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)

Dopamine neurons from various animal species differ in sensitivity to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)). Compared with striatal vesicles isolated from mice, those from rats have a higher density of the brain vesicular monoamine transporter (VMAT2) and a greater ability to sequester MPP(+), suggesting a larger storage capacity for MPP(+) in rat vesicles. In the present study, we examined whether striatal VMAT2-containing vesicles might provide protection against the neurotoxic effects of MPP(+) in vivo. Dose-response curves for striatally infused MPP(+) were determined in animals pretreated with or without a VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.; VMAT2 inhibitor) produced a 5-fold leftward shift in the MPP(+) dose-response curve and a significant lowering of the EC(50) concentration for MPP(+)-induced damage. These findings provide evidence for a substantial accumulation of MPP(+) in VMAT2-containing vesicles in vivo in the rat striatum and support the hypothesis that MPP(+) sequestration in vesicles can provide protection against its toxic actions. In mice, VMAT2 inhibition did not reliably enhance toxicity produced by a striatal infusion of MPP(+) or by systemic administration of MPTP. These data suggest that vesicular sequestration of MPP(+) may be of less importance in mice than in rats as relates to protection from the toxin. The present results also reveal that although VMAT2 inhibition enhanced striatal MPP(+) toxicity in the rat, the potency of MPP(+) in the rat striatum was less than that in mouse striatum. This implies that there are other factors that either exacerbate MPP(+) toxicity in the mouse or attenuate MPP(+) toxicity in rats.
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PMID:Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata. 1077

Previous studies have shown that dopamine (DA) uptake was decreased after preincubation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)) in in vitro slice and synaptosome models. The present study, conducted with and without preincubation, attempted to determine whether inhibition results from a direct effect of neurotoxins on neuronal DA transporter or from an alteration of the transporter secondary to other toxic events. DA uptake was inhibited about 50% in the presence of MPTP+O(2) or MPP(+) (0.1, 1 and 5 mM) in rat striatal slices and synaptosomes. Such inhibition was obtained in synaptosomes preincubated for 150 min with MPP(+) and then washed. Inhibition of DA uptake was lower in slices preincubated with MPTP (5 mM)+O(2) and then washed (30%). Experiments in synaptosomes prepared from slices preincubated with MPTP or MPP(+) showed greater inhibition of DA uptake with MPTP. The results suggest that the inhibition of DA uptake in vitro by MPTP or MPP(+) results initially from a direct effect on the transporter during its penetration in nerve endings and subsequently from a transporter alteration related to toxic events. Thus, the preincubation of striatal slices followed by DA uptake measurement in synaptosomes would appear to be a good in vitro model for studying the dopaminergic toxicity of MPTP.
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PMID:A new in vitro approach for investigating the MPTP effect on DA uptake. 1109 83

This is the first study to investigate the potential protective effects of the lipophilic kavapyrone (+/-)-kavain in the experimental MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD). Male C57BL/6 mice were treated with (+/-)-kavain (50, 100, or 200 mg/kg i.p.) or vehicle 60 min before and 60 min after a single administration of MPTP (30 mg/kg s.c.) or saline, respectively. Mice were sacrificed after 7 days and the neostriatum was analyzed for dopamine and its metabolites using HPLC with electrochemical detection. Furthermore, nigral sections were processed for tyrosine hydroxylase (TH) immunocytochemistry. To determine the effects of (+/-)-kavain (200 mg/kg) on MPTP metabolism, HPLC analysis of striatal MPP(+) (1-methyl-4-phenylpyridinium) levels was performed. MPTP treatment alone led to a significant depletion of striatal dopamine levels to 12.61% of saline controls. The lower dosages of (+/-)-kavain (50 and 100 mg/kg) showed only a nonsignificant attenuation of MPTP-induced dopamine depletion, but a high dosage of (+/-)-kavain (200 mg/kg) significantly antagonized the dopamine depletion to 58.93% of saline control values. Remarkably, the MPTP-induced decrease of TH-immunoreactivity as well as the loss of nigral neurons was completely prevented by (+/-)-kavain (200 mg/kg). Striatal MPP(+) levels were not altered by (+/-)-kavain treatment. In conclusion, we found that MPTP metabolism was not influenced by (+/-)-kavain and postulate the antiglutamatergic effects of (+/-)-kavain for its protective effects against MPTP toxicity. (+/-)-Kavain may be a novel candidate for further preclinical studies in animal models of PD and other disorders with glutamatergic overactivity.
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PMID:Neuroprotective effects of (+/-)-kavain in the MPTP mouse model of Parkinson's disease. 1117 Feb 21

Oxygen free radical formation has been implicated in dopaminergic toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron. Although MPTP produces a parkinsonian syndrome after its conversion to 1-methyl-4-phenylpyridine (MPP+) by type B monoamine oxidase (MAO-B) in the brain, the etiology of this disease remains obscure. MPP+ is one of the most potent dopamine (DA)-releasing agents. Iron-catalyzed DA autoxidation and oxidative stress may be involved in the pathogenesis of Parkinson's disease. If indeed the effect of MPP+ on hydroxyl radical (.OH) formation is due to DA release, reserpine-induced DA depletion may reduce MPP(+)-induced .OH formation. Imidapril, an angiotensin converting enzyme (ACE) inhibitor, can resist MPP(+)-induced .OH formation via suppression of release of DA by angiotensin. Histidine, a singlet oxygen (1O2) scavenger, protects MPP(+)-induced .OH formation. Fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist MPP(+)-induced .OH formation. The inhibitory effect on the susceptibility of LDL oxidation can reduce .OH generation. These drugs may be applied as antiparkinsonian agents. Further clinical investigation is necessary in the future.
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PMID:[Parkinsonism induced by MPTP and free radical generation]. 1123 1

The metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was examined in an effort to evaluate the role of flavin-containing monooxygenase (FMO) expressed in the brain of suncus (Suncus murinus) and rats. MPTP was metabolized to generate both 1-methyl-4-phenylpyridinium ion (MPP(+)) and MPTP N-oxide by brain homogenates from rats. Although the level of MPP(+)-producing activity was similar in suncus and rats, a remarkable difference was found between the animal species in MPTP N-oxygenase activity, which was not detectable in brain homogenates from suncus. The concentrations of MPP(+) in suncus brain after a single ip administration of MPTP were markedly higher than that in rats, probably because of the lack of FMO activity in the suncus brain. The MPTP N-oxygenase activity of microvessel homogenates of rat brain was 21-fold greater than that of whole brain homogenates. These results suggest that FMO(s) plays a significant role in the detoxification of MPTP in cerebral endothelial cells.
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PMID:Accumulation of the 1-methyl-4-phenylpyridinium ion in suncus (Suncus murinus) brain: implication for flavin-containing monooxygenase activity in brain microvessels. 1125 72

In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of Parkinson's disease (PD), dopaminergic (DA) neurons have been shown to die by apoptosis. Moreover, recent postmortem and in vitro results have indicated that apoptotic cell death induced by 1-methyl-4-phenylpyridinium (MPP(+)) may be mediated by caspase-3. To establish whether caspase-3 activation may indeed play a role in an in vivo model of PD, we studied caspase-3 activation in C57Bl/6 mice subchronically intoxicated with MPTP. We show that caspase-3 activation peaks early, at days 1 and 2 after the end of MPTP intoxication. In contrast, pycnotic neurons persist until day 7 postintoxication, indicating that caspase-3 activation is an early and transient phenomenon in apoptotic death of DA neurons. We further demonstrate that loss of tyrosine hydroxylase (TH) immunoreactivity in this model is indeed due to cell loss rather than to loss of TH protein expression. We conclude that mice subchronically intoxicated with MPTP represent a valid PD model to study and manipulate caspase activation in vivo.
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PMID:Caspase-3 activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. 1129 68

The vesicular monoamine transporter 2 (VMAT2) has sequence homology with bacterial multidrug transporters which in turn share homology with mammalian P-glycoprotein (P-GP). Both VMAT2 and P-GP can detoxify cells. 1-Methyl-4-phenylpyridinium (MPP(+)), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a substrate for VMAT2 that has several structural features in common with P-GP substrates and inhibitors. The present studies investigated whether P-GP is responsible for the elimination of MPP(+) from the brain. Additionally, VMAT2 and P-GP are inhibited by many of the same compounds. Thus we also investigated whether VMAT2 inhibitors could block P-GP in vitro and vice versa whether P-GP inhibitors could block VMAT2 mediated transport of [3H]-DA into synaptic vesicles. In mice treated with MPTP and a P-GP inhibitor (quinidine, trans-flupentixol or cyclosporine A), the elimination of MPP(+) from the striatum was significantly delayed. However, in experiments using various cell lines expressing either mouse or human P-GP, MPP(+) did not reverse the P-GP mediated resistance to vincristine, suggesting that MPP(+) is a poor substrate for P-GP. Additional experiments were performed using mdr1a/b double knockout mice which lack functional P-GP encoded by these two genes. Data from mdr1a/b knockout mice treated with MPTP also suggest that MPP(+) is not extruded from the brain by P-GP. In other studies, we demonstrated that the VMAT2 inhibitors tetrabenazine and Ro 4-1284 inhibit P-GP and that the P-GP inhibitors trans-flupentixol and quinidine inhibit VMAT2. Thus, several new drugs can be added to the list of compounds that are able to inhibit both VMAT2 and P-GP, providing further evidence of the similarity between these two transporters.
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PMID:Interactions of 1-methyl-4-phenylpyridinium and other compounds with P-glycoprotein: relevance to toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 1148 61

Increasing evidence suggests that apoptosis may be the underlying cell death mechanism in the selective loss of dopaminergic neurons in Parkinson's disease. Because the inhibition of caspases provides only partial protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP(+)) model of Parkinson's disease, we investigated the role of the proapoptotic c-Jun N-terminal kinase (JNK) signaling cascade in SH-SY5Y human neuroblastoma cells in vitro and in mice in vivo. MPTP/MPP(+) led to the sequential phosphorylation and activation of JNK kinase (MKK4), JNK, and c-Jun, the activation of caspases, and apoptosis. In mice, adenoviral gene transfer of the JNK binding domain of JNK-interacting protein-1 (a scaffold protein and inhibitor of JNK) inhibited this cascade downstream of MKK4 phosphorylation, blocked JNK, c-Jun, and caspase activation, the death of dopaminergic neurons, and the loss of catecholamines in the striatum. Furthermore, the gene transfer resulted in behavioral benefit. Therefore, inhibition of the JNK pathway offers a new treatment strategy for Parkinson's disease that blocks the death signaling pathway upstream of the execution of apoptosis in dopaminergic neurons, providing a therapeutic advantage over the direct inhibition of caspases.
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PMID:Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease. 1150 16

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes, via its metabolite MPP(+), damages of the nigrostriatal dopaminergic pathway, similar to those observed in Parkinson's disease. An intranigral injection of 10 microg MPP(+) in rat induced a decrease of about 30% of the neuronal dopamine transporter (DAT) activity 21 days after lesion. Based on the hypothesis that MPTP/MPP(+) neurotoxicity involves the nitric oxide (NO) production and/or an activation of poly(ADP-ribose) polymerase (PARP), we investigated the preventive effects of a treatment either with L-Name, a NO synthase (NOS) inhibitor or 3-aminobenzamide, a PARP inhibitor on the reduction of dopamine uptake induced by MPP(+). Rats received a daily injection i.p. of 50 mg/kg L-Name or 10 mg/kg 3-aminobenzamide 3 days before and during 21 days after the MPP(+) lesion. The results showed that inhibitors of NOS and PARP did not prevent the alteration of DAT activity induced by 10 microg MPP(+), indicating that NO and PARP were not involved in the biochemical cascade leading to the inhibition of rat DAT activity by MPP(+) in our experimental conditions.
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PMID:Impairment of the neuronal dopamine transporter activity in MPP(+)-treated rat was not prevented by treatments with nitric oxide synthase or poly(ADP-ribose) polymerase inhibitors. 1169 52

Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MPP(+))-mediated iNOS expression and NO-induced neurotoxicity, but MPP(+)-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MPP(+)-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.
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PMID:Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. 1172 29


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