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)

MPP(+), the major metabolite of the Parkinsonism-inducing compound MPTP, responsible for the destruction of the nigrostriatal pathway in primates and rodents, has been assayed in isolated rat liver mitochondria in the presence of physiological concentrations of dopamine or analogous concentrations of melanin-dopamine. 5 microM MPP(+) in the presence of 70 microM dopamine or melanin-dopamine, but not alone, decreased the heat production and oxygen consumption of a mitochondrial suspension activated with succinate and ADP. Both dopamine and oxidized dopamine plus MPP(+) also decreased the mitochondrial reductive power measured with MTT. Mitochondrial swelling was observed, associated with an increase in membrane mitochondrial potential, as a synergistic effect between low concentrations of MPP(+) and dopamine. It is suggested that cytosolic dopamine, by itself or via its autooxidation products, may play a relevant role in the mitochondrial toxicity of MPP(+). A failure in the regulation of the storage/release of dopamine could aggravate a mitochondrial damage and trigger the neurodegenerative process underlying MPTP toxicity and Parkinson's disease.
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PMID:MPP(+)-induced mitochondrial dysfunction is potentiated by dopamine. 1067 5

Riluzole, has previously been shown to be protective in animal models of Parkinson's disease in vivo. In the present study the effects of riluzole on the intrastriatal formation and accumulation of MPP(+), after i.p. injection of MPTP were tested in mice, using two different experimental protocols. In the first protocol, mice were treated with a single dose (15 mg/kg i.p.) of MPTP and MPP(+) accumulation was measured 30 min, 1 h and 3 h after the injection of the toxin. Riluzole (10 mg/kg p.o.), administered 30 min before MPTP, did not modify the accumulation kinetic of MPP(+). Contrarily to riluzole, a single dose of 50 mg/kg p.o. of 7-nitroindazole (7-NI), a non-selective non hypertensive inhibitor of nitric oxide synthase (NOS), significantly decreased MPP(+) levels. In the second protocol, consisting of 3 injections of MPTP (15 mg/kg i.p.), riluzole, administered 4 times at the dose of 5 mg/kg p.o., had no effect on MPP(+) levels. The protective effect of repeated treatments of riluzole and 7-NI against MPTP-induced depletion of dopamine (DA) is also reported. Our data obtained with 7-NI (in agreement with previous studies reported by others) suggest that a part of the protection observed with this NOS inhibitor is probably due to in vivo inhibition of monoamine oxidase-B (MAO-B). That riluzole does not modify MPP(+) accumulation demonstrates that its protective effect against MPTP toxicity was not due to an in vivo interference with MPTP metabolism.
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PMID:The protective effect of riluzole in the MPTP model of Parkinson's disease in mice is not due to a decrease in MPP(+) accumulation. 1072 11

To elucidate the toxicological relevance of hepatic aldehyde oxidase (AO) as a detoxification enzyme of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), we studied the metabolism and the hepatotoxicity of MPTP in intact rat livers exhibiting different AO activities by using a recirculating perfusion method. In the perfusate during a 90-min recirculation of 1 mM MPTP, the perfused liver from Jcl:Wistar rat, a strain showing high AO activity, generated almost equal amounts of 1-methyl-4-phenylpyridinium species (MPP(+)) and 1-methyl-4-phenyl-5,6-dihydro-2-pyridone (MPTP lactam) as major metabolites, together with 4-phenyl-1,2,3, 6-tetrahydropyridine, 1-methyl-4-phenyl-2-pyridone (MP 2-pyridone) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide. However, a marked decrease of MPTP lactam as well as MP 2-pyridone and a concomitant increase of MPP(+) were caused by coinfusion of 2-hydroxypyrimidine (2-OH PM), a competitive inhibitor of AO, into Jcl:Wistar rat liver. A quite similar metabolic profile was obtained on perfusion of AO-deficient WKA/Sea rat liver. Rather large amounts of MPP(+) were retained in the liver in all cases, but especially in Jcl:Wistar rat in the presence of 2-OH PM. Lactate dehydrogenase leakage into the perfusate from rat liver perfused with 1 mM MPTP was greater in the strain with lower AO activity, WKA/Sea, than in that with higher AO activity, Jcl:Wistar. Furthermore, inhibition of AO in Jcl:Wistar rat in the presence of 2-OH PM caused an enhancement of lactate dehydrogenase leakage. These results suggest that hepatic AO is a key detoxification enzyme for MPTP.
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PMID:Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in perfused rat liver: involvement of hepatic aldehyde oxidase as a detoxification enzyme. 1077 32

Significant differences exist in the sensitivity of mice and rats to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that cannot be explained by differences in exposure to or uptake of 1-methyl-4-phenylpyridinium (MPP(+)) into dopamine (DA) neurons. MPP(+) is also a substrate for the brain vesicular monoamine transporter (VMAT2), and sequestration into synaptic vesicles may be one mechanism of protection against MPP(+) toxicity. A greater sequestration of MPP(+) into vesicles of DA neurons in rats versus mice could explain the lower vulnerability of DA neurons in the rat to MPP(+) toxicity. To test this hypothesis, the kinetics of uptake for [(3)H]MPP(+) and [(3)H]DA as well as [(3)H]dihydrotetrabenazine binding to VMAT2 were compared in vesicles isolated from the striata of rats and mice. The K(m) value of [(3)H]MPP(+) transport was similar in the two species. In contrast, the maximal transport rate (V(max)) was 2-fold greater in vesicles from rats than in those from mice. Likewise, the K(m) value for [(3)H]DA transport was similar in both preparations, but the V(max) value was 2-fold greater in rat than in mouse vesicles. The B(max) value for [(3)H]dihydrotetrabenazine binding was also 2-fold greater in striatal vesicles from rats than in those from mice. Electron micrographs demonstrated that vesicles isolated from rats and mice were approximately the same size. Based on these observations, we propose that striatal vesicles from rats have more VMAT2 than vesicles from mice and that this species difference in VMAT2 density may help explain the reduced vulnerability of rat DA neurons to MPP(+) neurotoxicity.
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PMID:In vitro studies of striatal vesicles containing the vesicular monoamine transporter (VMAT2): rat versus mouse differences in sequestration of 1-methyl-4-phenylpyridinium. 1077 99

Dopamine neurons from various animal species differ in sensitivity to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)). Compared with striatal vesicles isolated from mice, those from rats have a higher density of the brain vesicular monoamine transporter (VMAT2) and a greater ability to sequester MPP(+), suggesting a larger storage capacity for MPP(+) in rat vesicles. In the present study, we examined whether striatal VMAT2-containing vesicles might provide protection against the neurotoxic effects of MPP(+) in vivo. Dose-response curves for striatally infused MPP(+) were determined in animals pretreated with or without a VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.; VMAT2 inhibitor) produced a 5-fold leftward shift in the MPP(+) dose-response curve and a significant lowering of the EC(50) concentration for MPP(+)-induced damage. These findings provide evidence for a substantial accumulation of MPP(+) in VMAT2-containing vesicles in vivo in the rat striatum and support the hypothesis that MPP(+) sequestration in vesicles can provide protection against its toxic actions. In mice, VMAT2 inhibition did not reliably enhance toxicity produced by a striatal infusion of MPP(+) or by systemic administration of MPTP. These data suggest that vesicular sequestration of MPP(+) may be of less importance in mice than in rats as relates to protection from the toxin. The present results also reveal that although VMAT2 inhibition enhanced striatal MPP(+) toxicity in the rat, the potency of MPP(+) in the rat striatum was less than that in mouse striatum. This implies that there are other factors that either exacerbate MPP(+) toxicity in the mouse or attenuate MPP(+) toxicity in rats.
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PMID:Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata. 1077

The present study elucidated the protective effect of beta-carbolines (harmaline, harmalol, and harmine) on oxidative neuronal damage. MPTP treatment increased activities of total superoxide dismutase, catalase, and glutathione peroxidase and levels of malondialdehyde and carbonyls in the basal ganglia, diencephalon plus midbrain of brain compared with control mouse brain. Coadministration of harmalol (48 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. Harmaline, harmalol, and harmine attenuated both the 500 microM MPP(+)-induced inhibition of electron flow and membrane potential formation and the 100 microM dopamine-induced thiol oxidation and carbonyl formation in mitochondria. The scavenging action of beta-carbolines on hydroxyl radicals was represented by inhibition of 2-deoxy-D-ribose degradation. Harmaline and harmalol (100 microM) attenuated 200 microM dopamine-induced viability loss in PC12 cells. The beta-carbolines (50 microM) attenuated 50 microM dopamine-induced apoptosis in PC12 cells. The compounds alone did not exhibit significant cytotoxic effects. The results indicate that beta-carbolines attenuate brain damage in mice treated with MPTP and MPP(+)-induced mitochondrial damage. The compounds may prevent dopamine-induced mitochondrial damage and PC12 cell death through a scavenging action on reactive oxygen species and inhibition of monoamine oxidase and thiol oxidation.
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PMID:Protective effect of harmalol and harmaline on MPTP neurotoxicity in the mouse and dopamine-induced damage of brain mitochondria and PC12 cells. 1089 27

The neuropathology of Parkinson's disease is reflected in experimental animals treated with the selective nigrostriatal dopaminergic neurotoxin MPTP. Neurons exposed to MPTP (MPP(+)) express morphological features of apoptosis, although the intracellular pathways that produce this morphology have not been established. The c-Jun NH(2)-terminal kinase (JNK) signaling cascade has been implicated as a mediator of MPTP-induced apoptotic neuronal death based on the ability of CEP-1347/KT-7515, an inhibitor of JNK activation, to attenuate MPTP-induced nigrostriatal dopaminergic degeneration. In these studies, MPTP-mediated activation of the JNK signaling pathway was assessed in the nigrostriatal system of MPTP-treated mice. MPTP elevated levels of phosphorylated JNK and JNK kinase (MKK4; also known as SEK1 or JNKK), by 2.5- and fivefold, respectively. Peak elevations occurred soon after administration of MPTP and coincided with peak CNS levels of MPP(+). Increased MKK4 phosphorylation, but not JNK phosphorylation, was found in the striatum, suggesting that activation of MKK4 occurs in injured dopaminergic terminals. Both JNK and MKK4 phosphorylations were attenuated by pretreatment with l-deprenyl, indicating that these phosphorylation events were mediated by MPP(+). Moreover, CEP-1347/KT-7515 inhibited MPTP-mediated MKK4 and JNK signaling at a dose that attenuates MPTP-induced dopaminergic loss. These data implicate this signaling pathway in MPTP-mediated nigrostriatal dopaminergic death and suggest that it may be activated in the degenerative process in Parkinson's disease.
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PMID:MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. 1093 3

MPP(+), an active metabolite of MPTP, causes a dopaminergic neuronal degeneration similar to that observed in Parkinson's disease. Current data suggest that MPP(+)-induced cytotoxicity may be mediated by oxygen free radicals. To evaluate this hypothesis, we first investigated whether MPP(+) could cause oxidative stress by producing oxygen free radicals in the SH-SY5Y, human neuroblastoma cell line. MPP(+) was toxic to the cells dose-dependently but did not increase the level of lipid peroxidation at toxic concentrations. Second, we examined the effects of various antioxidants and an inhibitor of nitric oxide synthase (NOS) on the development of MPP(+) cytotoxicity. Pretreatment with antioxidants such as ascorbic acid, Trolox, phenyl-tertiary-butyl-nitrone (PBN), which show protective effects on tert-butyl hydroperoxide (tBOOH) toxicity did not attenuate MPP(+) cytotoxicity. Similarly, the combination of antioxidant enzymes, SOD and catalase (50 U/ml, respectively), did not protect the cells from the toxic action of MPP(+). Also N-nitro-l-arginine methyl ester (NAME), a competitive inhibitor of NOS, and combined incubation with NAME and antioxidant enzymes failed to attenuate MPP(+) cytotoxicity. On the other hand, a sublethal dose of MPP(+) potentiated iron and H(2)O(2)-induced cytotoxicity. These results suggest that oxygen free radicals may not be a primary cause of MPP(+)-induced cell death but that MPP(+) increases the vulnerability of cells to oxidative stress.
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PMID:MPP(+) increases the vulnerability to oxidative stress rather than directly mediating oxidative damage in human neuroblastoma cells. 1096 95

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), via its major metabolite 1-methyl-4-phenylpyridinium (MPP(+)), produces in primates including humans clinical, biochemical, and neuropathological changes similar to those which occur in idiopathic Parkinson's disease. Ebselen is an antioxidant drug with glutathione peroxidase-like activity and a proven neuroprotective action in stroke patients. Here we show that Ebselen, when administered before, during, and after MPTP injections, prevents both neuronal loss and clinical symptoms in a primate MPTP model of Parkinson's disease. Ebselen also prevents peroxide radical overproduction induced by serum withdrawal in cultured PC12 cells and hydroxyl radical generation induced by the mitochondrial toxin, MPP(+), in vivo in rat brain. Moreover, Ebselen inhibits MPP(+)-induced toxicity in PC12 cells, without interacting with the dopamine uptake system. Our results demonstrate that compounds which prevent mitochondrial dysfunction and free radical production may be useful as preventive treatment of Parkinson's disease.
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PMID:The antioxidant ebselen prevents neurotoxicity and clinical symptoms in a primate model of Parkinson's disease. 1108 89

MPTP is known to cause PD symptoms in primates and in rodents. In order to exert its neurotoxicity MPTP must be converted by monoamine oxidase B into MPP(+) which is the true toxic agent. MPP(+) is taken up by the dopaminergic neurons of the substantia nigra in which it induces cell death. The present work reviews and discusses papers in which specific methods were used to determine whether cell death induced by MPTP/MPP(+) should be considered as apoptosis or necrosis. These two cell death modes may be distinguished using morphological and biochemical criteria. The effect of MPTP/MPP(+) was studied in vitro and in vivo. The results show that no univocal answer is possible. The most widespread interpretation is that MPTP/MPP(+) causes apoptosis when its neurotoxic effect is only sligh and necrosis when it is stronger. Similar considerations may be made also concerning the type of cell death occurring in the dopaminergic neurons in the substantia nigra of PD patients.
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PMID:Cell death induced by MPTP, a substrate for monoamine oxidase B. 1109 Sep 54


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