MPP+ (1-methyl-4-phenylpyridine) is a neurotoxin to dopamine-, norepinephrine- and serotonin-containing neurons

Namura, I.; Douillet, Patrice; Sun, Ching-Long J.; Pert, Agu; Cohen, Robert M.; Chiueh, Chuang C.

doi:10.1016/0014-2999(87)90775-8

Cited by 53 publications

(17 citation statements)

References 20 publications

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“…Thus, MPP +, by product inhibition of the enzyme which catalyses its in vivo formation from MPTP, may increase endogenous 5-HT at low concentrations, whereas destruction of 5HT nerve endings may take place at higher concentrations. The in vitro finding of increased 5-HT levels following MPP + is supported by the in vivo observation that this neurotoxin causes behavioural effects linked to 5-HT activation (Namura et al, 1987).…”

Section: Discussionsupporting

confidence: 57%

“…This does not seem to occur over the large concentration range of MPP+ studied. However, Namura et al (1987) showed that MPP +, injected directly into the locus coeruleus, destroyed noradrenergic neurones. The reasons for the differences observed in the hippocampal region (NA rich) and in the caudate nucleus (NA poor) are currently being investigated in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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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“…A recent study shows that the oxidative metabolite of MPTP also destroys other monoaminergic neurons and cells following intracerebral administration (Namura et al, 1987). Therefore, the destruction of the nigrostriatal system as evidenced by the decrease in striatal dopamine content may not be due to a specific chemical lesioning effect of MPP + or MPDP + on dopaminergic neurons but rather to the stereotaxic administration of these chemicals into the specific brain region containing cell bodies of the nigrostriatal dopaminergic pathway.…”

Section: Discussionmentioning

confidence: 96%

Neurotoxic damage to the nigrostriatal system in rats following intranigral administration of MPDP+ and MPP+

Sun

Johannessen

Gessner

et al. 1988

J. Neural Transmission

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Unilateral intranigral administration of the oxidative metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenyl-dihydropyridine (MPDP+) or 1-methyl-4-phenylpyridine (MPP+) produced dose-dependently a depletion of dopamine in the ipsilateral striatum of rats two weeks following treatment. d-Amphetamine and apomorphine induced circling toward the lesioned side in these unilaterally treated animals. No contralateral circling behavior was observed after challenging with apomorphine. This dopamine lesioning effect of MPP+ was not blocked by pretreatment of animals with a dopamine uptake blocker, GBR 12909. Furthermore, MPP+ increased the 45Ca accumulation into cells at the site of injection and produced "nonspecific" cell membrane and/or cytotoxic damage seen by histological procedures. These results indicate that MPDP+ and MPP+ produced localized cytotoxic damage to nigrostriatal neurons, caused a decrease in striatal dopamine, and disrupted the nigrostriatal system's functioning following intranigral administration to rats. It is postulated that the cationic surfactant properties of MPDP+ and MPP+ might contribute to its neurotoxic effects.

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“…It would seem that traumatic damage to dopaminergic neurons during implantation of the microdialysis cannula may compromise cell integrity and induce vulnerability of some cells to high MPP + concentrations even in the absence of transporter. Alternatively, the possibility that modulatory influences of other neurotransmitter systems, which are also known to be affected by MPP~infusion (Namura et al, 1987;Miyake and Chiueh, 1989), might affect DA neuron responsiveness cannot be ruled out.…”

Section: Resultsmentioning

confidence: 99%

Dopamine Transporter Is Required for In Vivo MPTP Neurotoxicity: Evidence from Mice Lacking the Transporter

Gainetdinov

Fumagalli

Jones

et al. 1997

Journal of Neurochemistry

295

168

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Abstract:The neurotoxic effect of 1 -methyl-4-phenyl-1 2,3,6-tetrahydropyridine (MPTP) was tested on mice lacking the dopamine (DA) transporter (DAT-/-mice). Striatal tissue DA content and glial fibrillary acidic protein (GFAP) mRNA expression were assessed as markers of MPTP neurotoxicity. MPTP (30 mg/kg, s.c., bid.) produced an 87% decrease in tissue DA levels and a 29-fold increase in the level of GFAP mRNA in the striatum of wild-type animals 48 h after administration. Conversely, there were no significant changes in either parameter in DAT-I--mice. Heterozygotes demonstrated partial sensitivity to MPTP administration as shown by an intermediate value (48%) of tissue DA loss. Direct intrastriatal infusion of the active metabolite of MPTP, 1 -methyl-4-phenylpyridinium (MPP t; 10 mM), via a microdialysis probe produced a massive efflux of DA in wild-type mice (>320-fold). In the DAT-/ -mice the same treatment produced a much smaller increase in extracellular DA (sixfold), which is likely secondary to tissue damage due to the implantation of the dialysis probe. These observations show that the DAT is a mandatory component for expression of MPTP toxicity in vivo. Key Words: Dopamine transporter-MPTP neurotoxicity-MPP+ -Glial fibrillary acidic protein-Microdialysis. J. Neurochem. 69, 1322-1325 (1997).1 -Methyl-4-phenyl-1 ,2,3,6-tetrahydropyridine (MPTP) is a potent neurotoxin that produces selective damage of midbrain dopaminergic neurons in humans and animals and therefore elicits neurochemical and neuropathological changes that are similar to idiopathic Parkinson's disease (for reviews, see Snyder and D'Amato, 1986;Kopin, 1992;Tipton and Singer, 1993). Many studies have attempted to elucidate the critical steps in MPTP neurotoxicity. Metabolic conversion of MPTP to a toxic metabolite, 1-methyl-4-phenylpyridinium (MPP~) mediated by monoamine oxidase B in glial cells (Heikkila et al., 1984), and selective uptake of MPP ± by dopaminergic neurons via the plasma membrane dopamine (DA) transporter (DAT) (Javitch et al., 1985) have been suggested as important steps in determining accessibility of the toxin into the neuron. Cellular neurotoxicity of MPP + is believed to be mainly mediated by inhibition of mitochondrial respiration by blockade of NADH oxidation (Ramsay and Singer, 1986), but generation of free radicals as well as other possible mechanisms have also been suggested (Chiueh et al., 1992;Tipton and Singer, 1993). Accumulation of the neurotoxin into synaptic vesicles via the vesicular monoamine transporter has been demonstrated as an important intraneuronal mechanism conferring MPP~resistance (Liu et al., 1992).This study focuses on elucidating the role of the DAT in MPTP toxicity in vivo in the mouse. The importance of the DAT in MPP + transport has been well documented in vitro (Javitch et al., 1985;Pifi et al., 1993), but the role of the DAT in MPTP neurotoxicity in vivo has been exclusively inferred from the protective effect of DAT inhibitors (Kopin, 1992). The recent availability of genetically altered...

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MPP+ (1-methyl-4-phenylpyridine) is a neurotoxin to dopamine-, norepinephrine- and serotonin-containing neurons

Cited by 53 publications

References 20 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

Neurotoxic damage to the nigrostriatal system in rats following intranigral administration of MPDP+ and MPP+

Dopamine Transporter Is Required for In Vivo MPTP Neurotoxicity: Evidence from Mice Lacking the Transporter

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