on dopamine and DOPAC content. 4 Following 24 h pretreatment with MPP +, the uptake of [3H]-dopamine into rabbit caudate nucleus slices was either enhanced (at 0.32 pM, 1 pM and 3.2 pM MPP +) or reduced (at 32 JM MPP+).5 Preincubation of slices with 1OpM MPP + for only 1 h increased their 3H-labelling (in contrast to 24 h pretreatment) whereas after 9 h no net increase was detectable. After 1 and 9 h MPP + pretreatment, much less deaminated metabolites of [3H]-dopamine were found in the incubation medium of MPP+ treated slices than in the medium of control slices. These findings suggest that MPP + strongly inhibits the enzyme monoamine oxidase (MAO) within dopaminergic (and 5-hydroxytryptaminergic) (Snyder & D'Amato, 1986). In favour of the role of the substantia nigra in the pathogenesis it was assumed that within pigmented cell bodies of nigral neurones MPP+ was bound to neuromelanin and gradually released in a depot-like fashion, maintaining a toxic intracellular concentration of MPP +. However, since monoamine uptake is more prominent in nerve endings than in cell bodies (Snyder & D'Amato, 1986), the dopaminergic terminal field in the striatum rather than the cell bodies of the substantia nigra could be a primary target for MPP + toxicity.In the present investigation we studied the effects of long term incubation with MPP+ in caudate tissue of the rabbit in vitro in order to establish clear concentration-effect relationships and to provide a more accessible and less expensive experimental model than that of MPTP-induced Parkinsonism in primates in vivo. Acute dopamine releasing effects of MPTP and of MPP + in rat CNS tissue have already been described (Schmidt et al., 1984;Markstein & Lahaye, 1985;Rollema et al., 1986a). However, acute effects may not reflect adequately the toxic effects of MPP + on the dopaminergic system in vivo since, ultimately, the destruction of dopaminergic cells leads to MPTP-induced Parkinsonism.The analysis of subacute effects of MPTP or MPP + on cultured neuronal cells (Mytilineou & Cohen, 1984) Ci mmol-1) in a volume of 4ml...

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Section: Discussioncontrasting

confidence: 54%

“…However, in the light of the present findings, i.e. the increase of both endogenous 5-HT and the 5-HT/5-HIAA ratio by nanomolar concentrations of the neurotoxin (Figure 2), the ability of MPP + to inhibit MAO in 5-hydroxytryptaminergic terminals may be of greater importance than suggested by Singer et al (1987).…”

Section: Discussioncontrasting

confidence: 52%

An in vitro model of 1‐methyl‐4‐phenyl‐pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis

Feuerstein

Hedler

Jackisch

et al. 1988

British J Pharmacology

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“…There is evidence in the literature supportive of a role for mitochondrial dysfunction in other neurodegenerative disorders such as Alzheimer's disease (67) and a form of Parkinson's disease (68). Studies of scrapie-infected hamsters have reported physical disruption of the mitochondria as well as decreased activity of important mitochondrial enzymes (69).…”

Section: Discussionmentioning

confidence: 99%

Prion Protein Fragment PrP-(106–126) Induces Apoptosis via Mitochondrial Disruption in Human Neuronal SH-SY5Y Cells

O'Donovan

Deirdre

Cotter

2001

Journal of Biological Chemistry

139

118

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The synthetic peptide PrP-(106 -126) has previously been shown to be neurotoxic. Here, for the first time, we report that it induces apoptosis in the human neuroblastoma cell line SH-SY5Y. The earliest detectable apoptotic event in this system is the rapid depolarization of mitochondrial membranes, occurring immediately upon treatment of cells with PrP-(106 -126). Subsequent to this, cytochrome c release and caspase activation were observed. Caspase inhibitors demonstrated that while the peptide activates caspases they are not an absolute requirement for apoptosis. Parallel to caspase activation, PrP-(106 -126) was also observed to trigger a rise in intracellular calcium through release of mitochondrial calcium stores. This leads to the activation of calpains, another family of proteases. A calpain inhibitor demonstrated that while calpains are activated by the peptide they also are not an absolute requirement for apoptosis. Interestingly a combination of caspase and calpain inhibitors significantly inhibited apoptosis. This illustrates alternative pathways leading to apoptosis via caspases and calpains and that blocking both pathways is required to inhibit apoptosis. These results implicate the mitochondrion as a primary site of action of PrP-(106 -126).

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“…However, most of the debate centered around the 'mitochondrial hypothesis', namely that, despite their dissimilar structures, MPP ÷ acts like rotenone to inhibit mitochondrial respiration versus the 'oxidative stress' hypothesis, which assumes that the effects of hydroxyl and superoxide radicals caused nigrostriatal cell death. The ultimate question, which remains open, is whether the similarity in neuronal lesions and neurological symptoms elicited by MPTP and its congeners and those seen in idiopathic parkinsonism suggests that evironmental compounds of related structure may be causative agents in human parkinsonism [13][14]. The present review summarizes recent advances in these areas and other advances of interest to the biochemical community.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of the neurotoxicity of MPTP

1990

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This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-l-l,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP + (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the Z-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP + and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP + and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP ÷, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.Monoamine oxidase; MPTP (l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine); Neurotoxin; NADH dehydrogenase

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Biochemical Events in the Development of Parkinsonism Induced by 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine

Cited by 238 publications

References 40 publications

An in vitro model of 1‐methyl‐4‐phenyl‐pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis

An in vitro model of 1‐methyl‐4‐phenyl‐pyridinium (MPP+) toxicity: incubation of rabbit caudate nucleus slices with MPP+ followed by biochemical and functional analysis

Prion Protein Fragment PrP-(106–126) Induces Apoptosis via Mitochondrial Disruption in Human Neuronal SH-SY5Y Cells

Mechanism of the neurotoxicity of MPTP

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