Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High concentrations of the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) are toxic to the catecholaminergic cell line PC12, derived from rat phenochromocytoma. Prolonged exposure of wild-type PC12 cells to 500 microM MPP+ yields toxin-resistant colonies at a frequency of 2 X 10(-4). These spontaneously arising MPP(+)-resistant cells are morphologically quite distinct from wild-type PC12 cells, and are lacking in most of their characteristic catecholaminergic properties. In contrast, among PC12 cells infected with the murine retrovirus ZIPNEOSV(X), 20% are resistant to the toxin MPP+, a resistance frequency approximately 1,000 times higher than for uninfected cells. The morphology and catecholaminergic phenotype of the virus-infected MPP+ resistant cells are quite similar to those of wild-type PC12 cells. The results presented in this study suggest a unique mechanism of MPP+ resistance in the infected PC12 cells which may be conferred by the presence and/or expression of the retrovirus ZIPNEOSV(X).
 ...
PMID:Infection with murine retrovirus confers resistance to the neurotoxin 1-methyl-4-phenylpyridinium ion in PC 12 cells. 169 21

U-78518F, a 21-aminosteroid from the novel family of lipid peroxidation inhibitors (lazaroids), increased survival of dopamine (DA) neurons in mesencephalic cell cultures incubated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Protection against DA neuron death occurred with increasing concentrations of U-78518F up to 30 microM. Non-specific toxicity produced with higher concentrations of MPP+ was not affected by the lazaroid. U-78518F inhibited cellular uptake of [3H]MPP+ and [3H]DA, but not that of gamma-[3H]aminobutyric acid. In human striatal membrane preparations, U-78518F competed with [3H]mazindol for binding to the DA transporter, with a calculated Ki value of 10 microM. Two of four lazaroids tested inhibited [3H]DA uptake in the cell culture system. The protective effects of 21-aminosteroids in MPP(+)-induced neurotoxicity are, in part, a function of the interaction of these agents with the DA transporter.
 ...
PMID:21-aminosteroids interact with the dopamine transporter to protect against 1-methyl-4-phenylpyridinium-induced neurotoxicity. 172 40

Apoptosis is a prominent mechanism of programmed cell death in lymphocytes and in cancer cells not previously found in neurons. We have identified apoptosis and internucleosomal DNA degradation in cultures of cerebellar granule neurons. 1-methyl-4-phenylpyridinium, a selective neurotoxin that destroys the dopaminergic nigrostriatal pathway and results in a parkinsonian syndrome, increases the rate of apoptosis and kills cerebellar granule cells in culture via induction of programmed cell death. Inhibition of gene expression in granule cells with cycloheximide prevents the MPP(+)-induced apoptosis and the DNA fragmentation. Our findings demonstrate a new pathway of neuron death and suggest the possibility that neurodegenerative diseases may result from the inappropriate activation of programmed cell death by apoptosis.
 ...
PMID:Apoptosis and DNA degradation induced by 1-methyl-4-phenylpyridinium in neurons. 176 96

The toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its oxidized metabolite, and two recently synthesized 2'-alkyl derivatives of MPTP (methyl and ethyl), found to be more toxic in vivo in mice, have been compared in two neuroblastoma hybrid cell lines (NCB-20 and 140-3) that express the B form of monoamine oxidase (MAO), as tissue culture models for the mode of action of MPTP in the central nervous system. Unlike previously reported studies with cultured cells of neuronal origin expressing only MAO A, both of these cell lines were sensitive to MPTP. Consistent with the in vivo findings, the 2'-alkyl derivatives were much more toxic than MPTP and comparable to the oxidized metabolite MPP+ in their effects on cell survival and morphology. The cells could be protected against the reduced toxins, but not MPP+, by either the MAO A selective inhibitor, clorgyline or the MAO B selective inhibitor, deprenyl. The effectiveness of the MAO inhibitors in blocking the action of the reduced toxins was consistent with their ability to inhibit MAO activity in the cell cultures, but did not reflect MAO-substrate specificity of the toxins. Inhibitors of serotonin and dopamine uptake, which have been found to protect against MPTP toxicity in vivo, were generally ineffective in the cell cultures, with the exception of a marginal increase in survival of MPP(+)-treated 140-3 cells in the presence of the serotonin uptake inhibitor fluoxetine. These findings are discussed in relation to proposed in vivo mechanisms of MPTP cytotoxicity.
 ...
PMID:Toxicity of MPTP and structural analogs in clonal cell lines of neuronal origin expressing B type monoamine oxidase activity. 177 93

The neurotoxin MPP+ potently inhibited the striatal binding of [3H]-tyramine, a putative marker for the vesicular transporter of dopamine, and provoked a massive in vivo release of striatal dopamine. Tetrabenazine, an established ligand for the vesicular catecholamine carrier, potently inhibited [3H]-tyramine binding, tyramine-provoked striatal efflux of dopamine and the fast component of MPP(+)-induced dopamine release. It is concluded that MPP+ in the striatum, besides interacting with additional intracellular targets, avidly binds at a vesicular site functionally involved with the outward transport of dopamine.
 ...
PMID:Interaction of 1-methyl-4-phenylpyridinium ion and tyramine with a site putatively involved in the striatal vesicular release of dopamine. 179 20

In situ hybridization studies were performed to study the changes in proenkephalin mRNA levels in the neostriatum of rats with long-term (18 months) unilateral lesions of the nigrostriatal dopamine (DA) pathway induced by 1-methyl-4-phenylpyridinium ion (MPP+) and in animals bearing embryonic DA grafts implanted into the DA depleted striatum. In the ipsilateral striatum of MPP(+)-lesioned animals, there was a 2-fold increase in the levels of proenkephalin mRNA compared with those in the contralateral striatum of the same animals or the ipsilateral striatum of control animals. High resolution analysis using emulsion autoradiography showed that increase in proenkephalin gene expression in response to DA-denervation by MPP+ was due to an increase in the hybridization signal over individual expressing cells as well as to an increase in the number of labelled cells. In the DA-grafted striatum the levels of proenkephalin mRNA were significantly (P less than 0.01) reduced when compared with those in the MPP(+)-lesioned striatum due to both a decrease in the number of labelled cells as well as the hybridization density per individual cell. Moreover, when compared with the ipsilateral striatum of control animals, the levels of proenkephalin mRNA in the DA-grafted striatum was slightly lower due to a 20% decrease in the number of labelled cells rather than a decrease in the hybridization signal per individual cell. The results of this study are important in two respects. Firstly, they clearly show that the increase in proenkephalin gene expression in the striatum of rats with complete nigrostriatal DA lesions, can be maintained for many months after the lesion.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Increased proenkephalin mRNA levels in the rat neostriatum following lesion of the ipsilateral nigrostriatal dopamine pathway with 1-methyl-4-phenylpyridinium ion (MPP+): reversal by embryonic nigral dopamine grafts. 185 29

(3-si,4-re)-2,5-Dihydroxyacetanilide epoxidase (DHAE I), a key enzyme in the biosynthesis of the epoxysemiquinone antibiotic LL-C10037 alpha by Streptomyces LL-C10037 [Gould, S.J., & Shen, B. (1991) J. Am. Chem. Soc. 113, 684-686], and (3-re,4-si)-2,5-dihydroxyacetanilide epoxidase (DHAE II) isolated from Streptomyces MPP 3051--which yields the (3R,4S)-epoxyquinone mirror image product of DHAE I--are described. DHAE I was purified 640-fold. Gel permeation chromatography indicated an Mr of 117,000 +/- 10,000; SDS-PAGE gave a major band of 22,300 daltons, indicating that DHAE I is either a pentamer or hexamer in solution. The enzyme had a pH optimum of 6.5, a Km of 8.4 +/- 0.5 microM, and a Vmax of 3.7 +/- 0.2 mumol min-1 mg-1. DHAE II was purified 1489-fold. The enzyme was shown to be a dimer of Mr 33,000 +/- 2000, with 16,000-dalton subunits, with a pH optimum of 5.5 and a Km of 7.2 +/- 0.4 microM. Both enzymes required only O2 and substrate; flavin and nicotinamide coenzymes had little or no effect. Neither catalase nor EDTA affected the activity of either enzyme, but complete inhibition of both was obtained with 1,10-phenanthroline. The activity of the purified DHAE I could be enhanced, but only by Mn2+ (relative V = 246 at 0.04 mM), Ni2+ (relative V = 266 at 0.2 mM), or Co2+ (relative = 498 at 0.2 mM). Reconstitution from a DHAE I apoenzyme, generated by treatment with 1,10-phenanthroline followed by Sephadex G-25 chromatography, occurred only by addition of one of these three metals.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Opposite facial specificity for two hydroquinone epoxidases: (3-si,4-re)-2,5-dihydroxyacetanilide epoxidase from Streptomyces LL-C10037 and (3-re,4-si)-2,5-dihydroxyacetanilide epoxidase from Streptomyces MPP 3051. 189 11

Elucidation of the mechanism(s) by which 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+) cause parkinsonism in humans and other primates has prompted consideration of possible endogenous MPTP/MPP(+)-like neurotoxins in the etiology of idiopathic Parkinson's disease. Here we examined inhibition of mitochondrial respiration in vitro and neurotoxicity in rats in vivo produced by beta-carbolinium compounds that are presumed to form following Pictet-Spengler cyclization of serotonin. We also evaluated N-methylisoquinolinium, a putative endogenous neurotoxin, in the same manner. The latter compound exhibited MPP(+)-like mitochondrial respiratory inhibition, whereas the beta-carbolinium compounds, although more potent inhibitors of electron transport, exhibited weak accumulation-dependent enhancement of inhibition in intact mitochondria. It is interesting that the beta-carbolinium compounds inhibited succinate- as well as glutamate-supported respiration, and are best described as inhibitor-uncouplers. The results of partitioning experiments suggest that both the low accumulation potential and the inhibition of succinate respiration may be a consequence of the beta-carboliniums being in equilibrium with neutral "anhydro" bases. Relative to MPP+, all compounds tested had weak dopaminergic uptake activity in vitro and weak dopaminergic toxicity in vivo, consistent with other findings of relatively low neurotoxic potential for presumed endogenous pyridiniums.
 ...
PMID:Dopaminergic neurotoxicity in vivo and inhibition of mitochondrial respiration in vitro by possible endogenous pyridinium-like substances. 194 Sep 17

Cultures of dissociated embryonic rat mesencephalic cells were exposed to 10 microM 1-methyl-4-phenylpyridinium (MPP+), a concentration shown earlier to result in loss of greater than 85% of tyrosine hydroxylase (TH)-positive neurons without affecting the total number of cells observed by phase-contrast microscopy. To characterize better the selectivity of the toxic action of MPP+, other parameters were measured reflecting survival and function of dopaminergic or nondopaminergic neurons. Exposure of cultures to 10 microM MPP+ for 48 h reduced TH activity to 11% of control values without reducing protein levels. [3H]Dopamine uptake was reduced to less than 4% of control values, whereas the uptake of gamma-[3H]aminobutyric acid ([3H]GABA) was not affected in these cultures. This same treatment failed to reduce the number of cholinergic cells visualized in septal cultures and did not affect either choline acetyltransferase activity or high-affinity choline uptake. To assess for possible recovery of dopaminergic neurons, cultures were exposed to 10, 1.0, or 0.1 microM MPP+ for 48 h and then kept for up to 6 days in MPP(+)-free medium. After exposure to 10 microM MPP+, the number of TH-positive neurons, their neurite density, TH activity, and [3H]dopamine uptake remained at constant, reduced levels throughout the period of observation after termination of exposure, whereas GABA uptake remained normal. Treatment with lower concentrations of MPP+, i.e., 1.0 and 0.1 microM, induced less pronounced dopaminergic toxic effects. However, no recovery was seen after posttreatment incubation in toxin-free medium. These findings provide evidence that MPP+ treatment results in highly selective and irreversible toxicity for cultured dopaminergic neurons.
 ...
PMID:Toxicity of 1-methyl-4-phenylpyridinium for rat dopaminergic neurons in culture: selectivity and irreversibility. 196 53

Since the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, it has been postulated that (a) MPTP-like toxin(s) such as 1,2,3,4-tetrahydroisoquinoline (TIQ) may induce Parkinson's disease. As the neuronal degeneration in MPTP-induced parkinsonism is thought to be caused by the inhibition of the mitochondrial respiration by 1-methyl-4-phenylpyridinium ion (MPP+), we studied the effects of TIQ-like alkaloids including dopamine-derived ones on the mitochondrial respiration using mouse brains. TIQ, tetrahydropapaveroline (THP), and tetrahydropapaverine (THPV) produced significant inhibition of the state 3 and 4 respiration and respiratory control ratio supported by glutamate + malate, the activity of Complex I and the ATP synthesis. Among those compounds, THPV was most potent. Toxic properties of these compounds on mitochondria were quite similar to that of MPP+. Our results support the hypothesis that (a) MPTP- or MPP(+)-like substance(s) may be responsible for the nigral degeneration in Parkinson's disease.
 ...
PMID:Inhibition of mitochondrial respiration by 1,2,3,4-tetrahydroisoquinoline-like endogenous alkaloids in mouse brain. 197 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>