Abstract
A method and model are described to quantify in vivo turnover rates and half-lives of fatty acids within brain phospholipids. These “kinetic” parameters can be calculated by operational equations from measured rates of incorporation of intravenously injected fatty acid radiotracers into brain phospholipids. To do this, it is necessary to determine a “dilution factor” λ, which estimates the contribution to the brain precursor acyl-CoA pool of fatty acids released from phospholipids through the action of PLA1, or PLA2. Some calculated fatty acid half-lives are minutes to hours, consistent with active participation of phospholipids in brain function and structure. The fatty acid method can be used to identify enzyme targets of drugs acting on phospholipid metabolism. For example, a reduced brain turnover of arachidonate by chronic lithium, demonstrated in rats by the fatty acid method, suggests that this agent, which is used to treat bipolar disorder, has for its target an arachidonate-specific PLA2. In another context, when combined with in vivo imaging by quantitative autoradiography in rodents or positron emission tomography in macaques or humans, the fatty acid method can localize and quantify normal and modified PLA2-mediated signal transduction in brain.
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REFERENCES
Porcellati, G., Goracci, G., and Arienti, G. Lipid turnover.1983. pp.277–294, in A.Lajtha (Ed.), Handbook of Neurochemistry, Vol. 5, New York: Plenum.
Fisher, S.K., and Agranoff, B.W.1987.Receptor activation and inositol lipid hydrolysis in neural tissues. J. Neurochem.48:999–1017.
Axelrod, J., Burch, R.M., and Jelsema, C.L.1988.Receptor-mediated activation of phospholipase A2 via GTP-binding proteins:arachidonic acid and its metabolites as second messengers.Trends Neurosci.11:117–123.
Stephenson, D.T., Manetta, J.V., White, D.L., Chiou, X.G., Cox, L., Gitter, B., May, P.C., Sharp, J.D., Kramer, R.M., and Clemens, J.A.1994.Calcium-sensitive cytosolic phospholipase A2 (cPLA2)is expressed in human brain astrocytes. Brain Res. 637:97–105.
Bazan, N.G., and Rodriguez de Turco, E.1980.Membrane lipids in the pathogenesis of brain edema:phospholipids and arachidonic acid, the earliest membrane components changed at the onset of ischemia. Adv.Neurol.28:197–205.
Rabin, O., Deutsch, J., Grange, E.,Pettigrew, K.D., Chang, M.C.J., Rapoport, S.I., and Purdon, A.D. 1997.Changes in cerebral acyl-CoA concentrations following ischemia-reperfusion in awake gerbils. J. Neurochem. 68:2111–2118.
Nariai, T., DeGeorge, J.J., Greig, N.H., and Rapoport, S.I. 1991.In vivo incorporation of [9, 10-3 H ]palmitate into a rat metastatic brain-tumor model. J. Neurosurg.74:643–649.
Castelli, M.G., Butti, G., Chiabrando, C., Cozzi, E., Fanelli, R., Gaetani, P., Silvani, V., and Paoletti, P.1987.Arachidonic acid metabolic profiles in human meningiomas and gliomas. J. Neuro-oncol. 5:369–375.
Singh, A.K.1994.Age-dependent neurotoxicity in rats chronically exposed to low level lead ingestion:phospholipid metabolism in synaptosomes and microvessels. Toxicol. Ind. Health 10:89–101.
Tithof, P.K., Ruehle, K., and Ganey, P.E.1996.Dieldrin and lindane activate neutrophils by a mechanism that involves calcium-independent phospholipase A2.Toxicologist 30 (no.l, part 2):54.
Bourre, J.-M., Francois, M., Youyou, A., Dumont, O., Piciotti, M., Pascal, G., and Durand, G.1989.The effects of dietary cc-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats. J.Nutrit. 119:1880–1892.
Ginsberg, L., Rafique, S., Xuereb, J.H., Rapoport, S.I., and Gershfeld, N.L.1995.Disease and anatomic specificity of ethanolamine plasmalogen deficiency in Alzheimer's disease brain. Brain Res. 698:223–226.
Farooqui, A.A., Rapoport, S.I., and Horrocks, L.A.1997.Membrane phospholipid alterations in Alzheimer's disease: Deficiency of ethanolamine plasmalogens. Neurochem. Res. 22: 523–527.
Pettegrew, J.W., Moossy, J., Withers, G., McKeag, D., and Panchalingam, K.1988.31 P nuclear magnetic resonance study of the brain in Alzheimer's disease. J. Neuropathol. Exp. Neurol.47:235–248.
Hibbeln, J.R., Palmer, J.W., and Davis, J.M.1989.Are disturbances in lipid-protein interactions by phospholipase-A2 a predisposing factor in affective illness? Biol. Psychiatry25:945–961.
Stoll, A.L., Severus, W.E., Freeman, M.P., Rueter, S., Zboyan, H.A., Diamond, E., Cress, K.K., and Marangell, L.B. 1999.Omega 3 fatty acids in bipolar disorder:A preliminary double-blind, placebo-controlled trial. Arch. Gen. Psychiatry56:407–412.
Robinson, P.J., Noronha, J., De George, J.J., Freed, L.M., Nariai, T., and Rapoport, S.I.1992.A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids:review and critical analysis. Brain Res. Rev.17:187–214.
Rapoport, S.I.1996.In vivo labeling of brain phospholipids by long-chain fatty acids:relation to turnover and function. Lipids 31: S97–S101.
Rapoport, S.I., Purdon, D., Shetty, H.U., Grange, E., Smith, Q., Jones, C., and Chang, M.C.J.1997.In vivo imaging of fatty acid incorporation into brain to examine signal transduction and neuroplasticity involving phospholipids. Ann. N. Y. Acad. Sci. 820:56–74.
Arai, T., Wakabayashi, S., Channing, M.A., Dunn, B.B., Der, M.G., Bell, J.M., Herscovitch, P., Eckelman, W.C., Rapoport, S.I., and Chang, M.C. 1995.Incorporation of [1-carbon-ll ] palmitate in monkey brain using PET. J. Nucl. Med.36: 2261–2267.
Chang, M.C.J., Arai, T., Freed, L.M., Wakabayashi, S., Channing, M.A., Dunn, B.B., Der, M.G., Bell, J.M., Sasaki, T., Herscovitch, P., Eckelman, W.C., and Rapoport, S.I.1997.Brain incorporation of [l-11 C ]-arachidonate in normocapnic and hypercapnic monkeys, measured with positron emission tomography. Brain Res.755:74–83.
Rapoport, S.I., Chang, M.C., Connolly, K., Carson, R., and Eckelman, W.C.1999.In vivo brain imaging of signal transduction using [11 C ]arachidonic acid and positron emission tomography.Soc. Neurosci.Abstr.24
Nariai, T., DeGeorge, J.J., Lamour, Y., and Rapoport, S.I. 1991.In vivo brain incorporation of [l-14 C ]arachidonate in awake rats, with or without cholinergic stimulation, following unilateral lesioning of nucleus basalis magnocellularis. Brain Res. 559: 1–9.
Hayakawa, T., Chang, M.C.J., Bell, J.M., Seemann, R., Rapoport, S.I., and Appel, N.M.1998.Fatty acid incorporation depicts brain activity in a rat model of Parkinson's disease. Brain Res. 807:177–181.
Grange, E., Deutsch, J., Smith, Q.R., Chang, M., Rapoport, S.I., and Purdon, A.D.1995.Specific activity of brain palmitoyl-CoA pool provides rates of incorporation of palmitate in brain phospholipids in awake rats. J. Neurochem. 65:2290–2298.
Washizaki, K., Smith, Q.R., Rapoport, S.L, and Purdon, A.D. 1994.Brain arachidonic acid incorporation and precursor pool specific activity during intravenous infusion of unesterified [3 H ]arachidonate in the anesthetized rat. J. Neurochem. 63: 727–736.
Deutsch, J., Grange, E., Rapoport, S.I., and Purdon, A.D.1994.Isolation and quantitation of long chain acyl-coenzyme A esters in brain tissue by a solid phase extraction. Anal. Biochem. 220:321–323.
Deutsch, J., Rapoport, S.I., and Purdon, A.D.1996.Isolation and HPLC separation of polyunsaturated species of rat brain. acyl-CoA produced during decapitation-ischemia.Phosphorous, Sulfur, and Silicon 109–110:389–392.
Chang, M.C.J., Bell, J.M., Purdon, A.D., Chikhale, E.G., and Grange, E.1999.Dynamics of docosahexaenoic acid metabolism in the central nervous system:Lack of effect of chronic lithium treatment. Neurochem. Res. 24:399–406.
Folch, J., Lees, M., and Sloane Stanley, G.H. 1957.A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226:497–509.
Skipski, V.P., Good, J.J., Barclay, M., and Reggio, R.B.1968.Quantitative analysis of simple lipid classes by thin-layer chromatography. Biochim. Biophys. Acta 152:10–19.
Bazan, N.G. Supply of n-3 polyunsaturated fatty acids and their significance in the central nervous system.1990.pp.1–24.in: R.J.Wurtman and J.J.Wurtman (Eds.), Nutrition and the Brain., Vol. 8, New York: Raven Press.
Staufenbiel, M.1988.Fatty acids covalently bound to erythrocyte proteins undergo a differential turnover in vivo. J. Biol. Chem.263:13615–13622.
Wosilait, W.D., and Soler-Argilaga, C.1975.A theoretical analysis of multiple binding of palmitate by bovine serum albumin: the relationship to uptake of free fatty acids by tissues. Life Sci.17:159–166.
Shafrir, E., Gatt, S., and Khasis, S.1965.Partition of fatty acids of 20–24 carbon atoms between serum albumin and lipoproteins. Biochim. Biophy. Acta.98:365–371.
Meresse, S., Delbart, C., Fruchart, J.-C., and Cecchelli, R.1989.Low-density lipoprotein receptor on endothelium of brain capillaries. J. Neurochem.53:340–345.
Dehouck, B., Fenart, L., Dehouck, M.P., Pierce, A., Torpier, G., and Cecchelli, R.1997.A new function for the LDL receptor: Transcytosis of LDL across the blood-brain barrier. J. Cell Biol. 138:877–889.
Purdon, D., Arai, T., and Rapoport, S.I.1997.No evidence for direct incorporation of esterified palmitic acid from plasma into brain lipids of awake adult rat. J. Lipid Res.38:526–530.
Scott, B.L., and Bazan, N.G.1989.Membrane docosahexaenoate is supplied to the developing brain and retina by the liver. Proc. Natl. Acad. Sci. U.S.A.86:2903–2907.
Svenson, A., Holmer, E., and Andersson, L.O.1974.A new method for the measurement of dissociation rates for complexes between small ligands and proteins as applied to the palmitate and bilirubin complexes with serum albumin. Biochim. Biophys. Acta. 342:54–59.
Pardridge, W.M., and Mietus, L.J.1980.Palmitate and cholesterol transport through the blood-brain barrier. J. Neurochem.34:463–466.
Robinson, P.J., and Rapoport, S.I.1986.Kinetics of protein binding determine rates of uptake of drugs by brain. Am. J. Physiol. 251: R1212-R1220.
Yamazaki, S., DeGeorge, J.J., Bell, I.M., and Rapoport, S.I. 1994.Effect of pentobarbital on incorporation of plasma palmitate into rat brain. Anesthesiology80:151–158.
Watkins, P.A.1997.Fatty acid activation. Prog. Lipid Res. 36:55–83.
Semenkovich, C.F.1997.Regulation of fatty acid synthase (FAS). Prog. Lipid Res.36:43–53.
Yamashita, A., Sugiura, T., and Waku, K.1997.Acyltransferases and transacylases involved in fatty acid remodeling of phospholipids and metabolism of bioactive lipids in mammalian cells. J. Biochem. 122:1–16.
Dennis, E.A.1994.Diversity of group types, regulation, and function of phospholipase A2. J. Biol. Chem.269: 13057–13060.
Pete, M.J., Ross, A.H., and Exton, J.H.1994.Purification and properties of phospholipase Al from bovine brain.J. Biol. Chem.269:19494–19500.
Noronha, J.G., Larson, D.M., and Rapoport, S.I.1989.Regional cerebral incorporation of plasma [14-C ]palmitate, and cerebral glucose utilization in water-deprived Long-Evans and Brattleboro rats. Exp. Neurol.103:267–276.
Greville, G.D., and Tubbs, P.K.1968.The catabolism of long-chain fatty acids in mammalian tissues. Essays Biochem.4: 155–212.
Tutwiler, G.F., Ho, W., and Mohrbacher, R.J.1981.2-Tetrade-cylglycidic acid.Methods Enzymol.72:533–551.
Chang, M.C.J., Wakabayashi, S., and Bell, J.M.1994.The effect of methyl palmoxirate on incorporation of [U-14 C ]palmitate into rat brain. Neurochem. Res. 19:1217–1223.
Chang, M.C.J., Connolly, C., Hill, D., Purdon, A.D., Hayakawa, T., Grimes, G., and Shetty, H.U. 1998.Pharmacokinetics of methyl palmoxirate, an inhibitor of B-oxidation, in rats and humans. Life Sci.63:PL297–PL302.
Osmundsen, H., Cervenka, J., and Bremer, J.1982.A role for 2, 4-enoyl-CoA reductase in mitochondrial B-oxidation of polyun-saturated fatty acids.Effects of treatment with clofibrate on oxidation of polyunsaturated acylcarnitines by isolated rat liver. Biochem.J. 208:749–757.
Murphy, E.1998.Personal communication.
DeGeorge, J.J., Noronha, J.G., Bell, J.M., Robinson, P., and Rapoport, S.I.1989.Intravenous injection of [l-14 C ]arachidonate to examine regional brain lipid metabolism in unanesthetized rats. J.Neurosci. Res.24:413–423.
Noronha, J.G., Bell, J.M., and Rapoport, S.I.1990.Quantitative brain autoradiography of [9, 10-3 H ]palmitic acid incorporation into brain lipids.J.Neurosci. Res.26:196–208.
DeGeorge, J.J., Nariai, T., Yamazaki, S., Williams, W.M., and Rapoport, S.I.1991.Arecoline-stimulated brain incorporation of intravenously administered fatty acids in unanesthetized rats. J.Neurochem.56:352–355.
Nariai, T., DeGeorge, J.J., Greig, N.H., Genka, S., Rapoport, S.I., and Purdon, A.D.1994.Differences in rates of incorporation of intravenously injected radiolabeled fatty acids into phospholipids of intracerebrally implanted tumor and brain in awake rats. Clin. Exp. Metastasis12:213–225.
Deutsch, J., Rapoport, S.I., and Purdon, A.D.1997.Relation between free fatty acid and acyl-CoA concentrations in rat brain following decapitation. Neurochem. Res. 22:759–765.
Shetty, H.U., Smith, Q.R., Washizaki, K., Rapoport, S.I., and Purdon, A.D.1996.Identification of two molecular species of rat brain phosphatidylcholine that rapidly incorporate and turn over arachidonic acid in vivo. J. Neurochem.67:1702–1710.
Contreras, M.A., Chang, M.C.J., Kirkby, D., Bell, J.M., and Rapoport, S.I.1999.Reduced palmitate turnover in brain phospholipids of pentobarbital-anesthetized rats. Neurochem. Res. 24:833–841.
Purdon, A.D., and Rapoport, S.I.1998.Energy requirements for two aspects of phospholipid metabolism in mammalian brain. Biochem. J. 335:313–318.
Sun, G.Y., and Su, K.L.1979.Metabolism of arachidonoyl phosphoglycerides in mouse brain subcellular fractions. J. Neurochem.32:1053–1059.
Connor, W.E., Neuringer, M., and Lin, D.S.1990.Dietary effects on brain fatty acid composition: the reversibility of n-3 fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys. J. Lipid Res.31:237–247.
Stinson, A.M., Wiegand, R.D., and Anderson, R.E.1991.Recycling of docosahexaenoic acid in rat retinas during n-3 fatty acid deficiency. J. Lipid Res.32:2009–2017.
Farooqui, A.A., Yang, H.-C., Rosenberger, T.H., and Horrocks, L.A.1997.Phospholipase A2 and its role in brain tissue. J. Neurochem.69:889–901.
Berridge, M.J., Downes, C.P., and Hanley, M.R.1982.Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem. J.206: 587–595.
Atack, J.R., Broughton, H.B., and Pollack, S.J.1995.Inositol monophosphatase-a putative target for Li+in the treatment of bipolar disorder.Trends Neurosci.18:343–349.
Chang, M.C.J., and Jones, C.R.1998.Chronic lithium treatment decreases brain phospholipase A2 activity. Neurochem. Res.23:887–892.
Cooper, J.R., Bloom, F.E., and Roth, R.H.1991.The Biochemical Basis of Neuropharmacology, 6th ed, pp.454, Oxford University Press, New York.
DeGeorge, J.L, Ousley, A.H., McCarthy, K.D., Lapetina, E.G., and Morell, P.1987.Acetylcholine stimulates selective liberation and re-esterification of arachidonate and accumulation of inositol phosphates and glycerophosphoinositol in C62B glioma cells. J. Biol. Chem. 262:8077–8083.
Jones, C.R., Aral, T., Bell, J.M., and Rapoport, S.I.1996.Preferential in vivo incorporation of [3H ]arachidonic acid from blood into rat brain synaptosomal fractions before and after cholinergic stimulation. J. Neurochem.67:822–829.
Jones, C.R., Arai, T., and Rapoport, S.I.1997.Evidence for the involvement of docosahexaenoic acid in cholinergic stimulated signal transduction at the synapse. Neurochem. Res. 22:663–670.
Grange, E., Rabin, O., Bell, J., Rapoport, S.I., and Chang, M.C.J.1998.Manoalind, a phospholipase A2 inhibitor, inhibits arachidonate incorporation and turnover in brain phospholipids of awake rat. Neurochem. Res. 23:1251–1257.
Bogdanovic, N., Islam, A., Nilsson, L., Bergstrom, L., Winblad, B., and Adem, A.1993.Effects of nucleus basalis lesion on muscarinic receptor subtypes. Exp Brain Res97:225–232.
Yamazaki, S., Noronha, J.G., Bell, J.M., and Rapoport, S.I. 1989.Incorporation of plasma [14]C ]palmitate into the hypoglossal nucleus following unilateral axotomy of the hypoglossal nerve in adult rat, with and without regeneration. Brain Res. 477:19–28.
De Micheli, E., Chang, M.C.L, and Rapoport, S.I.1996.In vivo imaging of cortical membrane remodeling in rats with chronic unilateral ablation of nucleus basalis magnocellularis: Use of radiolabeled palmitic acid. Brain Res.735:36–41.
Holmes, T.C., Nitsch, R.M., Erfurth, A., and Wurtman, R.J. 1993.Phospholipid and phospholipid metabolites in rat frontal cortex are decreased following nucleus basalis lesions. Ann. N. Y. Acad. Sci. 695:241–243.
Scherman, D., Desnos, C., Darchen, F., Pollak, P., Javoy-Agid, P., and Agid, Y.1989.Striatal dopamine deficiency in Parkinson's disease: Role of aging. Ann.Neurol.26:551–557.
Biggs, C.S., and Starr, M.S.1997.Dopamine and glutamate control each other's release in the basal ganglia:a microdialysis study of the entopeduncular nucleus and substantia nigra. Neurosci. Biobehav. Rev.21:497–504.
Graham, W.C., Grossman, A.R., and Woodruff, G.N.1990.Autoradiographic studies in animal models of hemi-parkisonism reveal dopamine D2 but not Dl receptor supersensitivity.I.6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat. Brain Res.514:93–102.
Hayakawa, T., Chang, M., Bell, J., Seemann, R., and Rapoport, S.I.1997.Effect of D2 dopamine receptor activation on [3H ]arachidonic acid incorporation in rats with unilateral 6-hydroxydopamine lesions. Soc. Neurosci. Abstr. 23:2432.
Rapoport, S.I. Anatomic and functional brain imaging in Alzheimer's disease.1995.pp. 1401–1415 in F.E. Bloom and D.J. Kupfer (eds.), Psychopharmacology:the Fourth Generation of Progress, New York: Raven.
Rapoport, S.I.1999.Investigative New Drug Application # 46, 139:Methyl palmoxirate.
Chang, M.C.J., Grange, E., Rabin, O., and Bell, J.M.1997.Incorporation of [U-l4]C ]palmitate into rat brain:effect of an inhibitor of f5-oxidation. J. Lipid Res.38:295–300.
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Rapoport, S.I. In Vivo Fatty Acid Incorporation into Brain Phospholipids in Relation to Signal Transduction and Membrane Remodeling. Neurochem Res 24, 1403–1415 (1999). https://doi.org/10.1023/A:1022584707352
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DOI: https://doi.org/10.1023/A:1022584707352