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)

Parkinson's disease (PD) is a movement disorder resulting from nigrostriatal dopaminergic neurodegeneration. The impairment of mitochondrial function and dopamine synaptic transmission are involved in the pathogenesis of PD. Two mitochondrial inhibitors, 1-methyl-4-phenylpyridine (MPP(+)) and rotenone, have been used to induce dopaminergic neuronal death both in in vitro and in vivo models of PD. Because the uptake of MPP(+) is mediated by the dopamine transporter (DAT), we used a cell-permeable rotenone-induced PD model to investigate the role of DAT and dopamine D2 receptor (D2R) on dopaminergic neuronal loss. Rotenone subcutaneously infused for 14 days induced PD symptoms in rats, as indicated by reduced spontaneous locomotor activity (hypokinesis), loss of tyrosine hydroxylase (TH, a marker enzyme for dopamine neurons) immunoreactivity in the substantia nigra and striatum, obvious alpha-synuclein accumulation, downregulated DAT protein expression, and upregulated D2R expression. Interestingly, rotenone also caused significant noradrenergic neuronal loss in the locus coeruleus. Melatonin, an antioxidant, prevented nigrostriatal neurodegeneration and alpha-synuclein aggregation without affecting the rotenone-induced weight loss and hypokinesis. However, rotenone-induced hypokinesis was markedly reversed by the DAT antagonist nomifensine and body weight loss was attenuated by the D2R antagonist sulpiride. In addition, both antagonists significantly prevented the reduction of striatal TH or DAT immunoreactivity but not the loss of nigral TH- and DAT-immunopositive neurons. These results suggested that oxidative stress and DAT downregulation are involved in the rotenone-induced pathogenesis of nigrostriatal dopaminergic neurodegeneration, whereas D2R upregulation may simply represent a compensatory response.
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PMID:Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats. 1828 73

Rolipram, a specific inhibitor of the phosphodiesterase IV (PDE IV), has recently been shown to exert neuroprotective effects in an Alzheimer transgenic mouse model and in hypoxic-ischemic damage in the rat brain. It activates the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway and it inhibits inflammation. We tested the neuroprotective effects of the specific PDE IV inhibitor rolipram in C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that rolipram administered at 1.25 mg/kg or 2.5 mg/kg doses significantly attenuated MPTP-induced dopamine depletion in the striatum, and reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra. There was a bell-shaped dose effect with greater efficacy at the 1.25 mg/kg dose than 2.5 mg/kg and a higher dose of rolipram, 5 mg/kg, had no protective effect and even increased the mortality of animals when co-administered with MPTP. Rolipram did not interact with MPTP in its absorption into the brain and in its metabolism to 1-methyl-4-phenylpyridinium (MPP(+)). Our data show a neuroprotective effect of the PDE IV specific inhibitor rolipram against dopaminergic neuron degeneration, suggesting that PDE IV inhibitors might be a potential treatment for Parkinson's disease.
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PMID:Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV. 1832 79

Neuroprotective effects of melatonin against oxidative stress-induced neuronal cell degeneration in human SH-SY5Y neuroblastoma cells were investigated in this report. The results demonstrate that exogenous administration of H(2)O(2) and 1-methyl, 4-phenyl, pyridinium ion (MPP(+)) significantly decreased cell viability in SH-SY5Y cultured cells. Desipramine, a monoamine uptake blocker was able to abolish the toxic effects of MPP(+) but not H(2)O(2) in reduction of cell viability. Conversely, melatonin reversed the toxic effects of H(2)O(2) and MPP(+) on cell viability. In addition, the reduction of phosphorylation of tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis, and phosphorylation of cyclic AMP responsive element-binding protein by H(2)O(2) and MPP(+) was also diminished by melatonin. These results demonstrate some effective roles of melatonin on neuroprotection and its action on the modulation of tyrosine hydroxylase phosphorylation.
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PMID:Protection against cell death and sustained tyrosine hydroxylase phosphorylation in hydrogen peroxide- and MPP-treated human neuroblastoma cells with melatonin. 1850 12

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) caused by an abnormal rate of apoptosis. Endogenous stem cells in the adult mammalian brain indicate an innate potential for regeneration and possible resource for neuroregeneration in PD. We previously showed that guanosine prevents apoptosis even when administered 48 hr after the toxin 1-methyl-4-phenylpyridinium (MPP(+)). Here, we induced parkinsonism in rats with a proteasome inhibitor. Guanosine treatment reduced apoptosis, increased tyrosine hydroxylase-positive dopaminergic neurons and expression of tyrosine hydroxylase in the SNc, increased cellular proliferation in the SNc and subventricular zone, and ameliorated symptoms. Proliferating cells in the subventricular zone were nestin-positive adult neural progenitor/stem cells. Fibroblast growth factor-2-expressing cells were also increased by guanosine. Thus, guanosine protected cells from apoptosis and stimulated "intrinsic" adult progenitor/stem cells to become dopaminergic neurons in rats with proteasome inhibitor-induced PD. The cellular/molecular mechanisms underlying these effects may open new avenues for development of novel therapeutics for PD.
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PMID:Guanosine improves motor behavior, reduces apoptosis, and stimulates neurogenesis in rats with parkinsonism. 1881 92

Striatal administration of 1-methyl-4-phenylpyridinium (MPP(+)), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson's disease. Copper acts as a prosthetic group of several antioxidant enzymes and recent data show that copper attenuated MPP(+)-evoked neurotoxicity. We evaluated the effect of copper (as a supplement) upon proteins nitration (60 kDa) and tyrosine hydroxylase (TH) inactivation induced by MPP(+) (10 microg/8 microL) injection into the rat striatum. Copper pretreatment (10 micromol/kg i.p.) prevented both MPP(+)-induced proteins nitration and TH inactivation. Copper treatment also prevented the dopamine-depleting effect of MPP(+) injection. Those results were accompanied by a significant reduction of enzymatic activity of the constitutive nitric oxide synthase (cNOS), whereas, the protein levels of the three isoforms of NOS remained unchanged. Results indicate that the effect of copper against MPP(+)-induced proteins nitration and TH inactivation in the striatum of rat may be mediated by a reduction of cNOS activity.
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PMID:Copper reduces striatal protein nitration and tyrosine hydroxylase inactivation induced by MPP+ in rats. 1942 87

Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by the selective loss of dopaminergic neurons of the nigrostriatal pathway. Epidemiological studies have shown an inverse relationship between coffee consumption and susceptibility to PD. Cytochrome P450 1A2 (CYP1A2) is involved in caffeine metabolism and its clearance. Caffeine, on the other hand, antagonizes adenosine A(2A) receptor and regulates dopamine signaling through dopamine transporter (DAT). The present study was undertaken to investigate the expression of CYP1A2, adenosine A(2A) receptor and DAT in mouse striatum and to assess their levels in 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropryridine (MPTP) treated mouse striatum with and without caffeine treatment. The animals were treated intraperitoneally daily with caffeine (20 mg/kg) for 8 weeks, followed by MPTP (20 mg/kg)+caffeine (20 mg/kg) for 4 weeks or vice versa, along with respective controls. Tyrosine hydroxylase immunoreactivity, levels of dopamine and 1-methyl 4-phenylpyridinium ion (MPP(+)), expressions of CYP1A2, adenosine A(2A) receptor and DAT and CYP1A2 catalytic activity were measured in control and treated mouse brain. Caffeine partially protected MPTP-induced neurodegenerative changes and modulated MPTP-mediated alterations in the expression and catalytic activity of CYP1A2, expression of adenosine A(2A) receptor and DAT. The results demonstrate that caffeine alters the striatal CYP1A2, adenosine A(2A) receptor and DAT expressions in mice exposed to MPTP.
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PMID:Effect of caffeine on the expression of cytochrome P450 1A2, adenosine A2A receptor and dopamine transporter in control and 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine treated mouse striatum. 1952 64

Parkinson's disease is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of dopaminergic neurons in substantia nigra pars compacta, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Oxidative stress may contribute to MPTP- and Parkinson's disease-related neurodegeneration. Fucoidan is a sulfated polysaccharide extracted from brown seaweeds which possesses a wide variety of biological activities including potent antioxidative effects. Here we investigated the effect of fucoidan treatment on locomoter activities of animals, striatal dopamine and its metabolites and survival of nigral dopaminergic neurons in MPTP-induced animal model of Parkinsonism in C57/BL mice in vivo and on the neuronal damage induced by 1-methyl-4-phenylpyridinium (MPP(+)) in vitro, and to study the possible mechanisms. When administered prior to MPTP, fucoidan reduced behavioral deficits, increased striatal dopamine and its metabolites levels, reduced cell death, and led to a marked increase in tyrosine hydroxylase expression relative to mice treated with MPTP alone. Furthermore, we found that fucoidan inhibited MPTP-induced lipid peroxidation and reduction of antioxidant enzyme activity. In addition, pre-treatment with fucoidan significantly protected against MPP(+)-induced damage in MN9D cells. Taken together, these findings suggest that fucoidan has protective effect in MPTP-induced neurotoxicity in this model of Parkinson's disease via its antioxidative activity.
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PMID:Fucoidan protects against dopaminergic neuron death in vivo and in vitro. 1954 63

The main contributory factors of Parkinson's disease (PD) are aging, genetic factors, and environmental exposure to pesticides and heavy metals. CYP2D22, a mouse ortholog of human CYP2D6, is expected to participate in a chemically induced PD phenotype due to its structural resemblance with CYP2D6. Despite its expected participation in PD, its expression in the nigrostriatal tissues and modulation by the chemicals that induce PD or offer neuroprotection have not yet been investigated. The present study was undertaken to investigate CYP2D22 expression in mouse striatum and to assess its involvement in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD phenotype and nicotine-mediated neuroprotection. The animals were treated intraperitoneally daily with nicotine (1 mg/kg) for 8 weeks, followed by MPTP (20 mg/kg) + nicotine (1 mg/kg) for 2-4 weeks and vice versa, along with respective controls. In some sets of experiments, the animals were treated with ketoconazole (300 mg/kg), a CYP3AH/CYP2D22 inhibitor, along with nicotine and/or MPTP. Tyrosine hydroxylase (TH)-immunoreactivity in the substantia nigra, the expression of nicotinic acetylcholine receptors (nAChRs) alpha6 and alpha4, dopamine content, and 1-methyl-4-phenylpyridinium ion (MPP(+)) level in the striatum were measured to confirm the MPTP-induced PD phenotype and nicotine-mediated neuroprotection. CYP2D22 and nAChRs expressions were measured in the striatum by RT-PCR/western blotting and dopamine level; CYP2D22 catalytic activity and MPP(+) content were determined by high-performance liquid chromatography (HPLC). MPTP increased dopaminergic neuronal degeneration and the striatal MPP(+) level and reduced striatal dopamine content; it attenuated expression/activity of CYP2D22 and nAChRs that were significantly restored in nicotine-treated animals. Ketoconazole reduced the nicotine-mediated increase in CYP2D22 expression and activity, dopamine content, and TH-immunoreactivity. The results indicate the expression of CYP2D22 in mouse striatum and its possible role in the MPTP-induced PD phenotype and nicotine-mediated neuroprotection.
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PMID:The expression of CYP2D22, an ortholog of human CYP2D6, in mouse striatum and its modulation in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease phenotype and nicotine-mediated neuroprotection. 1959 27

Disturbances in Ca(2+) homeostasis have been implicated in a variety of neuropathological conditions including Parkinson's disease (PD). However, the importance of store-operated Ca(2+) entry (SOCE) channels in PD remains to be investigated. In the present study, we have scrutinized the significance of TRPC1 in 1-methyl-4-phenyl-1,2,3,6-tetrahyrdro-pyridine (MPTP)-induced PD using C57BL/6 animal model and PC12 cell culture model. Both sub-acute and sub-chronic treatments of MPTP significantly reduced TRPC1, and tyrosine hydroxylase levels, but not TRPC3, along with increased neuronal death. Furthermore, MPTP induces mitochondrial dysfunction, which was associated with reduced mitochondrial membrane potential, decreased level of Bcl(2), Bcl-xl, and an altered Bcl-xl/Bax ratio thereby initiating apoptosis. Importantly, TRPC1 overexpression in PC12 cells showed significant protection against MPP(+) induced neuronal apoptosis, which was attributed to the restoration of cytosolic Ca(2+) and preventing loss of mitochondrial membrane potential. Silencing of TRPC1 or addition of TRPC1 channel blockers decreased mitochondrial membrane potential, whereas activation of TRPC1 restored mitochondrial membrane potential in cells overexpressing TRPC1. TRPC1 overexpression also inhibited Bax translocation to the mitochondria and thereby prevented cytochrome c release and mitochondrial-mediated apoptosis. Overall, these results provide compelling evidence for the role of TRPC1 in either onset/progression of PD and restoration of TRPC1 levels could limit neuronal degeneration in MPTP mediated PD.
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PMID:TRPC1 inhibits apoptotic cell degeneration induced by dopaminergic neurotoxin MPTP/MPP(+). 1969 1

To assess potential efficacy of mechano growth factor (MGF) for chronic neurodegenerative disorders, we studied whether MGF protects dopamine (DA) neurons subjected to neurotoxic stress. We show that a short 24-amino acid C-terminal peptide of MGF (MGF24) upregulates heme oxygenase-1 (HO-1) expression and protects SH-SY5Y cells against apoptosis and cell loss induced by three DA cell-specific neurotoxins: 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenylpyridinium (MPP(+)), and rotenone. MGF24 maintains the mitochondrial membrane potential and blocks the release of mitochondrial apoptotic-inducing factor into the cytoplasm induced by 6-OHDA, MPP(+), and rotenone. Chemical inhibition of HO-1 with zinc protoporphyrin-IX prevents neuroprotection by MGF24 against the three neurotoxins. MGF24 does not activate Akt signaling nor does Akt inhibition block MGF24 protection of SH-SY5Y cells. In 6-OHDA-lesioned rats, central or peripheral MGF24 administration protects against the development of contralateral forelimb under-utilization, reduces ipsilateral nigral DA cell body loss, and attenuates tyrosine hydroxylase fiber loss in the ipsilateral striatum, independent of IGF-1 receptor activation. Peripheral MGF24 administration upregulates HO-1 expression in striatal and midbrain tissue. This report is the first to demonstrate that a small peptide, MGF24, upregulates HO-1, an important cell defense mediator, and protects DA cells, suggesting new strategies for neuroprotection in Parkinson's disease.
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PMID:C-terminal mechano growth factor protects dopamine neurons: a novel peptide that induces heme oxygenase-1. 1973 55


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