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)

The ability of 1-deprenyl to protect against the parkinsonian effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of conversion of MPTP to MPP+ (1-methyl-4-phenylpyridinium) catalyzed by MAO-B. We report here that deprenyl-treatment in mice has an additional neuroprotective element associated with the rapid metabolization of 1-deprenyl to 1-methamphetamine and 1-amphetamine. 1-Methamphetamine and 1-amphetamine inhibit MPP(+)-uptake into striatal synaptosomes prepared from rats. Post-treatment by 1-deprenyl, 1-methamphetamine, 1-amphetamine (at times when MPTP is no longer present in the striatum of mice) protects against neurotoxicity in C57BL mice by blocking the uptake of MPP+ into dopaminergic neurons, and even against the neurotoxicity induced by 2'CH3-MPTP, which is partly bioactivated by MAO-A. These findings may have clinical implications since deprenyl has recently been found to delay the progression of Parkinson's disease.
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PMID:Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2'-methyl-MPTP. 793 Dec 28

Orally administered Madopar (levodopa/benserazide 4:1) dose-dependently antagonized haloperidol-induced (1 mg/kg s.c.) catalepsy in MPP(+)-lesioned mice. Pretreatment with a new selective catechol-O-methyltransferase (COMT) inhibitor, tolcapone (30 mg/kg p.o.), slightly potentiated the antagonistic effect of Madopar (15 mg/kg p.o.) on haloperidol-induced catalepsy. The ability of tolcapone to increase the Madopar effect was significantly attenuated by high doses of 3-O-methyldopa (3-OMD) (800 mg/kg i.p.). This might suggest a competitive blockade of the active transport of levodopa through the blood-brain barrier. In conclusion, the inhibitory effect of tolcapone on the O-methylation of levodopa to 3-OMD by COMT is largely due to improved levodopa and dopamine availability in the brain, and to the reduced formation of 3-OMD.
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PMID:The COMT inhibitor tolcapone potentiates the anticataleptic effect of Madopar in MPP(+)-lesioned mice. 795 69

7-Methylpyrido[3,4-c]psoralen (7-MPP) had been designed to be a monofunctional sensitizer in which the pyrone double bond, being engaged in a pyridine ring, would be incapable of participating in the formation of a cyclobutane ring with a DNA component. However, one example of photosensitization of thymine-thymine dimer formation in DNA by 7-MPP had been reported. This paper proves that 7-MPP can sensitize interstrand crosslinks in pBR322 DNA. It also proves that 7-MPP photosensitizes double strand cleavage reactions in the DNA with an unusually large degree of site selectivity.
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PMID:Crosslinking and cleavage of pBR322 DNA photosensitized by 7-methylpyrido[3,4-c]psoralen. 802 47

Two isoforms of protein serine/threonine phosphatase were isolated and sequenced from mouse testis. A deletion of 48 nucleotides of PP2C beta 4 cDNA in comparison with PP2C beta 3 cDNA resulted in different COOH-terminal sequences of 12 and 15 amino acids, respectively. These COOH-terminal sequences of PP2C beta 3 and PP2C beta 4 were further found to be different from those of isoforms MPP beta 1 and MPP beta 2 of mouse PP2C beta reported (Terasawa, et al. Arch. Biochem. Biophys. 307: 342-349, 1993). The common sequence of 378 amino acids from these four isoforms of mouse PP2C beta exhibited 95% identity with the corresponding sequence of rat PP2C beta. The mRNAs of approximately 2.0 Kb for PP2C beta 3 and PP2C beta 4 were expressed only in testis, while the mRNAs of 3.3 Kb and 8.5 Kb for MPP beta 1 and MPP beta 2, respectively, were found in somatic tissues.
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PMID:Molecular cloning and expression of cDNAs encoding two isoforms of protein phosphatase 2C beta from mouse testis. 803 26

It is now generally accepted that the nigrostriatal degenerative properties of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine are mediated by the brain monoamine oxidase B generated 1-methyl-4-phenylpyridinium metabolite (MPP+). In this article, the results are described of ongoing efforts to evaluate the MPP(+)-type neurotoxic potential of the haloperidol (HP)-derived pyridinium metabolite HPP+, a 1,4-disubstituted structural analog of MPP+, which is formed in humans and rats treated with HP. Previous studies in the rat have shown that intrastriatal perfusion of HPP+ leads to the irreversible depletion of striatal dopamine and serotonin. Furthermore, HPP+ was a potent inhibitor of NADH-supported mitochondrial respiration. This article reports that HPP+ also is toxic to dopaminergic and serotonergic neurons in cultures of embryonic mesencephalic cells, as measured by loss of the ability of exposed cells to accumulate tritium-labeled dopamine and serotonin and by immunochemical staining techniques. HPP+ also inhibited the uptake of these labeled neurotransmitters by synaptosomes prepared from mouse neostriata (dopamine) and cortical tissues (serotonin). Because HP is unlikely to be a substrate for brain monoamine oxidase B, the production and accumulation of HPP+ in the brain is probably not comparable to that of MPP+. On the other hand, chronic exposure to HP could result in brain levels of this lipophilic quaternary pyridinium species that might coincide with the late-appearing tardive dyskinesias that are observed in some HP-treated patients months and, more often, years after the initiation of HP therapy.
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PMID:1-Methyl-4-phenylpyridinium-like neurotoxicity of a pyridinium metabolite derived from haloperidol: cell culture and neurotransmitter uptake studies. 807 74

The protective role of basic fibroblast growth factor (FGF-2) for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and methylpyridiniumion (MPP+)-lesioned dopaminergic (DAergic) nigrostriatal neurons was studied, using dissociated cell cultures of embryonic day (E) 14 rat mesencephalon. Cells were grown in different culture media and received FGF-2 (5 ng/ml) and/or the toxins (5 microM) at various schedules, but were consistently allowed to differentiate for 3 days prior to becoming exposed to the toxin. Survival of tyrosine hydroxylase (TH)-immunoreactive cells at 7 days was only markedly impaired by MPTP, if horse serum (HS) or bovine serum albumin (BSA) were omitted from the culture medium. FGF-2 increased the number of TH-immunoreactive cells, and this increase was not diminished by MPTP under any culture condition. Uptake of 3H-DA was significantly reduced by MPTP in HS- and BSA-containing, but not in protein-less cultures. A protective effect by FGF-2 was only seen in the presence of BSA. MPP+ caused a more pronounced reduction in 3H-DA uptake than MPTP, and this effect was partially reversed by the addition of FGF-2, unless cultures contained HS. Neurofilament protein (NF), and indirect measure for the total number of neurons present in the cultures, was not significantly reduced by MPTP or MPP+ corroborating the specificity of the toxin for DAergic neurons, which constitute only a minor fraction in these cultures. In line with the wide spectrum of target neurons of FGF-2, this factor significantly increased NF contents under any culture condition. Quantification of the amounts of glial fibrillary acidic protein (GFAP) revealed stimulatory effects of FGF-2 (2.5- to 4-fold) and at least 10-fold higher levels in the presence as compared to the absence of HS. These data show that FGF-2 can protect DAergic neurons against MPTP- and MPP(+)-mediated damage. However, the effects of the toxins as well as of FGF-2 are partially dependent on culture conditions. Variations in the effectiveness of toxins and FGF-2 are not overtly related to the total numbers of neurons or astroglial cells, but may reflect culture type-dependent alterations of neuronal and glial metabolism.
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PMID:FGF-2-mediated protection of cultured mesencephalic dopaminergic neurons against MPTP and MPP+: specificity and impact of culture conditions, non-dopaminergic neurons, and astroglial cells. 809 65

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, (MPTP), produces a parkinsonian syndrome both in man and in experimental animals. Its toxicity is mediated by a metabolite, the 1-methyl-4-phenylpyridinium ion (MPP+). When injected into the striatum, MPP+ is accumulated by dopaminergic nerve terminals and retrogradely transported to the substantia nigra pars compacta (SNc) where it causes neuronal degeneration. MPP+ accumulates in mitochondria and blocks complex I of the electron transport chain. A proposed mechanism of neurotoxicity is excitotoxic neuronal degeneration induced by this energy depletion. We examined whether either prior decortication or administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) could prevent or diminish the selective nigral neuronal degeneration that follows unilateral intrastriatal injection of MPP+. We quantified the extent of neuronal death in the SNc ipsilateral and contralateral to the injections on Nissl-stained sections with unbiased stereological techniques. One week after injection of MPP+, approximately 75% of the SNc neurons were lost on the side of the injection. The loss was a consequence of the reduction in both SNc volume and neuronal density. Both prior decortication or the administration of MK-801 for 2 days nearly completely prevented MPP(+)-induced neuronal loss in the ipsilateral SNc. These results are consistent with an NMDA receptor mediated excitotoxic mechanism for MPP(+)-induced nigral toxicity.
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PMID:Blockade of 1-methyl-4-phenylpyridinium ion (MPP+) nigral toxicity in the rat by prior decortication or MK-801 treatment: a stereological estimate of neuronal loss. 810 73

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

The aspartic proteinase (MPP) gene from the zygomycete fungus Mucor pusillus was introduced into an ascomycete fungus, Aspergillus oryzae, by protoplast transformation using the nitrate reductase (niaD) gene as the selective marker. Southern blot analysis indicated that the MPP gene was integrated into the resident niaD locus at a copy number of 1-2. MPP secreted by the recombinant A. oryzae was correctly processed but was more highly glycosylated than that produced in the original M. pusillus strain. Treatment with endo-beta-N-acetylglucosaminidase H and analysis of the carbohydrate composition of the secreted MPP revealed that the extra glycosylation of the MPP secreted by the recombinant A. oryzae was due to altered processing of mannose residues. The extra glycosylation of MPP affected its enzyme properties including its milk-clotting and proteolytic activities.
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PMID:Characterization of an aspartic proteinase of Mucor pusillus expressed in Aspergillus oryzae. 824 85

Two complementary DNA (cDNA) clones (pTK-1 and -2) encoding two distinct isotypes of mouse Mg(2+)-dependent protein phosphatase beta (MPP beta-1 and -2, respectively) were isolated from a melanocyte cDNA library. Although mouse pTK-1 is orthologous to the rat cDNA (JW5) reported previously [Wenk, J., Trompeter, H.I., Pettrich, K.G., Cohen, P.T.W., Campbell, D.G., and Mieskes, G. (1992) FEBS Lett. 297, 135-138], pTK-2 is a novel cDNA clone. It was strongly suggested that the pTK-1 and -2 cDNAs are splicing variants of a single pre-mRNA. The difference in the amino acid sequences between MPP beta-1 and -2 was observed only at the carboxy-terminal regions. Both the recombinant MPP beta-1 and -2 expressed in Escherichia coli cells were immunoreactive to an anti-MPP beta antibody and exhibited Mg(2+)-dependent and okadaic acid-insensitive protein phosphatase activities with similar substrate specificities. Although the mRNA of MPP beta-1 was expressed ubiquitously in various mouse tissues, that of MPP beta-2 was expressed exclusively in brain and heart. These results suggest the difference in the physiological roles of these two enzyme isotypes.
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PMID:Molecular cloning of a novel isotype of Mg(2+)-dependent protein phosphatase beta (type 2C beta) enriched in brain and heart. 827 20


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