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)

1. Phosphatidylinositol transfer proteins (PI-TP) are responsible for the transport of phosphatidylinositol (PI) and other phospholipids from endoplasmic reticulum to the other membranes and indirectly for lipid mediated signaling. Till now little is known about PI-TPs in brain aging and neurodegeneration. The aim of this study was to investigate expression of PI-TP in the brain during aging and in animal's model of Parkinson disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Moreover, in vitro, effect of 1-methyl-4-phenyl-pyridine cation (MPP(+)) on PI-TP, tyrosine hydroxylase (TH) protein level, and viability of cells was investigated. 2. Wistar rats 4, 24, and 36 months old and C57/BL mice and rat pheochromocytoma (PC12) cell line were used for the studies. Mice C57/BL received three injections of MPTP in saline at 2 h intervals in a total dose of 40 mg/kg and then after 3, 7, and 14 days they were used for the investigation. PC12 cells were treated with increasing concentration (50-300 microM) of MPP(+) for 24 h at 37 degrees C. The level of PI-TP(alpha and beta) and TH were determined using Western Blot analysis. 3. Our data indicated that PI-TP(alpha and beta) level decreased in brain of 36 months old rat by 20% comparing to the control value (4 months old). In animal's model of PD, PI-TP(alpha and beta) level was significantly lower by 85, 69, 64% in striatum at 3, 7, and 14 days after MPTP injection, respectively, compared to the control value. MPP(+) decreased PI-TP(alpha and beta), TH expression, and viability of PC12 cells in a dose-dependent manner. H(2)O(2), menadione, and NO donor significantly decreased the PI-TP level and viability of PC12 cells. 4. Our results indicate the lower protein expression of PI-TP(alpha and beta) in aged brain and in PD and suggest that oxidative stress may be responsible for the alteration of PI-TP.
 ...
PMID:Phosphatidylinositol transfer protein expression altered by aging and Parkinson disease. 1677 71

A parasite-derived protein, PDNF, produced by the Chagas' disease agent Trypanosoma cruzi, functionally mimics mammalian neurotrophic factors by delaying apoptotic death and promoting survival and differentiation of neurons, including dopaminergic cells, through the activation of nerve growth factor receptor TrkA. Because it is well established that neurotrophic factors regulate enzymes involved in the biosynthesis of neurotransmitters, we examined whether PDNF could also directly activate tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of dopamine and other catecholamine neurotransmitters. We found that primary cultures of rat ventral mesencephalon responded to PDNF by increasing the number of TH-positive neurons and, most importantly, preserved expression of TH in neurons treated with Parkinson disease-inducing neurotoxin 1-methyl-4-phenyl pyridinium (MPP(+)). In dopaminergic PC12 cells, PDNF induced TH transcription via CRE element in TH promoter followed by significant increase in TH protein and expansion of TH-positive cell population. Furthermore, PDNF stimulated TH enzymatic activity by enhancing phosphorylation of seryl residues 31 and 40 through the activation of MAPK/Erk1/2 and cAMP-dependent protein kinase A signaling, respectively. Therefore, our results indicate that PDNF, in addition to its functioning as survival and differentiation-promoting factor for dopaminergic neuronal cells, can directly influence activity of the rate-limiting enzyme that underlies catecholamine biosynthetic cascade. This novel feature of PDNF should help understand the mechanism of neuronal function altered by T. cruzi infection, specifically neurotransmitter secretion. In addition, the findings have potential implications in the therapy of Chagas' and other neurodegenerative disorders.
 ...
PMID:Enhancement of tyrosine hydroxylase expression and activity by Trypanosoma cruzi parasite-derived neurotrophic factor. 1680 15

The potent Parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is known to destroy dopaminergic neurons of the basal ganglia. Its neurotoxically active metabolite, 1-methyl-4-phenyl pyridinium (MPP(+)), has been examined in the present study to verify whether administration of the neurotoxin that depletes about 70% of the striatal dopamine (DA) can cause damage to nuclear components of the cells at the terminal region, the striatum. Unilateral intrastriatal infusion of MPP(+) (100 and 200 nmol in 4 microl saline) caused a dose-dependent depletion of striatal DA (69 and 92%, respectively), as measured employing HPLC electrochemistry. It also resulted in the loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and in the perikarya at substantia nigra pars compacta (SNpc) and acetylcholinesterase histoenzymological staining in the striatum. Specific nuclear staining employing Hoechst 33342 and acridine orange revealed distorted and spindle shaped nuclei, and perinuclear positioning of nucleolus, respectively, for the former and latter dyes in several of the cell populations in the ipsilateral striatum compared to the contralateral side. Existence of a widened lateral ventricle at the side that received the neurotoxin, as well as denser cellular population, as compared to the contralateral side under transmission electron microscope evidenced general shrinkage of the striatum. Extensive damage of the nuclei was visible in the cell bodies in the treated side. These results demonstrate non-specific damage extending to the cellular groups including cholinergic neurons in addition to dopaminergic neurons in the striatum to intrastriatal administration of the Parkinsonian neurotoxin, MPP(+).
 ...
PMID:Intrastriatal infusion of the Parkinsonian neurotoxin, MPP(+), induces damage of striatal cell nuclei in Sprague-Dawley rats. 1682 45

Human embryonic stem cells (hESCs) can proliferate indefinitely yet also differentiate in vitro, allowing normal human neurons to be generated in unlimited numbers. Here, we describe the development of an in vitro neurotoxicity assay using human dopaminergic neurons derived from hESCs. We showed that the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)), which produces features of Parkinson's disease in humans, was toxic for hESC-derived dopaminergic neurons. Treatment with glial cell line-derived neurotrophic factor protected tyrosine hydroxylase-positive neurons against MPP(+)-induced apoptotic cell death and loss of neuronal processes as well as against the formation of intracellular reactive oxygen species. The availability of human dopaminergic neurons, derived from hESCs, therefore allows for the possibility of directly examining the unique features of human dopaminergic neurons with respect to their responses to pharmacological agents as well as environmental and chemical toxins.
 ...
PMID:An in vitro model of human dopaminergic neurons derived from embryonic stem cells: MPP+ toxicity and GDNF neuroprotection. 1710 14

In the present study, we investigated the neuroprotective effects of echinacoside, a phenylethanoid glycoside extracted from the medicinal Chinese herb Cistanches salsa, against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic toxicity. We confirmed that exposure to MPTP in mice leads to permanent behavioral deficits and depletion of dopamine and its metabolites. When administered prior to MPTP, echinacoside reduced behavioral deficits, increased striatal dopamine and dopamine metabolite levels, reduced cell death, and led to a marked increase in tyrosine hydroxylase expression relative to mice treated with MPTP alone. In addition, pre-treatment with echinacoside significantly reduced caspase-3 and caspase-8 activation in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in cerebellar granule neurons. Taken together, these findings suggest that echinacoside improves the behavioral and neurochemical outcomes in MPTP mice model of Parkinson's disease and inhibits caspase-3 and caspase-8 activation in cerebellar granule neurons, making the compound an attractive candidate treatment for various neurodegenerative disorders, including Parkinson's disease.
 ...
PMID:Neuroprotective effects of echinacoside in the mouse MPTP model of Parkinson's disease. 1735 68

The potent parkinsonian neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is known to cause dopaminergic neurodegeneration in nigrostriatal system. In the present study we investigated the nuclear morphology of cells in the substantia nigra pars compacta (SNpc) region of rats following unilateral intranigral infusion of the active metabolite, 1-methyl-4-phenyl pyridinium ion (MPP(+)), which resulted in a dose-dependent and prolonged dopamine depletion in the ipsilateral striatum. There appeared a substantial loss of tyrosine hydroxylase immunoreactive neurons in the SNpc that received the neurotoxin. Specific nuclear staining with Hoechst 33342 or acridine orange revealed bright pyknotic, shrunken, distorted nuclei and condensed chromatin with perinuclear nucleolus respectively following visualization with the former and latter dyes in the ipsilateral SNpc, as compared to the round, intact nuclei and centrally positioned nucleolus in the contralateral side. Ultrastructural details of the nucleus under transmission electron microscope confirmed distorted nuclear organization with shrunken or condensed nuclei and disrupted nuclear membrane. These features are typical of nucleus undergoing apoptosis, and suggest that MPP(+) causes dopaminergic neuronal death through an apoptotic mode. Typical laddering pattern of genomic DNA isolated from the ipsilateral SN in agarose gel electrophoresis conclusively established apoptosis following intranigral administration of MPP(+) in rats.
 ...
PMID:Apoptotic mode of cell death in substantia nigra following intranigral infusion of the parkinsonian neurotoxin, MPP+ in Sprague-Dawley rats: cellular, molecular and ultrastructural evidences. 1740 60

Recent studies from our laboratory demonstrated that the protein kinase C (PKC) delta isoform is an oxidative stress-sensitive kinase and a key mediator of apoptotic cell death in Parkinson's Disease (PD) models (Eur J Neurosci 18:1387-1401, 2003; Mol Cell Neurosci 25:406-421, 2004). We showed that native PKC delta is proteolytically activated by caspase-3 and that suppression of PKC delta by dominant-negative mutant or small interfering RNA against the kinase can effectively block apoptotic cell death in cellular models of PD. In an attempt to translate the mechanistic studies to a neuroprotective strategy targeting PKC delta, we systematically characterized the neuroprotective effect of a PKC delta inhibitor, rottlerin, in 1-methyl-4-phenylpyridinium (MPP(+))-treated primary mesencephalic neuronal cultures as well as in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD. Rottlerin treatment in primary mesencephalic cultures significantly attenuated MPP(+)-induced tyrosine hydroxylase (TH)-positive neuronal cell and neurite loss. Administration of rottlerin, either intraperitoneally or orally, to C57 black mice showed significant protection against MPTP-induced locomotor deficits and striatal depletion of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid. Notably, rottlerin post-treatment was effective even when MPTP-induced depletion of dopamine and its metabolites was greater than 60%, demonstrating its neurorescue potential. Furthermore, the dose of rottlerin used in neuroprotective studies effectively attenuated the MPTP-induced PKC delta kinase activity. Importantly, stereological analysis of nigral neurons revealed rottlerin treatment significantly protected against MPTP-induced TH-positive neuronal loss in the substantia nigra compacta. Collectively, our findings demonstrate the neuroprotective effect of rottlerin in both cell culture and preclinical animal models of PD, and they suggest that pharmacological modulation of PKC delta may offer a novel therapeutic strategy for treatment of PD.
 ...
PMID:Neuroprotective effect of protein kinase C delta inhibitor rottlerin in cell culture and animal models of Parkinson's disease. 1756 7

Protein nitration due to oxidative and nitrative stress has been linked to the pathogenesis of Parkinson's disease (PD), but its relationship to the loss of dopamine (DA) or tyrosine hydroxylase (TH) activity is not clear. Here we quantified protein-bound 3-nitrotyrosine (3-NT) by a novel gas chromatography/negative chemical ionization tandem mass spectrometry technique and DA and 3,4-dihydroxyphenylalanine (DOPA) by HPLC in tissues or medium of organotypic, mouse mesencephalon cultures after acute or chronic treatments with the peroxynitrite donor 3-morpholino-sydnonimine (SIN-1), the dopaminergic toxin 1-methyl-4-phenylpyridinium (MPP(+)) or the lipophilic complex I inhibitor rotenone. Incubation with SIN-1 (24 h) or MPP(+) treatments (48 h) caused dose-dependent protein nitration reaching a maximum of eightfold increase by 10 mM SIN-1 or twofold by 10 microM MPP(+), but significant DA depletions occurred at much lower concentrations of MPP(+) (1 microM). Chronic MPP(+) or rotenone treatments (3 weeks) caused maximum protein nitration by 1 microM (twofold) or 10nM (fourfold), respectively. Co-treatment with the nitric oxide synthase inhibitor l-NAME (300 microM) prevented protein nitration by MPP(+), but did not protect against MPP(+)-induced DA depletion or inhibition of TH activity. Acute incubation with 100 microM SIN-1 inhibited TH activity, which could be blocked by co-treatment with the tetrahydrobiopterin precursor l-sepiapterin, but tissue DA depletions required higher doses of SIN-1 (>1 mM, 24 h) and longer survival. In conclusion, protein nitration and TH activity or DA depletion are not directly related in these models.
 ...
PMID:Nitration of soluble proteins in organotypic culture models of Parkinson's disease. 1790 Jul 61

Parkinson's disease is characterized by the progressive degeneration of midbrain dopaminergic neurons. Buddleia lindleyana is a traditional Chinese herb, commonly called Zui Yu Cao. The purification and identification of pedicularioside A and other phenylethanoid glycosides from this plant have been reported. However, their neuroprotective effects on the 1-methyl-4-phenylpyridinium ion (MPP(+))-induced death of rat mesencephalic neuron primary cultures and the precise mechanism of this protection remains unclear. We used the 3-(4, 5-dimethylthiozol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay for cellular growth to examine the effects of five phenylethanoid glycosides isolated from B. lindleyana, including pedicularioside A, leucosceptoside A, isoacteoside, acteoside, and arenariside, on the viability of mesencephalic neurons treated with MPP(+). Of the compounds tested, pedicularioside A exhibited the greatest degree of protection from MPP(+)-induced cell death. We also observed a marked increase in the number of tyrosine hydroxylase immunoreactive neurons. Pedicularioside A inhibited expression of the caspase-3 gene and cleavage of poly (ADP-ribose) polymerase (PARP) in cultures exposed to MPP(+). Our results suggest that pedicularioside A has a neuroprotective effect to improve the survival of mesencephalic neurons (dopaminergic neurons and non-dopaminergic neurons). The mode of action appears to be the inhibition of caspase-3 gene expression, thereby protecting mesencephalic neurons from MPP(+)-induced cell death.
 ...
PMID:Pedicularioside A from Buddleia lindleyana inhibits cell death induced by 1-methyl-4-phenylpyridinium ions (MPP+) in primary cultures of rat mesencephalic neurons. 1803 49

Many studies showed that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which was widely used to produce Parkinson's disease (PD)-like models in animals can elicit apoptosis with increase of caspase activity via its neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)). Another pathway shown in MPTP-mediated nigrostriatal dopaminergic cell death involved the c-Jun-N-terminal kinases (JNKs) which are stress-activated protein kinases (SAPKs). Activation of the JNKs leads to the activation of transcription factors such as c-Jun that regulates its own expression. However, it is not known whether the activation of c-Jun is crucial in the stimulation of caspases leading to apoptosis observed in PD-like models. The aim of this study was to investigate the cellular expression and phosphorylation of c-Jun and the caspase-9 activity in rat injured with an intranigral injection of MPP(+). Furthermore, we determined the effects of a cell-permeable peptide TAT-JBD, inhibiting selectively JNKs, on apoptosis markers and on the expression of tyrosine hydroxylase (TH). Our results showed that MPP(+) induced not only an activation of c-Jun but also an early and robust stimulation of caspase-9 in midbrain of rats. Furthermore, a preliminary intravenous injection of TAT-JBD reduced the caspase-9 activation specifically induced by MPP(+) suggesting a control of the JNKs pathway on the intrinsic way of apoptosis in MPP(+)-toxicity. However, the inhibition of the JNK pathway did not prevent TH inhibition, DNA fragmentation and Bad expression in MPP(+)-lesioned substantia nigra of rats. Therefore, the possibility of intervention on the JNK pathway as a therapeutic strategy in Parkinson's disease is questionable.
 ...
PMID:A cell-permeable peptide inhibitor TAT-JBD reduces the MPP+-induced caspase-9 activation but does not prevent the dopaminergic degeneration in substantia nigra of rats. 1803 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>