1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroblastic apoptosis in the subventricular zone is caused by 1-methy-4-phenylpiridinium (MPP+) converted from MPTP through MAO-B
Intraperitoneal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration induces apoptosis of subventricular zone (SVZ) doublecortin (Dcx)-positive neural progenitor cells (migrating neuroblasts, A cells). Actually, a metabolite of MPTP, 1-methy-4-phenylpiridinium (MPP(+)), is responsible for neural progenitor cell toxicity. In the present study, to examine whether the MPTP-induced SVZ cell apoptosis is caused directly by MPP(+) metabolized through monoamine oxidase B (MAO-B), MPTP or MPP(+) was intracerebroventricularly (icv) injected into C57BL/6 mice. At Day 1 postinjection, many terminal deoxynucleotidyl transferase-mediated dUTP endlabeling (TUNEL)-positive cells were observed in the SVZ of both low (36μg) and high (162μg) dose MPTP- and MPP(+)-injected mice. The number of Dcx-positive A cells showed a significant decrease following high dose of MPTP- or MPP(+)-injection on Days 1 and 3, respectively, whereas that of EGFR-positive C cells showed no change in mice with any treatment. In addition, prior icv injection of a MAO-B inhibitor, R(-)-deprenyl (deprenyl), inhibited MPTP-induced apoptosis, but not MPP(+)-induced apoptosis. MAO-B- and GFAP-double positive cells were detected in the ependyma and SVZ in all mice. It is revealed from these results that icv injection of MPTP induces apoptosis of neural progenitor cells (A cells) in the SVZ via MPP(+) toxicity. In addition, it is suggested that the conversion from MPTP to MPP(+) is caused mainly by MAO-B located in ependymal cells and GFAP-positive cells in the SVZ.
Available from: PubMed Central
- "MPTP crosses the blood-brain barrier and is bioactivated enzymatically to give 1-methyl-4-phenylpyridinium (MPP+) [1, 8, 9], which is selectively uptaken into dopaminergic cells via dopamine-activated transporter (DAT) and produces inhibition of mitochondrial complex I, energy depletion, and cell death  (Figure 1). Besides its use in experimental models of neurotoxicity, the toxic outcome caused by MPTP is a matter of investigation due to the differences in response among experimental models [10, 11]. This might result from a change in the balance between the rate of metabolism to toxic products (MPP+ and MPDP+) (activation) and the rate of detoxification (inactivation) [12–16]. "
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ABSTRACT: Metabolic enzymes are involved in the activation/deactivation of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyiridine (MPTP) neurotoxin and its naturally occurring analogs 2-methyltetrahydro-β-carbolines. The metabolic profile and biotransformation of these protoxins by three enzymes, monoamine oxidase (MAO), cytochrome P450, and heme peroxidases (myeloperoxidase and lactoperoxidase), were investigated and compared. The metabolite profile differed among the enzymes investigated. MAO and heme peroxidases activated these substances to toxic pyridinium and β-carbolinium species. MAO catalyzed the oxidation of MPTP to 1-methyl-4-phenyl-2,3-dihydropyridinium cation (MPDP+), whereas heme peroxidases catalyzed the oxidation of MPDP+ to 1-methyl-4-phenylpyridinium (MPP+) and of 2-methyltetrahydro-β-carboline to 2-methyl-3,4-dihydro-β-carbolinium cation (2-Me-3,4-DHβC+). These substances were inactivated by cytochrome P450 2D6 through N-demethylation and aromatic hydroxylation (MPTP) and aromatic hydroxylation (2-methyltetrahydro-β-carboline). In conclusion, the toxicological effects of these protoxins might result from a balance between the rate of their activation to toxic products (i.e.,
N-methylpyridinium-MPP+ and MPDP+- and N-methyl-β-carbolinium—βC+—) by MAO and heme peroxidases and the rate of inactivation (i.e., N-demethylation, aromatic hydroxylation) by cytochrome P450 2D6.
07/2013; 2013(4587):248608. DOI:10.1155/2013/248608
Available from: Takafumi Sai
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ABSTRACT: In the present study, we evaluated the influence of intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)) on the placenta. There was no increase in apoptotic cells in the placentas of C57BL/6 mice treated with 25.0 mg/kg MPTP or 17.1 mg/kg MPP(+), indicating that a single injection of the chemicals may induce very slight cytotoxicity in the placenta at 12 hr after administration. The decrease in the expression of monoamine oxidase (MAO)-A in the labyrinth zone and that of MAO-B in the basal zone may be due to the decrease in cell activity, whereas the increase of MAO-B expression in the labyrinth zone after MPTP treatment may be due to a responsive reaction caused by MPTP, one of the substrates of MAO-B. The results represent histological evidence that MAO-B may be involved in the metabolism of MPTP to MPP(+) in the labyrinth zone of the mouse placenta. In the present study, no increase in apoptotic cells indicates that MPTP and MPP(+) are hardly toxic to the placenta, and the histological change in MAO-B expression may indicate the possibility of involvement of placental MAO-B in MPTP metabolism.
Journal of Toxicologic Pathology 03/2013; 26(1):73-7. DOI:10.1293/tox.26.73 · 0.53 Impact Factor
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ABSTRACT: One of the toxicities caused by 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is damage to dopaminergic neurons. When injected into C57BL/6J mice, MPTP penetrates into the brain and is converted to 1-methyl-4-phenylpyridinium (MPP(+)) by monoamine oxidase (MAO)-B in astrocytes. MPP(+) has high affinity for the dopamine transporter (DAT) on dopaminergic neurons, and is taken up into the cell to cause cell death. There have been relatively few researches on the acute MPTP toxicity to embryonic or newborn mice. In the present study, we attempted to evaluate the influence of MPTP and MPP(+) on embryonic and newborn mice by measuring sequential changes in major indexes of MPTP toxicity and MPTP metabolism; levels of Tyrosine Hydroxylase (TH), DAT, MAO-A and MAO-B. In addition, we measured the levels of dopamine and its metabolites, 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA), in the brain of newborn mice. A single injection of MPTP and MPP(+) reduced the levels of dopamine and its metabolites, DOPAC and HVA, in the brain of newborn mice about 6-12 hr after the injection. Similarly the levels of mRNAs and proteins of DAT and TH were lowered in the brain of embryonic and newborn mice as well. The levels of these indexes were generally recovered at 24 hr after injection, indicating that the neurotoxicity induced by a single injection of MPTP or MPP(+) is temporary and recoverable in embryonic and newborn mice. By contrast, no significant changes in the expression levels of MAO-A and MAO-B were observed in either MPTP- or MPP(+)-treated mice.
The Journal of Toxicological Sciences 06/2013; 38(3):445-58. DOI:10.2131/jts.38.445 · 1.29 Impact Factor
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