Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:28289-54-5 (MPTP)
 5,211 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective loss of central dopaminergic neurons in vitro and in vivo can be initiated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) through its metabolite phenylpyridium ion (MPP+). Such MPTP-mediated cytotoxicity can be blocked by (-)-Deprenyl, a monoamine oxidase (MAO)-B inhibitor, but the exact mechanisms of MPP(+)-induced cytotoxicity and (-)-Deprenyl's protection against such neurotoxicity are not fully understood. Using a hybrid clone MES 23.5, a dopaminergic cell line that does not contain MAO-B, we document that MPP+ induces apoptotic cell death. Application of (-)-Deprenyl at concentrations of 0.1-10 microM significantly reduces MPP(+)-induced apoptosis in MES 23.5 cells; (-)-Deprenyl at higher concentrations (> 100 microM) that completely inhibit MAO-B activity, however, induces apoptosis. Pretreatment with N-(2-aminoethyl)-p-chlorobenzamide (Ro 16-6491), a selective MAO-B inhibitor, does not protect MES 23.5 cells against MPP(+)-induced cell death. These results suggest that the protective action of (-)-Deprenyl against MPP+ neuro-toxicity in dopaminergic cell line may be independent of the inhibition of MAO-B.
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PMID:(-)-Deprenyl protection of 1-methyl-4 phenylpyridium ion (MPP+)-induced apoptosis independent of MAO-B inhibition. 913 70

In vivo administration of either 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (MA) produces damage to the dopaminergic nervous system which may be due in part to the generation of reactive oxygen species (ROS). The resistance of superoxide dismutase (SOD) over-expressing transgenic mice to the effects of both MPTP and MA suggests the involvement of superoxide in the resulting neurotoxicity of both compounds. Superoxide can be converted by SOD to hydrogen peroxide, which itself can cause cellular degeneration by reacting with free iron to produce highly reactive hydroxyl radicals resulting in damage to proteins, nucleic acids and membrane phospholipids. Hydrogen peroxide has also been reported to be produced via inhibition of NADH dehydrogenase by MPP + formed during oxidation of MPTP by MAO-B and by dopamine auto-oxidation following MA-induced dopamine release from synaptic vesicles within nerve terminals. To test whether hydrogen peroxide is an important factor in the toxicity of either of these two neurotoxins, we created clonal PC12 lines expressing elevated levels of the hydrogen peroxide-reducing enzyme glutathione peroxidase (GSHPx). Elevation of GSHPx levels in PC12 was found to diminish the rise in ROS levels and lipid peroxidation resulting from MA but not MPTP treatment. Elevated levels of GSHPx also appeared to prevent decreases in transport-mediated dopamine uptake produced via MA administration as well as to attenuate toxin-induced cell loss as measured by either MTT reduction or LDH release. Our data, therefore, suggest that hydrogen peroxide production likely contributes to MA toxicity in dopaminergic neurons.
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PMID:Elevated expression of glutathione peroxidase in PC12 cells results in protection against methamphetamine but not MPTP toxicity. 919 Oct 89

The ability of 7-nitroindazole (7-NI) to protect against MPTP-induced neurotoxicity has been attributed to its inhibition of neuronal nitric oxide synthase. In the present study, 7-NI was found to counteract almost completely striatal dopamine depletion caused by a single subcutaneus injection of 20 mg/kg MPTP in mice. This effect, however, was accompanied by a significant reduction in the striatal levels of MPP+, the toxic metabolite generated via monoamine oxidase B-catalyzed MPTP oxidation. In the presence of 7-NI, a dose of 40 mg/kg MPTP produced MPP concentrations similar to those measured after treatment with 20 mg/kg MPTP alone. A comparison of neurotoxicity in these two experimental conditions (i.e., mice treated with 20 mg/kg alone versus 40 mg/kg MPTP plus 7-NI) revealed only a slight (20%), but statistically significant, protection of dopamine depletion with 7-NI. These data indicate that the mechanism by which 7-NI counteracts MPTP neurotoxicity in mice is not due solely to inhibition of neuronal nitric oxide synthase, but involves a reduction in MPP+ formation.
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PMID:Inhibition of monoamine oxidase contributes to the protective effect of 7-nitroindazole against MPTP neurotoxicity. 932 8

1. MPTP and its major metabolite MPP+ have significant effects on body temperature regulation in mice, which are both age and strain dependent. 2. These effects were produced by intraperitoneal injection of either MPTP or MPP+ suggesting that the predominant site of action lies outside the blood-brain barrier. 3. The initial hyperthermia induced in CD-1 mice, which was sufficient to lead to the induction of HSP 72, appears to have a protective effect with regard to striatal dopamine depletion. 4. Cultured CHO cells are sensitive to MPP+ cytotoxicity at high concentrations. This toxicity can be reduced by heat shocking the cells prior to the addition of MPP(+)-containing media. 5. In summary, these in vivo and in vitro data strongly suggest that heat shock proteins (HSP 72) play a neuroprotective role in MPTP-induced neurotoxicity.
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PMID:Role of heat shock proteins in MPTP-induced neurotoxicity. 936 85

Three steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity were compared with the neurodegenerative effects of the toxin in mice and rats. Firstly, we compared the neurotoxicity of MPTP, mediated by monoamine oxidase (MAO)-B, to that of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP), an analogue oxidized by MAO-A and MAO-B. Both toxins caused degeneration of dopamine terminals in mice but not in rats. In NMRI mice noradrenaline terminals were also affected by both toxins. Pretreatment with deprenyl to prevent MAO-B-mediated oxidation in the capillary endothelium enhanced dopamine toxicity to 2'-CH3-MPTP in nucleus accumbens but no potentiation was seen in striatum and the olfactory tubercle. Secondly, synaptosomal uptake of the 1-methyl-4-phenylpyridinium ion (MPP+) was studied. Uptake in rats was not significantly different from that in the two mice strains. Thirdly, no significant differences were found in MPP(+)-induced lactate production in striatal slices or synaptosomes. We conclude that the lack of effect of MPTP in rats is not due to mechanisms specific for MPTP but probably to the ability of rat catecholamine neurons to cope with, and survive, impaired energy metabolism.
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PMID:Comparison of key steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in rodents. 939 88

Systemic administration of MPTP to experimental animals induces neurodegeneration of dopaminergic neurons in the central nervous system. MPTP crosses the blood-brain barrier where it is taken up by astrocytes and converted to MPP+ by monamine oxidase-B (MAO-B). Subsequently, MPP+ is selectively taken up by dopaminergic neurons upon which it exerts intracellular neurotoxic effects. Systemic administration of the selective MAO-B inhibitor deprenyl prevents the conversion of MPTP to MPP+ and by this mechanism is able to protect against MPTP neurotoxicity. Deprenyl has also been reported to exert neuroprotective effects that are independent of its MAO-B inhibitory properties, but since MPP+ itself does not cross the blood-brain barrier it is difficult to directly study the MAO-B independent in vivo effects of MPP+ itself. One approach is to use organotypic tissue cultures of the canine substantia nigra (CSN) which permit administration of precise concentrations of pharmacological agents directly to mature, well-developed and metabolically active dopaminergic neurons. These neurons as well as other components of the cultures exhibit morphological and biochemical characteristics identical to their in vivo counterparts. This study was undertaken to evaluate the neuroprotective effects of deprenyl in MPP(+)-treated cultures by measuring changes in the levels of HVA as an indicator of dopamine release and metabolism by dopaminergic neurons and to correlate this indication of dopaminergic function with morphological evidence of survival or loss of dopaminergic neurons in mature CSN cultures. Mature CSN cultures, at 44 days in vitro (DIV), were exposed to either MPP+ alone, deprenyl alone or simultaneously to both deprenyl and MPP+ or to MPP+ following 4 day pretreatment with deprenyl. Exposure to MPP+ alone caused significant reduction in HVA levels, evidence of widespread injury and ultimate disappearance of large neurons in the cultures. These effects were attenuated by simultaneous exposure to MPP+ and deprenyl and the destructive effects of MPP+ appeared to be prevented by pretreatment with deprenyl. Thus the neuroprotective effects of deprenyl on MPP(+)-induced reduction of HVA levels in living cultures appears similar to the effects of deprenyl on dopamine levels and tyrosine hydroxylase activity reported by others in cultures previously exposed to deprenyl and MPP+. These studies also confirm that the neuroprotective effects of deprenyl against MPP+ in dopaminergic neurons are, at least in part, independent of deprenyl's inhibition of MAO-B.
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PMID:Attenuation of 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity by deprenyl in organotypic canine substantia nigra cultures. 945 19

In this study, we examined the possibility that MPTP and 6-hydroxydopamine (6-OHDA) act on distinct cell death pathways in a murine dopaminergic neuronal cell line, MN9D. First, we found that cells treated with 6-OHDA accompanied ultrastructural changes typical of apoptosis, whereas MPP+ treatment induced necrotic manifestations. Proteolytic cleavage of poly-(ADP-ribose)polymerase by caspase was induced by 6-OHDA, whereas it remained uncleaved up to 32 h after MPP+ treatment and subsequently disappeared. Accordingly, 6-OHDA- but not MPP(+)-induced cell death was significantly attenuated in the presence of a broad-spectrum caspase inhibitor, N-benzyloxy-carbonyl-Val-Ala-Asp-fluomethylketone (Z-VAD-fmk). As measured by fluorometric probes, the level of reactive oxygen species (ROS) significantly increased after 6-OHDA treatment. In contrast, the level of dihydroethidium-sensitive ROS following MPP+ treatment remained unchanged while a slight increase in dichlorofluorescin-sentive ROS was temporarily observed. As demonstrated by immunoblot analysis, the level of superoxide dismutase was down-regulated following 6-OHDA treatment, whereas it remained unchanged after MPP+ treatment. Cotreatment of cells with antioxidants such as N-acetylcysteine or Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP, cell-permeable superoxide dismutase mimetic) rescued 6-OHDA- but not MPP(+)-induced cell death, whereas inclusion of catalase or N(G)-nitro-L-arginine had no effect in both cases. In addition, 6-OHDA induced ROS-mediated c-Jun N-terminal kinase (JNK) activation that was attenuated in the presence of N-acetylcysteine or MnTBAP but not catalase or Z-VAD-fmk. In contrast, MPP+ has little effect on JNK activity, indicating that ROS and/or ROS-induced cell death signaling pathway seems to play an essential role in 6-OHDA-mediated apoptosis but not in MPP(+)-induced necrosis in a mesencephalon-derived, dopaminergic neuronal cell line.
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PMID:Two distinct mechanisms are involved in 6-hydroxydopamine- and MPP+-induced dopaminergic neuronal cell death: role of caspases, ROS, and JNK. 1039 38

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is dependent upon the MAO-B (monoamine oxidase type B)-catalyzed production of 1-methyl-4-phenylpyridinium ion (MPP(+)) and is likely to involve a perturbation of energy metabolism. Protection against MPTP neurotoxicity has been shown by treating mice with 7-nitroindazole (7-NI), a reversible inhibitor of both MAO-B and neuronal nitric oxide synthase (nNOS) activity. The objective of the present study was to evaluate (i) the relationship between the neuroprotective effect of 7-NI and MPTP-induced energy deficiency, and (ii) the role of nitric oxide production as a potential mechanism for energy perturbation after MPTP exposure. Maximum protection against striatal dopamine depletion and nigral neuronal loss was achieved when 7-NI (50 mg/kg, i.p.) was administered to C57BL/6 mice immediately before and after MPTP (50 mg/kg, s.c.). This short-term regimen of 7-NI administration parallels the time when MPTP exposure causes energy failure. 7-NI also completely prevented the loss of striatal ATP that occurs in mice during the initial hours after MPTP administration. In contrast, N(G)-nitro-L-arginine (two injections of 50 mg/kg each, given i.p. 20 and 4 h prior to MPTP), another NOS inhibitor, failed to affect MPTP-induced ATP depletion. Taken together, data indicate that (i) a temporal and causal relationship exists between the neuroprotective effect of 7-NI and its ability to counteract ATP reduction, and (ii) MAO-B rather than NOS inhibition is the mechanism by which 7-NI counteracts MPTP-induced ATP depletion.
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PMID:7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced ATP loss in the mouse striatum. 1048 97

We have studied the interaction of coenzyme Q with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)), the real neurotoxin to cause Parkinson's disease. Incubation of MPTP or MPDP(+) with rat brain synaptosomes induced complete reduction of endogenous ubiquinone-9 and ubiquinone-10 to corresponding ubiquinols. The reduction occurred in a time- and MPTP/MPDP(+) concentration-dependent manner. The reduction of ubiquinone induced by MPDP(+) went much faster than that by MPTP. MPTP did not reduce liposome-trapped ubiquinone-10, but MPDP(+) did. The real toxin MPP(+) did not reduce ubiquinone in either of the systems. The reduction by MPTP but not MPDP(+) was completely prevented by pargyline, a type B monoamine oxidase (MAO-B) inhibitor, in the synaptosomes. The results indicate that involvement of MAO-B is critical for the reduction of ubiquinone by MPTP but that MPDP(+) is a reductant of ubiquinone per se. It is suggested that ubiquinone could be an electron acceptor from MPDP(+) and promote the conversion from MPDP(+) to MPP(+) in vivo, thus accelerating the neurotoxicity of MPTP.
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PMID:1-Methyl-4-phenyl-2,3-dihydropyridinium is transformed by ubiquinone to the selective nigrostriatal toxin 1-methyl-4-phenylpyridinium. 1056 96

The endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3, 4-tetrahydroisoquinoline (salsolinol), which is structurally similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has been reported to inhibit mitochondrial complex I (NADH-Q reductase) activity as does the MPTP metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)). However, the mechanism of salsolinol leading to neuronal cell death is still unknown. Thus, we correlated indices of cellular energy production and cell viability in human dopaminergic neuroblastoma SH-SY5Y cells after exposure to salsolinol and compared these results with data obtained with MPP(+). Both toxins induce time and dose-dependent decrease in cell survival with IC(50) values of 34 microM and 94 microM after 72 h for salsolinol and MPP(+), respectively. Furthermore, salsolinol and MPP(+) produce a decrease of intracellular net ATP content with IC(50) values of 62 microM and 66 microM after 48 h, respectively. In contrast to MPP(+), salsolinol does not induce an increase of intracellular net NADH content. In addition, enhancing glycolysis by adding D-glucose to the culture medium protects the cells against MPP(+) but not salsolinol induced cellular ATP depletion and cytotoxicity. These results suggest that cell death induced by salsolinol is due to impairment of cellular energy supply, caused in particular by inhibition of mitochondrial complex II (succinate-Q reductase), but not complex I.
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PMID:1-Methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) is toxic to dopaminergic neuroblastoma SH-SY5Y cells via impairment of cellular energy metabolism. 1065 Jan 31


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