Modulation of phosphatidylcholine synthesis in vitro

Parthasarathy, S.; El-Rahman, M.M.A. Abd; Baumann, Wolfgang J.

doi:10.1016/0005-2760(81)90020-5

Cited by 11 publications

(4 citation statements)

References 25 publications

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“…centrophenoxine) is a nootropic drug that is marketed as a memory enhancer. This drug, which readily crosses the blood-brain barrier, has been reported to inhibit enzymes involved in PC biosynthesis [ 36 , 37 ], increase acetylcholine, scavenges radicals [ 38 ], and ameliorate rotenone-induced motor dysfunction in rodents [ 34 , 35 ]. MFX rapidly hydrolyzes into 4-chlorophenoxyacetic acid and dimethylethanolamine (DMAE) at neutral pH, and DMAE is considered to be the active product because of its ability to scavenge hydroxyl radicals [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson’s Disease

Wang

Zhang

et al. 2016

PLoS ONE

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We have been investigating the role that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) content plays in modulating the solubility of the Parkinson’s disease protein alpha-synuclein (α-syn) using Saccharomyces cerevisiae and Caenorhabditis elegans. One enzyme that synthesizes PE is the conserved enzyme phosphatidylserine decarboxylase (Psd1/yeast; PSD-1/worms), which is lodged in the inner mitochondrial membrane. We previously found that decreasing the level of PE due to knockdown of Psd1/psd-1 affects the homeostasis of α-syn in vivo. In S. cerevisiae, the co-occurrence of low PE and α-syn in psd1Δ cells triggers mitochondrial defects, stress in the endoplasmic reticulum, misprocessing of glycosylphosphatidylinositol-anchored proteins, and a 3-fold increase in the level of α-syn. The goal of this study was to identify drugs that rescue this phenotype. We screened the Prestwick library of 1121 Food and Drug Administration-approved drugs using psd1Δ + α-syn cells and identified cyclosporin A, meclofenoxate hydrochloride, and sulfaphenazole as putative protective compounds. The protective activity of these drugs was corroborated using C. elegans in which α-syn is expressed specifically in the dopaminergic neurons, with psd-1 depleted by RNAi. Worm populations were examined for dopaminergic neuron survival following psd-1 knockdown. Exposure to cyclosporine, meclofenoxate, and sulfaphenazole significantly enhanced survival at day 7 in α-syn-expressing worm populations whereby 50–55% of the populations displayed normal neurons, compared to only 10–15% of untreated animals. We also found that all three drugs rescued worms expressing α-syn in dopaminergic neurons that were deficient in the phospholipid cardiolipin following cardiolipin synthase (crls-1) depletion by RNAi. We discuss how these drugs might block α-syn pathology in dopaminergic neurons.

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Section: Discussionmentioning

confidence: 99%

Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson’s Disease

Wang

Zhang

et al. 2016

PLoS ONE

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“…We previously reported (40,41) that two of the key enzymes ofphosphatidylcholine synthesis in mammalian systems-namely, cholinephosphotransferase (ChoPTase; CDPcholine:1,2-diacylglycerol cholinephosphotransferase, EC 2.7.8.2) (42) and lysolecithin acyltransferase (LLAcylTase; acyl-CoA:1-acylglycero-3-phosphocholine O-acyltransferase, EC 2.3.1.23) (43)-are inhibited by centrophenoxine (CPO; N,N-dimethylaminoethyl p-chlorophenoxyacetate) and neophenoxine (NPO; (N,Ndimethylaminoethyl p-chlorophenoxyethyl ether). The structural similarity of CPO and clofibrate prompted us to study the effect of clofibric acid (CPIB; p-chlorophenoxyisobutyric acid) and several other hypolipidemic drugs on the two enzymes of choline phospholipid metabolism.…”

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“…CDP[methyl-14C]choline was purchased from Amersham and was diluted with unlabeled CDPcholine (Sigma). 1-Acyl-sn-glycero-3-phosphocholine was prepared from purified rat liver phosphatidylcholine by the action of phospholipase A2 (Ophiophagus hannah venom, Miami Serpentarium Laboratories, Miami, FL) according to established procedures (45 ChoPTase activity was determined according to Coleman and Bell (47) as modified in our laboratory (41,48). The assay, carried out in the presence of bovine serum albumin (1 mg/ml), used 100 nmol of rat liver 1,2-diacyl-sn-glycerol, 100 ,uM CDP[methyl-14C]choline (2.5 mCi/mmol), and 30 ,ug ofprotein in a final volume of 200 ,ul (370C, 10 min).…”

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Hypolipidemic drugs are inhibitors of phosphatidylcholine synthesis.

Parthasarathy¹,

Kritchevsky²,

Baumann³

1982

Proc. Natl. Acad. Sci. U.S.A.

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Beeinflussung des Lands Zyklus durch Inhibitoren und Cofaktoren

1988

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und y-Linolensaure eine Rolle, da bei den endogenen Ekzematikem unter Therapie eine Konzentrationserhohung der Metaboliten des Linolsaurestoffwechsels zu beobachten ist. Aus unseren kinetischen Studien ist die hohe Metabolisierungsgeschwindigkeit der mehrfach ungesattigten Fettsauren zu erkennen. Hier liegt sicherlich eine Ursache fiir die in der Literatur gefundenen widerspriichhchen Fettsaureverteilungsmuster, denn dieser schnelle Abbau impliziert eine zeitlich genau standardisierte Blutentnahme nach der letzten oralen Applikation.Ungeklart bleibt letztlich immer noch die Frage nach der biologischen Funktionsweise der mehrfach ungesattigten Fettsauren beim endogenen Ekzem. Hierzu sind weitere Untersuchungen im Bereich der sich dynamisch iindernden Membranstrukturen und i m Bereich des Auf-bzw. Abbaus der Prostaglandine notwendig. L i t e r a t u r I G. 0. Burr u. M. M. Burr, J. Biol. Chem. 82,345 [1929].

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Modulation of phosphatidylcholine synthesis in vitro

Cited by 11 publications

References 25 publications

Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson’s Disease

Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson’s Disease

Hypolipidemic drugs are inhibitors of phosphatidylcholine synthesis.

Beeinflussung des Lands Zyklus durch Inhibitoren und Cofaktoren

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