Effect of Cytidine on Membrane Phospholipid Synthesis in Rat Striatal Slices

Savci, Vahide; Wurtman, Richard J.

doi:10.1046/j.1471-4159.1995.64010378.x

Cited by 63 publications

(31 citation statements)

References 44 publications

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“…Previous studies have shown that other circulating PC precursors, specifically choline and cytidine or uridine, also stimulate PC synthesis in slice preparations of rat striatum [30] or in PC12 cells [24] by combining to form CDP-choline, one of the two proximate precursors of PC synthesis [31]. The final step in PC synthesis, catalyzed by CDP choline:1,2-diacylglycerol phosphotransferase [32], attaches CDP-choline to diacylglycerol (DAG).…”

Section: Discussionmentioning

confidence: 99%

Polyunsaturated fatty acids stimulate phosphatidylcholine synthesis in PC12 cells

Richardson

Wurtman

2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The synthesis of phospholipids in mammalian cells is regulated by the availability of three critical precursor pools: those of choline, cytidine triphosphate and diacylglycerol. Diacylglycerols containing polyunsaturated fatty acids (PUFAs) apparently are preferentially utilized for phosphatide synthesis. PUFAs are known to play an important role in the development and function of mammalian brains. We therefore studied the effects of unsaturated, monounsaturated and polyunsaturated fatty acids on the overall rates of phospholipid biosynthesis in PC12 rat pheochromocytoma cells. Docosahexaenoic acid (DHA, 22:6n-3), eicosapentaenoic acid (EPA, 20:5n-3) and arachidonic acid (AA, 20:4n-6) all significantly stimulated the incorporation of 14 C-choline into total cellular phospholipids. In contrast, monounsaturated oleic acid (OA) and the unsaturated palmitic (PA) and stearic (SA) acids did not have this effect. The action of DHA was concentration-dependent between 5 and 50 μM; it became statistically significant by 3 hrs after DHA treatment and then increased over the ensuing 3 hours. DHA was preferentially incorporated into phosphatidylethanolamine (PE) and phosphatidylserine (PS), while AA predominated in phosphatidylcholine (PC).

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Section: Discussionmentioning

confidence: 99%

Polyunsaturated fatty acids stimulate phosphatidylcholine synthesis in PC12 cells

Richardson

Wurtman

2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…In PC12 cells, PC biosynthesis has also been reported to be regulated by the availability of diacylglycerol and by the activity of cholinephosphotransferase, the enzyme that catalyzes the final step of the CDPcholine pathway (2). Furthermore, cytidine and uridine (the product of cytidine deamination) can enhance PC biosynthesis in PC12 cells (45) and rat brain slices (46). Interestingly, treatment of PC12 cells with uridine increased CDP-choline levels and enhanced neurite outgrowth and branch formation in a dose-dependent manner (47).…”

Section: Ct␤2 Is Abundant In Axons Andmentioning

confidence: 99%

Phosphatidylcholine Biosynthesis via CTP:Phosphocholine Cytidylyltransferase β2 Facilitates Neurite Outgrowth and Branching

Carter

Demizieux

Campenot

et al. 2008

Journal of Biological Chemistry

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Hallmarks of neuronal differentiation are neurite sprouting, extension, and branching. We previously showed that increased expression of CTP:phosphocholine cytidylyltransferase ␤2 (CT␤2), an isoform of a key phosphatidylcholine (PC) biosynthetic enzyme, accompanies neurite outgrowth (Carter, J. M., Waite, K. A., Campenot, R. B., Vance, J. E., and Vance, D. E. (2003) J. Biol. Chem. 278, 44988 -44994). CT␤2 mRNA is highly expressed in the brain. We show that CT␤2 is abundant in axons of rat sympathetic neurons and retinal ganglion cells. We used RNA silencing to decrease CT␤2 expression in PC12 cells differentiated by nerve growth factor. In CT␤2-silenced cells, numbers of primary and secondary neurites were markedly reduced, suggesting that CT␤2 facilitates neurite outgrowth and branching. However, the length of individual neurites was significantly increased, and the total amount of neuronal membrane was unchanged. Neurite branching of PC12 cells is known to be inhibited by activation of Akt and promoted by the Akt inhibitor LY294002. Our experiments showed that LY294002 increases neurite sprouting and branching in control PC12 cells but not in CT␤2-deficient cells. CT␤2 was not phosphorylated in vitro by Akt. However, inhibition of Cdk5 by roscovitine blocked CT␤2 phosphorylation and reduced neurite outgrowth and branching. These results highlight the importance of CT␤2 in neurons for promoting neurite outgrowth and branching and represent the first identification of a lipid biosynthetic enzyme that facilitates these functions.

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“…Cytidine, a pyrimidine, is also known to play a role in phospholipid metabolism and membrane stability (Cansev, 2006;Carlezon et al, 2005;Savci and Wurtman, 1995). Biochemical alterations in the structure and function of neuronal membranes can affect the intracellular and extracellular processes and synaptic neurotransmission, all of which may be involved in the pathophysiology of mood disorders (Carlezon et al, 2005;Lands, 1992;Nomura et al, 2001;Pacheco and Jope, 1996).…”

Section: Introductionmentioning

confidence: 99%

Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

Yoon

Lyoo

Haws

et al. 2009

Neuropsychopharmacol

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Targeting the glutamatergic system has been suggested as a promising new option for developing treatment strategies for bipolar depression. Cytidine, a pyrimidine, may exert therapeutic effects through a pathway that leads to altered neuronal-glial glutamate cycling. Pyrimidines are also known to exert beneficial effects on cerebral phospholipid metabolism, catecholamine synthesis, and mitochondrial function, which have each been linked to the pathophysiology of bipolar depression. This study was aimed at determining cytidine's efficacy in bipolar depression and at assessing the longitudinal effects of cytidine on cerebral glutamate/glutamine levels. Thirty-five patients with bipolar depression were randomly assigned to receive the mood-stabilizing drug valproate plus either cytidine or placebo for 12 weeks. Midfrontal cerebral glutamate/glutamine levels were measured using proton magnetic resonance spectroscopy before and after 2, 4, and 12 weeks of oral cytidine administration. Cytidine supplementation was associated with an earlier improvement in depressive symptoms (weeks 1-4; p ¼ 0.02, 0.001, 0.002, and 0.004, respectively) and also produced a greater reduction in cerebral glutamate/glutamine levels in patients with bipolar depression (weeks 2, 4, and 12; p ¼ 0.004, 0.004, and 0.02, respectively). Cytidinerelated glutamate/glutamine decrements correlated with a reduction in depressive symptoms (p ¼ 0.001). In contrast, these relationships were not observed in the placebo add-on group. The study results suggest that cytidine supplementation of valproate is associated with an earlier treatment response in bipolar depression. Furthermore, cytidine's efficacy in bipolar depression may be mediated by decreased levels of cerebral glutamate and/or glutamine, consistent with alterations in excitatory neurotransmission.

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Effect of Cytidine on Membrane Phospholipid Synthesis in Rat Striatal Slices

Cited by 63 publications

References 44 publications

Polyunsaturated fatty acids stimulate phosphatidylcholine synthesis in PC12 cells

Polyunsaturated fatty acids stimulate phosphatidylcholine synthesis in PC12 cells

Phosphatidylcholine Biosynthesis via CTP:Phosphocholine Cytidylyltransferase β2 Facilitates Neurite Outgrowth and Branching

Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

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