Mechanism of Accumulation of the 1‐methyl‐4‐Phenylpyridinium Species into Mouse Brain Synaptosomes

Scotcher, Kevin P.; Irwin, Ian; DeLanney, Louis E.; Langston, J. William; Monte, Donato A. Di

doi:10.1111/j.1471-4159.1991.tb02057.x

Cited by 18 publications

(7 citation statements)

References 30 publications

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“…Administration of MPTP alone may cause ATP depletion only in neuronal cells able to accumulate relatively high levels of MPP+ via the dopaminergic uptake system (Javitch et al, 1985). In contrast, after 2-DG treatment, the threshold of concentration for MPP' action may be lowered, and inhibition of mitochondrial respiration may become evident in the form of ATP depletion even in cells that do not actively accumulate MPP+ (Scotcher et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

2‐Deoxyglucose Enhances 1‐Methyl‐4‐Phenyl‐1, 2, 3, 6‐Tetrahydropyridine‐Induced ATP Loss in the Mouse Brain

Chan

Langston

Irwin

et al. 1993

Journal of Neurochemistry

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The effects of 2‐deoxyglucose (2‐DG), an inhibitor of the uptake and use of glucose, on ATP loss caused by the neurotoxicant 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) were determined in the mouse brain. 2‐DG alone had no effect on brain ATP levels, but when administered 30 min before MPTP exposure, 2‐DG significantly enhanced MPTP‐induced ATP reduction. This was reflected as an increase in ATP loss in the striatum (from 15 to 27%) as well as a significant decrease in ATP in the cerebellar cortex, an area of the brain that was not affected after exposure to MPTP alone. In mice pretreated with 2‐DG, striatal ATP levels remained significantly decreased for >8 h after MPTP administration. In contrast, ATP levels in the cerebellar cortex returned to normal values within 4 h from MPTP exposure. Mazindol, a catecholamine uptake blocker, completely protected against MPTP‐induced loss of striatal ATP in the absence of 2‐DG, but it only partially prevented striatal ATP decrease after administration of both 2‐DG and MPTP; mazindol was also ineffective in protecting against ATP loss caused by 2‐DG and MPTP in the cerebellar cortex. 2‐DG/MPTP‐induced ATP loss appeared to be associated with the presence of the 1 ‐methyl‐4‐phenylpyridinium (MPP+) metabolite because (1) the pattern of ATP recovery in the striatum and cerebellar cortex appeared to reflect the pattern of MPP+clearance from these areas of the brain (i.e., significant MPP+ levels persisted longer in the striatum than in the cerebellar cortex), and (2) ATP decrease was completely prevented by blocking the conversion of MPTP to MPP+with the monoamine oxidase B inhibitor deprenyl. Data indicate that impairment of glucose metabolism dramatically enhances the effects of MPTP/MPP+ on cerebral energy supplies, making these effects relatively nonselective for dopaminergic neurons of the nigrostriatal pathway.

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Section: Discussionmentioning

confidence: 99%

2‐Deoxyglucose Enhances 1‐Methyl‐4‐Phenyl‐1, 2, 3, 6‐Tetrahydropyridine‐Induced ATP Loss in the Mouse Brain

Chan

Langston

Irwin

et al. 1993

Journal of Neurochemistry

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“…The redistribution of MPP+ between the intra-and extracellular compartments reached equilibrium after approximately 4 h, suggesting that MPP+ efflux from astro- cytes follows a concentration-dependent gradient. Since MPP+ is a charged compound, this efflux is likely to be more adequately described as the result of a nernstian electrochemical gradient (Sayre, 1989;Scotcher et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study has revealed that MPP+ possesses a low, but definite degree of lipid solubility since its positive charge is delocalized throughout the pyridinium ring (Reinhard et al, 1990). This property could provide a basis for the carrier-independent entry of MPP+ into cells and subcellular organelles (Reinhard et al, 1990;Scotcher et al, 1991). However, to date there has been no experimental evidence to support the possibility that MPP+ may be able to cross membranes in the opposite direction from the intracellular to the extracellular compartment.…”

Section: Introductionmentioning

confidence: 99%

Production and disposition of 1‐methyl‐4‐phenylpyridinium in primary cultures of mouse astrocytes

Monte

Irwin

et al. 1992

Glia

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Dopaminergic neurons are a primary target for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. However, the conversion of MPTP to its neurotoxic 1-methyl-4-phenylpyridinium metabolite (MPP+) is likely to occur in astrocytes via the monoamine oxidase (MAO)-dependent formation of the 1-methyl-4-phenyl-2,3-dihydropyridinium intermediate (MPDP+). The main purpose of this study was to characterize the molecular mechanism(s) by which MPP+, once generated by astrocytes, may reach the extracellular space to become available for the active accumulation into dopaminergic neurons. Primary cultures of mouse astrocytes were used as an in vitro model system. After the addition of MPTP, levels of MPP+ were found to increase at constant rates both intracellularly and extracellularly at time points when no sign of cytotoxicity was evident. In contrast, MPDP+ levels remained quite stable during 4 days of incubation in the presence of MPTP. Finally, when astrocytes were allowed to accumulate MPP+ by pretreatment with either MPTP or MPP+ and then were incubated in fresh medium not containing MPTP or MPP+, intracellular levels of MPP+ rapidly declined and corresponding amounts of this compound were found in the incubation medium. Results of this study are compatible with the following conclusions: 1) the MPP+ accumulated in the extracellular compartment during incubations with MPTP is not released from astrocytes as a consequence of its own cytotoxic effects; 2) MPP+ can be formed extracellularly presumably via autoxidation of MPDP+ after this latter compound has been generated within astrocytes and has crossed astrocyte membranes; and 3) despite its charged chemical structure, MPP+ can cross the plasma membrane toward the extracellular space after being formed within astrocytes.

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“…As mentioned in the introductory section, the reported preferential toxicity of MPP + on dopaminergic neurons has been ascribed to its specific uptake by the dopamine carrier. However, it was recently reported that MPP + can be internalized by synaptosomes through a passive diffusion mechanism (Scotcher et al ., 1991) . It is possible, therefore, that the ion penetrates into the GABAergic neurons of the SNR by such a mechanism, causing disruption ofmitochondrial oxidative metabolism .…”

Section: Histologymentioning

confidence: 99%

Neurotoxic Effect of Intranigral Injection of 1‐Methyl‐4‐Phenylpyridinium on GABA‐Containing Neurons and Its Relation to Circling Behavior

Jasso‐López

Tapia

1995

Journal of Neurochemistry

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The ionic species 1‐methyl‐4‐phenylpyridinium (MPP+) seems to be the metabolite responsible for the damage to dopaminergic neurons occurring after administration of the parkinsonian drug 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. In the present study we show that the unilateral stereotaxic microinjection of MPP+ into the substantia nigra pars reticulata in rats produces immediately intense and long‐lasting (up to 96 h) contralateral turning behavior in a dose‐dependent manner. This behavioral effect was correlated with a dose‐ and time‐dependent decrease (up to 90%) of glutamate decarboxylase activity and with a notable loss of neurons in the injected nigra reticulata. GABA levels in the injected nigra were also decreased, whereas the dopamine concentration in the ipsilateral striatum was not affected at 24 h, when maximal behavioral effects were observed. The circling behavior was prevented by the dopamine carrier blocker nomifensine only during the first 2 h, whereas the dopamine receptor antagonist haloperidol was ineffective. The results indicate that MPP+ is toxic for inhibitory GABAergic neurons in the nigra pars reticulata and, furthermore, suggest that disruption of the function of these GABAergic neurons may be involved in the abnormal motor behavior produced by the injection of MPP+ in the substantia nigra.

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Mechanism of Accumulation of the 1‐methyl‐4‐Phenylpyridinium Species into Mouse Brain Synaptosomes

Cited by 18 publications

References 30 publications

2‐Deoxyglucose Enhances 1‐Methyl‐4‐Phenyl‐1, 2, 3, 6‐Tetrahydropyridine‐Induced ATP Loss in the Mouse Brain

2‐Deoxyglucose Enhances 1‐Methyl‐4‐Phenyl‐1, 2, 3, 6‐Tetrahydropyridine‐Induced ATP Loss in the Mouse Brain

Production and disposition of 1‐methyl‐4‐phenylpyridinium in primary cultures of mouse astrocytes

Neurotoxic Effect of Intranigral Injection of 1‐Methyl‐4‐Phenylpyridinium on GABA‐Containing Neurons and Its Relation to Circling Behavior

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