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)

1. The calcium dependence of spontaneous transmitter release from nerve terminals of different lengths was examined at neuromuscular junctions in frog muscle. Miniature endplate potential (MEPP) frequency was positively correlated with the endplate potential (EPP) quantal content and was dependent on external Ca2+. The higher the resting MEPP frequency in a 0.25 mM-Ca2+ Ringer solution, the greater the dependence on external Ca2+. MEPP frequency in all terminals dropped to approximately the same low level in a Ca2(+)-free Ringer solution containing EGTA. This suggests that terminals with higher release levels have a larger Ca2+ influx at rest. 2. Several tests were done to try to characterize the mode of Ca2+ entry into resting terminals. omega-Conotoxin (omega-CgTx) blocked evoked release and reduced MEPP frequency, but not as effectively as zero Ca2(+)-EGTA Ringer solution. Some component of Ca2+ influx thus appears to enter through channels insensitive to omega-CgTx. Tetrodotoxin (TTX) did not affect MEPP frequency, indicating that the Ca2+ did not enter through TTX-sensitive Na+ channels that might be opening spontaneously at rest. Hyperpolarization of the terminal by reducing the K+ in the Ringer solution caused no consistent differences in MEPP frequency, suggesting that the Ca2+ influx is relatively insensitive to small changes in membrane potential around the resting level. Strong buffering of the Ringer solution with citrate, to overwhelm any differences in Ca2+ buffering within different junctional clefts, had no significant effect on the MEPP frequency. 3. Evidence that the Na(+)-Ca2+ exchanger helps set the internal Ca2+ level was obtained. Reduction of the Na+ concentration in the Ringer solution caused increases in MEPP frequency ranging from 6 to 440%. However, these changes were not correlated with resting MEPP frequency, hence differences in MEPP frequency probably are not the result of differences in Na(+)-Ca2+ exchanger function in terminals having a uniform Ca2+ leak. 4. Although MEPP frequency was generally correlated with quantal content, in subsets of junctions grouped according to their similar quantal contents, there was a positive correlation between MEPP frequency and terminal length. 5. In zero Ca2(+)-EGTA Ringer solution, the low residual MEPP frequency is independent of terminal length, even when MPP frequency is sharply increased by tetanic stimulation.
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PMID:Dependence of spontaneous release at frog junctions on synaptic strength, external calcium and terminal length. 257 68

We examined whether fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist 1-methyl-4-phenylpyridine (MPP(+))-induced hydroxyl radical generation (.OH) in the extracellular fluid of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/microliter/min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP(+) (5 mM; total dose 75 nmol) clearly produced an increase in.OH formation. However, fluvastatin (100 microM) reduced the.OH formation by the action of MPP(+). These results indicated that fluvastatin, a potent inhibitor of LDL oxidation, may resist the formation of.OH products of MPP(+).
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PMID:Protective effect of fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on MPP(+)-induced hydroxyl radical in the rat striatum. 1072 37

We determined the methamphetamine (MA), a potent dopamine (DA) releaser, enhances 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (&z.rad;OH) generation in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of .OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. After administration of MA (5 mg/kg i.v., every 2 h, four times), MA drastically increased DA release and the &z.rad;OH formation. When iron (II) was administered to the MA-treated animals, a marked elevation of DHBA was observed, compared with MPP(+)-only treated animals, that showed a positive linear correlation between DA and .OH formation trapped as DHBA (R(2)=0.985) in the dialysate. These results suggest that MA enhances the &z.rad;OH products of efflux/oxidation due to MPP(+).
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PMID:Methamphetamine enhances 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in the rat striatum. 1099 48

We examined the effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on extracellular potassium ion concentration ([K(+)](o))-enhanced hydroxyl radical (.OH) generation due to 1-methyl-4-phenylpyridinium ion (MPP(+)) was examined in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of KCl (20, 70 and 140 mM) increased MPP(+)-induced.OH formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in a concentration dependent manner. However, the application of L-NAME (5 mg/kg i.v.) abolished the [K(+)](o) depolarization-induced.OH formation with MPP(+). Dopamine (DA; 10 microM) also increased the levels of DHBA due to MPP(+). However, the effect of DA after application of L-NAME did not change the levels of DHBA. On the other hand, the application of allopurinol (20 mg/kg i.v., 30 min prior to study), a xanthine oxidase (XO) inhibitor was abolished the both [K(+)](o)- and DA-induced.OH generation. Moreover, when iron(II) was administered to MPP(+) then [K(+)](o) (70 mM)-pretreated animals, a marked increase in the level of DHBA. However, when corresponding experiments were performed with L-NAME-pretreated animals, the same results were obtained. Therefore, NOS activation may be no relation to Fenton-type reaction via [K(+)](o) depolarization-induced.OH generation. The present results suggest that [K(+)](o)-induced depolarization augmented MPP(+)-induced.OH formation by enhancing NO synthesis.
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PMID:Nitric oxide enhances MPP(+)-induced hydroxyl radical generation via depolarization activated nitric oxide synthase in rat striatum. 1138 16

To investigate whether nitric oxide (*NO) is neurotoxic or neuroprotective in the brain, we compared the in vivo role of S-nitroso-N-acetylpenicillamine (SNAP) with that of sodium nitroprusside (SNP) on ferrous citrate-induced oxidative stress and neuronal loss in the rat nigrostriatal dopaminergic system. It is known that light irradiation releases *NO from its donor compounds; these irradiated *NO donors were used as sham controls in this study. Intranigral infusion of ferrous citrate (4.2 nmol) into the rat midbrain substantia nigra compacta area caused acute lipid peroxidation in the substantia nigra and chronic dopamine depletion in the caudate nucleus. Coinfusion of freshly prepared SNAP (0-8.4 nmol) or *NO (about 2 nmol), but not SNP, rescued iron-induced dopamine depletion in the rat brain in vivo. In fact, SNP produced prooxidative effects similar to ferrous citrate both in vivo and in vitro, since SNP is a redox iron complex. Consistently, *NO and SNAP inhibited, whereas SNP potentiated, *OH generation and lipid peroxidation evoked by ferrous citrate in vitro. We previously reported that freshly prepared, but not irradiated, S-nitroso-L-glutathione (GSNO) protected brain dopamine neurons against oxidative stress in vivo. As well as these antioxidative properties, our recent reports (see (Ref. 1)) indicate that *NO/GSNO activated guanylyl cyclase, increased cGMP and that could lead to PKG-mediated expression of MnSOD, Bcl-2, and thioredoxin for preconditioning neuroprotection against 1-methyl-4-phenylpyridinium (MPP(+)).(1) In conclusion, *NO and S-nitrosothiols (e.g., GSNO and SNAP) can scavenge reactive oxygen species and activate the heme moiety of guanylyl cyclase, resulting in protection of brain dopamine neurons through both antioxidative and antiapoptotic mechanisms.
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PMID:Contradictory effects of sodium nitroprusside and S-nitroso-N-acetylpenicillamine on oxidative stress in brain dopamine neurons in vivo. 1207 63

The present study examined the ability of antioxidant effects of nicotine on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced hydroxyl radical (*OH) formation of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by non-enzymatic formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP(+) enhanced generation of.OH formation trapped as DHBA. However, nicotine (100 microM) significantly suppressed.OH formation induced by MPP(+). Iron (II) (2, 5 and 10 microM) increased the levels of DHBA in a concentration-dependent manner. However, in the presence of nicotine (100 microM), the effect of nicotine was suppressed. These results suggest that nicotine has a preventive effect on.OH generation by MPP(+) in rat striatum.
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PMID:Nicotine suppresses 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in rat striatum. 1221 48

We evaluated the hydroxyl radical (*OH) scavenging action of nonsteroidal anti-inflammatory drugs (NSAIDs), sodium salicylate (SA), diclofenac and celecoxib in Fenton's reaction and their neuroprotective effects in 1-methyl-4-phenylpyridinium (MPP(+))-induced striatal dopamine (DA) depletion in rats. Salicylate hydroxylation procedure employing HPLC-electrochemistry was used to assay formation of *OH in Fenton's reaction in test tubes. While SA dose- and time-dependently hydroxylated itself and inactivated *OH, celecoxib (up to 10 mM) showed no effect on *OH formation and diclofenac caused a reduction in *OH generation only at high doses (100 microM-10 mM). Administration of the non-selective cyclooxygenase (COX) inhibitor, SA (50, 100 mg/kg, i.p.) significantly attenuated striatal DA depletion caused by intrastriatal infusion of MPP(+) (100 nmol in 4 microl). Treatment with another nonselective, reversible COX inhibitor, diclofenac (5, 10 mg/kg) did not protect against MPP(+)-induced DA depletion. The selective COX-2 inhibitor, celecoxib (2.5-50 mg/kg) treatment exacerbated MPP(+)-induced decrease in DA. Failure of celecoxib or diclofenac to render protection in animals against MPP(+)-induced DA depletion indicates absence of prostaglandin involvement in MPP(+) action. These results also suggest that the neuroprotective ability of SA is independent of prostaglandin mediation. A relationship between inactivation of *OH by SA and its ability to protect DA depletion in the striatum caused by MPP(+) indicates a direct involvement of *OH in the action of this neurotoxin. The present study establishes potent neuroprotective activity of SA and suggests the use of aspirin in adjuvant therapy in Parkinson's disease.
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PMID:Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats. 1261 47

The transport of L-carnitine (4-N-trimethylamino-3-hydroxybutyric acid), a compound known to be transported by the organic cation transporter/carnitine transporter OCTN2, was studied in immortalized rat brain endothelial cells (RBE4). The cells were found to take up L-carnitine by a sodium-dependent process. This uptake process was saturable with an apparent Michaelis-Menten constant for L-carnitine of 54+/-10 microM and a maximal velocity of 215+/-35 pmol/mg protein/h. Besides L-carnitine, the cells also took up acetyl-L-carnitine and propionyl-L-carnitine in a sodium-dependent manner and TEA in a sodium-independent manner. RT-PCR with primers specific for the rat OCTN2 transporter revealed the existence of OCTN2 mRNA in RBE4 cells. Screening of a cDNA library from RBE4 cells with rat OCTN2 cDNA as a probe identified a positive clone which showed, when expressed in HeLa cells, the functional characteristics of OCTN2. The HeLa cells expressing the RBE4 OCTN2 cDNA showed a sixfold increase in L-carnitine uptake and a fourfold increase in TEA uptake in a sodium-containing buffer. Typical inhibitors for organic cation transporters (e.g. MPP(+) or TEA) showed an inhibitory effect on the transport of L-carnitine and TEA into the transfected cells. Similarly, unlabeled L-carnitine inhibited the transport of [3H]-L-carnitine and [14C]TEA in transfected HeLa cells. It is concluded that RBE4 cells, a widely used in vitro model of the blood-brain barrier (BBB), express the organic cation/carnitine transporter OCTN2.
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PMID:Molecular cloning and functional characterization of the OCTN2 transporter at the RBE4 cells, an in vitro model of the blood-brain barrier. 1264 65

The present study examined the antioxidant effect of phytic acid on iron (II)-enhanced hydroxyl radical (*OH) generation induced by 1-methyl-4-phenylpyridinium ion (MPP(+)) in the extracellular fluid of rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl/min) was infused through a microdialysis probe to detect the generation of *OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Phytic acid (100 microM) did not significantly decrease the levels of MPP(+)-induced *OH formation trapped as 2,3-DHBA. To confirm the generation of *OH by the Fenton-type reaction, iron (II) was infused through a microdialysis probe. Introduction of iron (II) (10 microM) enhanced MPP(+) induced *OH generation. However, phytic acid significantly suppressed iron (II)-enhanced *OH formation after MPP(+) treatment (n=6, P<0.05). These results suggest that the antiradical effect of phytic acid occurs by chelating iron required for the MPP(+)-enhanced *OH generation via the Fenton-type reaction.
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PMID:Phytic acid suppresses 1-methyl-4-phenylpyridinium ion-induced hydroxyl radical generation in rat striatum. 1283 20

The aim of this study is to investigate the placental transport mechanism of cationic compounds by comparison of the uptake of an organic cation into human placental basal membrane vesicles (BLMVs) with that into organic cation transporter 3 (OCT3)-expressing cells. Reverse transcription-polymerase chain reaction analysis demonstrated that OCT3 is the only OCT isoform expressed in the human placenta. The function of OCT3 was investigated by measuring the uptake of 1-methyl-4-phenylpyridinium (MPP(+)) into human embryonic kidney (HEK)293 cells stably expressing OCT3 (HEK/OCT3 cells). The OCT3-mediated uptake of MPP(+) was sodium- and chloride-independent and saturable, with a Michaelis constant (K(m)) of 82.5 microM. The OCT3-mediated uptake was inhibited by various cationic drugs in a concentration-dependent manner but not by anionic compounds, such as p-aminohippuric acid and captopril, or a zwitterion, carnitine. Western blotting analysis of membrane vesicles prepared from human term placenta revealed that OCT3 is expressed only in BLMVs but not in microvillous membrane vesicles. The uptake of MPP(+) into BLMVs was membrane potential-dependent and saturable, with a K(m) value of 51.8 muM, which is similar to that in HEK293/OCT3 cells. The inhibitory spectrum of various compounds on MPP(+) uptake by BLMVs was also similar to that in HEK293/OCT3 cells. These results suggest that OCT3 is expressed on the basal membrane of human trophoblast cells and plays an important role in the placental transport of cationic compounds.
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PMID:Functional analysis of organic cation transporter 3 expressed in human placenta. 1608 76


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