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)

An experimental parkinsonian syndrome (PS) was induced by systemic administration of MPTP or oxotremorine, by intranigral administration of MPP+ or injection of acetyl choline and proserine into the rostral part of both caudate nuclei. The development of extrapyramidal disorders was studied simultaneously with EEG recording. The electric activity (EA) was recorded in the sensorimotor cortex, caudate nuclei, ventrolateral nuclei of the thalami, substantia nigra and globus pallidus. Tremor, oligokinesia and rigidity were characterized by the appearance of paroxysmal activity on EA with high amplitude of slow and rapid waves. The data obtained allow us to conclude that PS neuropathophysiological basis is the formation of the generator of pathologically enhanced excitation (GPEE) in the caudate nuclei. It was found that akinesia-rigidity syndromes were observed in the rats with both MPTP and MPP(+)-induced PS. Tremor was observed after administration of oxotremorine or acetyl choline with proserine more often than after treatment with MPTP or MPP+. Some peculiarities of the GPEE activity in these forms of PS were observed. Also, there is dissociation in effects of antiparkinsonian drugs in different forms of PS.
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PMID:[The characteristics of a parkinsonian syndrome induced in an experiment by a deficiency of nigrostriatal dopamine and by stimulation of the cholinergic neurons of the caudate nucleus]. 816 Apr 97

Using a modified microdialysis procedure, we confirmed that intrastriatal administration of 1-methyl-4-phenylpyridinium ion (MPP+) induced a sustained overflow of dopamine accompanied by increased formation of hydroxyl free radicals (.OH) as reflected by salicylate hydroxylation. Pretreatment with l-deprenyl (selegiline 60 pmol, intrastriatal perfusion) significantly decreased the .OH formation elicited by MPP+ (75 nmol). There was a small decrease of dopamine efflux and an insignificant change of the ratio of 3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine following l-deprenyl pretreatment. These in vivo findings support prior in vitro data that an unique antioxidant property of l-deprenyl may be independent of its inhibition of type B monoamine oxidase. In addition, intranigral co-administration of l-deprenyl (4.2 nmol) with MPP+ (4.2 nmol) completely protected nigral neurons from probable oxidative injuries induced by MPP+ (4.2 nmol), as reflected by a near 50% loss of striatal dopamine ipsilateral to the side of infusion of drug into the substantia nigra. This apparent neuroprotective effect of l-deprenyl on midbrain nigral neurons was also confirmed by histological findings. The present in vivo data clearly demonstrate that l-deprenyl can protect nigral neurons against dopamine neurotoxicity produced by MPP+, as suggested by an earlier in vitro study. Thus, l-deprenyl can preserve the function of MPP(+)-damaged nigral neurons perhaps by its apparent antioxidant property in addition to its blockade of the bioactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium metabolites by type B monoamine oxidase.
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PMID:Apparent antioxidant effect of l-deprenyl on hydroxyl radical formation and nigral injury elicited by MPP+ in vivo. 827 76

MPP+ has been reported to inhibit reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase in mitochondria, which results in the formation of O2(.-). The current report demonstrates that H2O2 and HO. are also products of MPP+ interaction with NADH dehydrogenase. It is possible that MPP. formation precedes the formation of some of these active oxygen species. Reducing equivalents for radical formation come from NADH. MPP+ may be capable of interacting with submitochondrial particles at a site other than the rotenone site, which results in some formation of oxygen radicals. Plasma amine oxidase incubations with MPDP+ resulted in O2.- H2O2, and perhaps HO. formation. This is probably due to MPP. formation from the oxidation of MPDP+. This study presents new findings that indicate the potential importance of oxygen radical formation in mitochondria during MPTP toxicity.
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PMID:MPP+ and MPDP+ induced oxygen radical formation with mitochondrial enzymes. 839 43

The present study clearly demonstrated that l-deprenyl confers a substantial protective effect against MPP+ in the substantia nigra zona compacta in vivo. 32.39. The protection provided by l-deprenyl may not depend on its inhibition of type B monoamine oxidase. A unique antioxidant property of l-deprenyl by suppression of cycotoxic. OH formation and associated oxidative damage induced by MPP+ in the A9 melanized nigral neurons may contribute to the protection against MPP+ toxicity in the nigrostriatal system. The likelihood that l-deprenyl may confer neuroprotection against MPP+ toxicity through antioxidant effect is further strongly supported by our recent data that U-78517F (2-methlaminochromans) a potent inhibitor of ironcatalyzed lipid peroxidation, and DMSO an effective. OH scavenger also protect nigral neurons against MPP(+)-induced severe oxidative injury in the substantia nigra. This putative antioxidant effect of deprenyl may explore another mechanism which may in part contribute to its overt neuroprotection against several toxins, including 6-OHDA, DSP-4, and MPTP, and the possible clinical effects on slowing the neuronal degeneration in early Parkinson's disease, Alzheimer's disorder and even senescent changes.
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PMID:Suppression of hydroxyl radical formation and protection of nigral neurons by l-deprenyl (selegiline). 868 36

Levels of uric acid, xanthine, hypoxanthine, ascorbic acid (AA), dehydroascorbic acid (DHAA), glutathione (GSH), noradrenaline (NA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined in the striatum and/or in the brain stem of 3-month-old male Wistar rats given allopurinol (300 mg/kg day by gavage) for 3 days before a single MPTP 35 mg/kg dose IP. Allopurinol alone decreased uric acid and increased xanthine levels both in the striatum and in the brain stem; moreover, allopurinol decreased striatal DOPAC + HVA/DA ratio and increased 5-HIAA/5HT ratio in the brainstem. Allopurinol affected neither regional MPTP nor MPP+ disposition. Allopurinol potentiated the MPTP-induced decrease in the DOPAC+HVA/DA ratio and increase in striatal AA oxidation; in addition, allopurinol antagonised the MPTP-induced: (i) increase in uric acid levels; (ii) decrease in NA levels in both regions, in DA levels, and in the 5-HIAA/5-HT ratio in the brain stem: (iii) increase in AA oxidation in the brain stem. In conclusion, the MPP(+)-induced oxidative stress mediated by xanthine oxidase seems to be involved in DA depletion in the brainstem and in NA depletion in both regions; moreover, striatal uric acid may have an active role in the neuronal antioxidant pool.
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PMID:Further investigation of allopurinol effects on MPTP-induced oxidative stress in the striatum and brain stem of the rat. 874 98

Intranigral infusion of 1-Methyl-4-phenylpyridinium ion (MPP+, 2.1-16.8 nmol) dose-dependently injured nigral neurons as reflected by reduced dopamine levels in the ipsilateral striatum four days after the infusion of this toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Coadministration of deprenyl (4.2 nmol) with MPP+ into the substantia nigra protected against MPP(+)-induced moderate (20-50%) but not severe (over 70%) nigral injury as reflected in striatal dopamine reductions. However, supplementary treatment with deprenyl (0.25 mg/kg, s.c., twice daily for 4 days) after intranigral infusion of MPP+ significantly rescued nigral neurons from more severe damage caused by a higher MPP+ does (8.4 nmol) manifested by a lesser striatal dopamine decrease (-31%) compared to the non-deprenyl treated group (-70%). Thus, in addition to the blockade of bioactivation of MPTP, deprenyl can protect and/or rescue nigral neurons from MPP(+)-induced dopaminergic neurotoxicity. These in vivo data add further evidence to suggest that deprenyl, a putative and clinically unproven neuroprotective agent, may be of value in slowing the progressive nigral degeneration in "early" Parkinson's disease, but may prove to be less so in its terminal stages.
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PMID:Neuronal protective and rescue effects of deprenyl against MPP+ dopaminergic toxicity. 874 63

The ability of selegiline to protect against the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of the conversion of MPTP to 1-methyl-4-phenylpyridinium (MPP+), catalyzed by monoamine oxidase-B. Selegiline, however, has been found to rescue neurons in MPP(+)-treated mice after they have sustained lethal damage independently of monoamine oxidase-B inhibition. In our present study, we investigate whether selegiline can protect and/or rescue MPP(+)-injured dopaminergic neurons in co-cultures of mesencephalic and striatal cells of embryonic C57B1/6 mouse brains. Cells were exposed to selegiline (1, 10, 100 microM) in three different schemes: (i) in control cultures on the 8th day for 48 h; (ii) pretreatment: on the 8th day for 48 h, followed by administration of MPP+ (0.5 microM) on the 9th day for 24 h; (iii) delayed treatment: on the 9th day for 48 h, while MPP+ was administered on the 8th day and remained in culture during treatment with selegiline. In the delayed scheme, selegiline (1 microM) increased dopamine content, number of tyrosine hydroxylase immunoreactive cells and astrocytes in the cultures. We question whether selegiline protects cells injured by a toxic stressor via an astrocyte-mediated mechanism.
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PMID:Selegiline is neuroprotective in primary brain cultures treated with 1-methyl-4-phenylpyridinium. 881 31

MPP-production and uptake by dopaminergic terminals are critical steps in MPTP-induced Parkinson-like disorder. We reported evidence for a specific uptake of MPP by synaptic vesicles from mouse striatum. Its regional distribution suggests it as a marker of the dopamine vesicular carrier. We decided to further characterize such an MPP uptake. Tetrabenazine inhibits the dopamine uptake both in the striatum and in the cerebellum with similar Km values suggesting an identify of the vesicular carrier in these areas. On the contrary, 3H-MPP vesicular uptake had in the striatum a t1/2 of 60 sec, but was not detectable at any time in the cerebellum. Moreover, MPP inhibited the uptake of 3H-DA (Ki: 1.6 +/- 0.03 microM) and 3H-NE (Ki 2.6 +/- 0.01 microM) in the striatum but not in the cerebellum, even at molar concentration. These pharmacological data indicate that in nondopaminergic areas the monoamine carrier may be similar but not identical from that located in dopaminergic areas.
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PMID:Heterogeneity of monoaminergic vesicular carriers: pharmacological evidence using MPP+ as a marker. 889 Sep 44

1-Methyl-4-phenylpyridinium (MPP+), the cytotoxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has been shown to be toxic to a variety of cell types in culture. The addition of media containing 1 mM MPP+ to cultures of Chinese hamster ovary (CHO) fibroblasts led to the gradual depletion of cellular ATP stores and subsequent cell death. A 12-min heat shock of the cells at 45 degrees C, 3 h prior to the addition of MPP(+)-containing media, significantly attenuated cell death. Heat shock pretreatment led to an increased synthesis of all the major heat shock proteins (HSPs) in CHO cells. Further, the addition of the protein synthesis inhibitor, cycloheximide, prevented the protective effect of heat shock pretreatment, indicating that this protection was dependent upon new protein synthesis. In additional experiments, a rat fibroblast cell line which has been stably transfected with, and constitutively expresses a cloned human HSP-70 gene, was found to be more resistant to the cytotoxic effects of MPP+ than the parental fibroblast cell line. These results indicate that HSPs are protective toward the deleterious effects of MPP+ and that their synthesis represents an important parameter in the neurotoxicity of MPTP.
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PMID:Heat shock proteins protect cultured fibroblasts from the cytotoxic effects of MPP+. 890 68

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces Parkinsonism, is mediated by its metabolite 1-methyl-4-phenylpyridinium ion (MPP+). When injected into the striatum MPP+ is accumulated by dopaminergic nerve terminals and is then retrogradely transported to the substantia nigra compacta. The mechanism by which it mediates cell death involves both inhibition of complex I of the electron transport chain and free radical generation. In the present experiments we found that administration of the free radical spin trap N-tert-butyl-alpha-(2-sulfophenyl) nitrone (S-PBN) significantly attenuated substantia nigra cell loss produced by MPP+ administration into rat striatum. We also found that coadministration of coenzyme Q10 with nicotinamide, which attenuates energy depletion, significantly blocked MPP(+)-induced substantia nigra damage. Last, we found that a single administration of MPP+ into rat striatum can produce progressive cell loss in the substantia nigra and that administration of S-PBN starting 7 days after administration of MPP+ can block the ensuing neuronal damage. These observations suggest that a one-time exposure to a neurotoxic agent may result in progressive neuronal degeneration mediated by oxidative stress.
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PMID:MPP+ produces progressive neuronal degeneration which is mediated by oxidative stress. 912 70


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