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

The concentrations of dopamine (DA) and of the excitatory amino acids (EAAs) glutamate (Glu) and aspartate (Asp) were measured in dialysates from the striatum of awake rats in order to study the link between the release of DA and of EAAs induced by the infusion of 1-methyl-4-phenylpyridinium ion (MPP+). DA and EAAs were detected simultaneously by HPLC-EC. The infusion of MPP+ at the concentration of 1 mM elevated DA levels in the perfusates, but did not affect EAA release. However, MPP+ at 10 mM maximally stimulated Glu and Asp release to 230- and 68-fold of baseline, respectively. In this condition, pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (5 mg/kg, i.p.) prevented the MPP(+)-induced EAA release. In contrast, MK-801 had no effect on DA release induced either by 1 or 10 mM MPP+. These results suggest that MPP(+)-induced DA and EAA release are independently regulated processes. In addition, the finding that MK-801 inhibits MPP(+)-induced EAA release suggests that EAAs may act on NMDA receptors to stimulate their own release through a positive-feedback mechanism.
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PMID:The non-competitive NMDA-receptor antagonist MK-801 prevents the massive release of glutamate and aspartate from rat striatum induced by 1-methyl-4-phenylpyridinium (MPP+). 198 Dec 52

Extracellular concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid were measured by microdialysis in rat striatum 1 month after a unilateral infusion via a dialysis probe of a high concentration (10 mM) of 1-methyl-4-phenylpyridinium ion (MPP+) into the substantia nigra. The basal extracellular DA concentration at the lesioned side was about 20% of the concentration at the nonlesioned side. However, basal DOPAC dialysate levels from the lesioned striatum represented only 2.4% of those from the contralateral side. Intrastriatal infusion with nomifensine increased the dialysate content of DA about twofold and eightfold at the lesioned and nonlesioned sides, respectively. Co-infusion of nomifensine with (-)-sulpiride caused an additional pronounced rise of the DA output on top of the nomifensine-induced increase at the nonlesioned side, whereas no effect was observed at the lesioned side. Finally, MPP+ (10 mM) was infused for 45 min into both striata. The increase in the dialysate content of DA in response to MPP+ (considered as an index of the total striatal DA content) from the lesioned side was only 0.6% of the MPP(+)-induced DA increase from the nonlesioned side. A strong compensatory response to increased extracellular dopamine was observed in the ipsilateral striatum. This effect was achieved by a severe suppression of reuptake mechanisms, as well as of the autoreceptor feedback response. It is concluded that infusion of MPP+ into the substantia nigra can be used as a chronic biochemical model for clinically manifest parkinsonism.
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PMID:Responsiveness of striatal dopamine release in awake animals after chronic 1-methyl-4-phenylpyridinium ion-induced lesions of the substantia nigra. 200 46

To assess the utility of phosphinates as pretreatments against nerve agents, experiments were conducted to determine whether oximes can reactivate phosphinate-inhibited guinea pig acetylcholinesterase (AChE) and whether the toxicity of phosphinates is reduced by treatment with atropine and/or oxime. Three phosphinates, 4-nitrophenyl methyl(phenyl) phosphinate (MPP), 4-nitrophenyl chloromethyl(phenyl) phosphinate (CMPP), and 4-nitrophenyl 2-methoxyphenyl(methyl) phosphinate (MPMP), were used in these experiments. In the first group of experiments, 2-PAM or HI-6 was administered, im, 2 min after peak inhibition of whole blood AChE activity by the phosphinates. Both oximes significantly reactivated MPP- or CMPP-inhibited AChE; however, HI-6 was the better reactivator in both cases. Oximes were ineffective against MPMP. Efficacy studies revealed that neither HI-6 nor 2-PAM potentiated the toxic effects of MPP or CMPP and that atropine/oxime therapy provided greater protection (up to 100 LD50s) against either phosphinate than any single therapy. The reactivation and efficacy data, especially for CMPP, support the concept that oxime sensitive phosphinates may be useful as pretreatments against nerve agent intoxication.
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PMID:Evaluation of phosphinates as potential pretreatments for nerve agents. 204 71

1. In anaesthetized-closed chest dogs, exposure to hypoxia (60 min) caused a sustained increase in arterial pulmonary pressures (diastolic: DPP, mean: MPP and effective capillary: EPCP by 132, 66 and 104% respectively) and increased total pulmonary vascular resistance (TPVR, 143%) with minimal changes in systemic haemodynamics. 2. Under normoxia, cromakalim infusion (2 micrograms kg-1 min-1 for 30 min) progressively decreased diastolic systemic arterial pressure (DBP, 30%) and total systemic vascular resistance (TSVR, 54%). In contrast, DPP was increased by 45%, due to an increase in cardiac output (CO: 55%), while TPVR was essentially unchanged. 3. Under hypoxic conditions, cromakalim (2 micrograms kg-1 min-1 for 30 min) induced changes in systemic haemodynamics comparable to those seen under normoxia. However, DPP was decreased by 37% at the end of infusion. The compound progressively decreased TPVR in a dose-related manner and PaO2 (55.9 mmHg) was maintained since cardiac output was increased. 4. Thus, under normoxia, cromakalim induced haemodynamic effects on the pulmonary circulation which were directly related to an increase in CO, but were clearly different from those observed under hypoxia. In the hypoxia-induced constricted pulmonary vascular bed, cromakalim effectively reduced the elevated pulmonary vascular resistance at low doses but showed comparable vasodilator effects on the systemic circulation under both conditions. The findings suggest that a vasodilator agent like cromakalim may be useful in patients with respiratory conditions associated with elevated pulmonary vascular resistance.
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PMID:Pulmonary and systemic haemodynamic effects of cromakalim in conditions of normoxia and hypoxia in dogs. 208 9

The relationships between mitochondrial transmembrane potential, ATP concentration, and cytotoxicity were evaluated after exposure of isolated rat hepatocytes to different mitochondrial poisons. Both the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its fully oxidized metabolite, the 1-methyl-4-phenylpyridinium (MPP+) ion, caused a concentration- and time-dependent depolarization of mitochondrial membranes which followed ATP depletion and preceded cytotoxicity. The effect of MPTP, but not that of MPP+, was prevented by deprenyl, an inhibitor of MPTP conversion to MPP+ via monoamine oxidase type B. Addition of fructose to the hepatocyte incubations treated with either MPTP or MPP+ counteracted the loss of mitochondrial transmembrane potential. Fructose was also effective in protecting against the mitochondrial membrane depolarization as well as ATP depletion and cytotoxicity induced by antimycin. A, carbonyl cyanide p-trifluoromethoxyphenyl hydrazone, and valinomycin. Data confirm the key role played by MPP(+)-induced mitochondrial damage in MPTP toxicity and indicate that (i) ATP produced via the glycolytic pathway can be utilized by hepatocytes to maintain mitochondrial electrochemical gradient, and (ii) a loss of mitochondrial membrane potential may occur only when supplies of ATP are depleted.
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PMID:Relationships between the mitochondrial transmembrane potential, ATP concentration, and cytotoxicity in isolated rat hepatocytes. 212 6

This is a review of reserpine, haloperidol, and various phenothiazines that produce parkinsonism and other movement disorders. The by-products of illicit meperidine synthesis, MPTP and its more sinister companion, MPP, are also discussed. Movement disorders, transient or fixed, frank parkinsonism and/or dyskinesia, due to a variety of other medications and toxic agents are included. These are methanol, lithium, methyldopa, antimetabolites, antidepressants, sympathomimetic anorexiants, some types of antihistamines, and various combinations of agricultural chemicals.
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PMID:Drug-induced parkinsonism and other movement disorders. 219 87

In a previous study conducted over six months, we demonstrated that 1-methyl-4-phenylpyridinium ion (MPP+) the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, chronically infused (10 micrograms/24 h for seven days) into one median forebrain bundle of the rat can cause long-lasting damage to the nigrostriatal dopamine system. The present study was carried out in animals 18-19 months after MPP+ infusion to determine firstly, if the lesion was indeed permanent and secondly, if embryonic nigral dopamine suspension grafts implanted into the dopamine-denervated neostriatum can reverse the neurochemical and behavioural deficits induced by MPP+. All the animals within the MPP(+)-lesioned group showed robust contralateral and ipsilateral turning in response to apomorphine (0.05 mg/kg) and methamphetamine (2.5 mg/kg), respectively, at each time point of testing. In the grafted animals there was a progressive significant reduction in the number of rotations in response to both apomorphine and methamphetamine over the three-month test period. Autoradiographic analysis of [125I]sulpiride binding to striatal sections showed a 27% increase in dopamine D2 receptor density in the ipsilateral striatum of MPP(+)-lesioned animals. This increase in D2 receptor density was completely abolished by the dopamine grafts so that the D2 receptor density in the grafted striatum was similar to the contralateral striatum of MPP(+)-lesioned animals. This increase in D2 receptor density was completely abolished by the dopamine grafts so that the D2 receptor density in the grafted striatum was similar to the contralateral striatum of the grafted animals or the ipsilateral striatum of control non-lesioned animals. In all the animals of the lesioned and grafted groups there was a complete loss of dopamine neurons in the ipsilateral substantia nigra as demonstrated by tyrosine hydroxylase-immunohistochemistry and in-situ hybridization histochemistry. In all the animals that received nigral dopamine grafts, numerous cells were localized within the grafts which contained tyrosine hydroxylase immunoreactivity and tyrosine hydroxylase mRNA. Moreover, immunohistochemical staining showed a dense network of tyrosine hydroxylase-positive fibres within the grafted striatum. The results of the present study are important in two respects. Firstly, they demonstrate that MPP+ infusions into the rat nigrostriatal dopamine pathway can produce a permanent degeneration of nigral dopamine neurons. Thus, in animals assessed 18-19 months after the initial MPP(+)-lesion there was no significant behavioural or neurochemical compensation with time. Secondly, the results clearly show that embryonic nigral dopamine grafts implanted into the dopamine-denervated striatum can reverse the behavioural and neurochemical deficits induced by MPP+.
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PMID:Experimental hemiparkinsonism in the rat following chronic unilateral infusion of MPP+ into the nigrostriatal dopamine pathway--III. Reversal by embryonic nigral dopamine grafts. 224 21

The dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) derives from its metabolism to 1-methyl-4-phenyl-pyridinium cation (MPP+), which is then selectively accumulated in dopaminergic neurons. In an effort to assess the structural requirements governing MPP+ cytotoxicity, we evaluated dopaminergic toxicity of MPP+ analogues 3 weeks after their microinfusion into rat substantia nigra. We also evaluated the substrate suitability of MPP+ analogues for high-affinity dopamine uptake in striatal synaptosomes by measuring their ability to induce specific dopamine release. The intranigral neurotoxicity of MPP+ analogues in vivo correlates mainly with their in vitro inhibitory activity on mitochondrial respiration, consistent with a compromise in cellular energy production as the principal mechanism of MPTP-induced cell death. This study extends the structure-neurotoxicity data base beyond that obtainable using MPTP analogues, since many of these are not metabolized to pyridinium compounds. Such information is crucial to assess which possible endogenous or exogenous compounds may exert MPTP/MPP(+)-like toxicity.
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PMID:Structure-neurotoxicity trends of analogues of 1-methyl-4-phenylpyridinium (MPP+), the cytotoxic metabolite of the dopaminergic neurotoxin MPTP. 230 77

Rabbit renal brush-border membrane vesicles (BBMV) were used to study the transport of the cationic neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). An outwardly directed H(+)-gradient stimulated MPP+ uptake and led to the development of an active accumulation of MPP+ within the vesicles. H(+)-gradient driven MPP+ transport was saturable, with a maximal transport rate of 3 nmol.mg-1.min-1 and an apparent Michaelis constant (Kt) of 8 microM. MPP+ and tetraethylammonium (TEA) behaved as competitive inhibitors of one another's transport in renal BBMV, suggesting the presence of a common transport pathway for these organic cations. At an ambient pH of 7.5, preloading BBMV with MPP+ failed to stimulate TEA uptake, although trans TEA did stimulate MPP+ uptake. Increasing ambient pH to 8.5 (i.e., reducing competition between H+ and these organic cations for a common transport pathway) led to a clear reciprocal trans stimulation of TEA and MPP+ fluxes. With an equilibrium-shift protocol, a trans concentration of MPP+ energized uphill transport of TEA. We conclude that MPP+ and TEA share a common organic cation-H+ exchange pathway in the renal brush border, although turnover of an MPP(+)-loaded exchanger is slow compared with that for a TEA or H(+)-loaded exchanger.
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PMID:MPP+ is transported by the TEA(+)-H+ exchanger of renal brush-border membrane vesicles. 231 68

The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP(+)-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP(+)-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.
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PMID:In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species. 237 49


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