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. 2006 May 5;8(2):E314–E321. doi: 10.1007/BF02854902

Lipids and lipidomics in brain injury and diseases

Rao Muralikrishna Adibhatla 1,2,3,4,✉, J F Hatcher 1, R J Dempsey 1
PMCID: PMC3231558  PMID: 16796382

Abstract

Lipidomics is systems-level analysis and characterization of lipids and their interacting moieties. The amount of information in the genomic and proteomic fields is greater than that in the lipidomics field, because of the complex nature of lipids and the limitations of tools for analysis. The main innovation during recent years that has spurred advances in lipid analysis has been the development of new mass spectroscopic techniques, particularly the “soft ionization” techniques electrospray ionization and matrix-assisted laser desorption/ionization. Lipid metabolism may be of particular importance for the central nervous system, as it has a high concentration of lipids. The crucial role of lipids in cell signaling and tissue physiology is demonstrated by the many neurological disorders, including bipolar disorders and schizophrenia, and neurodegenerative diseases such as Alzheimer's, Parkinson's, and Niemann-Pick diseases, that involve deregulated lipid metabolism. Altered lipid metabolism is also believed to contribute to cerebral ischemic (stroke) injury. Lipidomics will provide a molecular signature to a certain pathway or a disease condition. Lipidomic analyses (characterizing complex mixtures of lipids and identifying previously unknown changes in lipid metabolism) together with RNA silencing, using small interfering RNA (siRNA), may provide powerful tools to elucidate the specific roles of lipid intermediates in cell signaling and open new opportunities for drug development.

Keywords: Acrolein; arachidonic acid; cerebral ischemia; cytidine-5′-diphosphocholine; CDP-choline; citicoline; docosahexaenoic acid; 4-hydroxynonenal; lipidomics; lipid; peroxidation; MALDI-TOF; ESI-MS-MS; neuroprotectin D1; 10,17S-docosatriene; phospholipases; phospholipids; RNA silencing; small interfering RNA; siRNA; reactive oxygen species; stroke

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References

  • 1.Piomelli D. The challenge of brain lipidomics. Prostaglandins Other Lipid Mediat. 2003;77:23–34. doi: 10.1016/j.prostaglandins.2004.09.006. [DOI] [PubMed] [Google Scholar]
  • 2.Fahy E, Subramaniam S, Brown HA, et al. A comprehensive classification system for lipids. J Lipid Res. 2005;46:839–862. doi: 10.1194/jlr.E400004-JLR200. [DOI] [PubMed] [Google Scholar]
  • 3.Wenk MR. The emerging field of lipidomics. Nat Rev Drug Discov. 2005;4:594–610. doi: 10.1038/nrd1776. [DOI] [PubMed] [Google Scholar]
  • 4.Hannun YA, Luberto C, Argraves KM. Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochemistry. 2001;40:4893–4903. doi: 10.1021/bi002836k. [DOI] [PubMed] [Google Scholar]
  • 5.Peterson BL, Cummings BS. A review of chromatographic methods for the assessment of phospholipids in biological samples. Biomed Chromatogr. 2006;20:227–243. doi: 10.1002/bmc.563. [DOI] [PubMed] [Google Scholar]
  • 6.Balazy M. Eicosanomics: targeted lipidomics of eicosanoids in biological systems. Prostaglandins Other Lipid Mediat. 2004;73:173–180. doi: 10.1016/j.prostaglandins.2004.03.003. [DOI] [PubMed] [Google Scholar]
  • 7.Hillard CJ. Lipids and drugs of abuse. Life Sci. 2005;77:1531–1542. doi: 10.1016/j.lfs.2005.05.004. [DOI] [PubMed] [Google Scholar]
  • 8.van Meer G. Cellular lipidomics. EMBO J. 2005;24:3159–3165. doi: 10.1038/sj.emboj.7600798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Rapaka RS, Piomelli D, Spiegel S, Bazan N, Dennis EA. Targeted lipidomics: signaling lipids and drugs of abuse. Prostaglandins Other Lipid Mediat. 2005;77:223–234. doi: 10.1016/j.prostaglandins.2005.06.005. [DOI] [PubMed] [Google Scholar]
  • 10.Belayev L, Marcheselli VL, Khoutorova L, et al. Docosahexaenoic acid complexed to albumin elicits high-grade ischemic neuroprotection. Stroke. 2005;36:118–123. doi: 10.1161/01.STR.0000149620.74770.2e. [DOI] [PubMed] [Google Scholar]
  • 11.Forrester JS, Milne SB, Ivanova PT, Brown HA. Computational lipidomics: a multiplexed analysis of dynamic changes in membrane lipid composition during signal transduction. Mol Pharmacol. 2004;65:813–821. doi: 10.1124/mol.65.4.813. [DOI] [PubMed] [Google Scholar]
  • 12.Han X, Gross RW. Global analyses of cellular lipidomes directly from crude extracts of biological samples by ESI mass spectrometry: a bridge to lipidomics. J Lipid Res. 2003;44:1071–1079. doi: 10.1194/jlr.R300004-JLR200. [DOI] [PubMed] [Google Scholar]
  • 13.Han X, Yang J, Cheng H, Yang K, Abendschein DR, Gross RW. Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction. Biochemistry. 2005;44:16684–16694. doi: 10.1021/bi051908a. [DOI] [PubMed] [Google Scholar]
  • 14.Hunt AN, Fenn HC, Clark GT, Wright MM, Postle AD, McMaster CR. Lipidomic analysis of the molecular specificity of a cholinephosphotransferase in situ. Biochem Soc Trans. 2004;32:1060–1062. doi: 10.1042/BST0321060. [DOI] [PubMed] [Google Scholar]
  • 15.Marcheselli VL, Hong S, Lukiw WJ, et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem. 2003;278:43807–43817. doi: 10.1074/jbc.M305841200. [DOI] [PubMed] [Google Scholar]
  • 16.Brugger B, Erben G, Sandhoff R, Wieland FT, Lehmann WD. Quantitative analysis of biological membrane lipids at the low picomole level by nano-electrospray ionization tandem mass spectrometry. Proc Natl Acad Sci USA. 1997;94:2339–2344. doi: 10.1073/pnas.94.6.2339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Pulfer M, Murphy RC. Electrospray mass spectrometry of phospholipids. Mass Spectrom Rev. 2003;22:332–364. doi: 10.1002/mas.10061. [DOI] [PubMed] [Google Scholar]
  • 18.Schiller J, Suss R, Arnhold J, et al. Matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry in lipid and phospholipid research. Prog Lipid Res. 2004;43:449–488. doi: 10.1016/j.plipres.2004.08.001. [DOI] [PubMed] [Google Scholar]
  • 19.Fisher M, Brott TG. Emerging therapies for acute ischemic stroke: new therapies on trial. Stroke. 2003;34:359–361. doi: 10.1161/01.STR.0000054627.69159.C2. [DOI] [PubMed] [Google Scholar]
  • 20.Siao CJ, Fernandez SR, Tsirka SE. Cell type-specific roles for tissue plasminogen activator released by neurons or microglia after excitotoxic injury. J Neurosci. 2003;23:3234–3242. doi: 10.1523/JNEUROSCI.23-08-03234.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Adibhatla RM, Hatcher JF, Dempsey RJ. Effects of citicoline on phospholipid and glutathione levels in transient cerebral ischemia. Stroke. 2001;32:2376–2381. doi: 10.1161/hs1001.096010. [DOI] [PubMed] [Google Scholar]
  • 22.Adibhatla RM, Hatcher JF, Dempsey RJ. Phospholipase A2, hydroxyl radicals and lipid peroxidation in transient cerebral ischemia. Antioxid Redox Signal. 2003;5:647–654. doi: 10.1089/152308603770310329. [DOI] [PubMed] [Google Scholar]
  • 23.Adibhatla RM, Hatcher JF. Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. J Neurosci Res. 2003;73:308–315. doi: 10.1002/jnr.10672. [DOI] [PubMed] [Google Scholar]
  • 24.Muralikrishna Adibhatla R, Hatcher JF. Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic Biol Med. 2006;40:376–387. doi: 10.1016/j.freeradbiomed.2005.08.044. [DOI] [PubMed] [Google Scholar]
  • 25.Adibhatla RM, Hatcher JF, Larsen EC, Chen X, Sun D, Tsao FH. CDP-choline significantly restores phosphatidylcholine levels by differentially affecting phospholipase A2 and CTP-phosphocholine cytidylyltransferase after stroke. J Biol Chem. 2006;281:6718–6725. doi: 10.1074/jbc.M512112200. [DOI] [PubMed] [Google Scholar]
  • 26.Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79:1431–1568. doi: 10.1152/physrev.1999.79.4.1431. [DOI] [PubMed] [Google Scholar]
  • 27.Rao AM, Hatcher JF, Kindy MS, Dempsey RJ. Arachidonic acid and leukotriene C4: role in transient cerebral ischemia of gerbils. Neurochem Res. 1999;24:1225–1232. doi: 10.1023/A:1020916905312. [DOI] [PubMed] [Google Scholar]
  • 28.Rao AM, Hatcher JF, Dempsey RJ. CDP-choline: neuroprotection in transient forebrain ischemia of gerbils. J Neurosci Res. 1999;58:697–705. doi: 10.1002/(SICI)1097-4547(19991201)58:5<697::AID-JNR11>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  • 29.Rao AM, Hatcher JF, Dempsey RJ. Lipid metabolism in ischemic neuronal death. Recent Res Develop Neurochem. 1999;2:533–549. [Google Scholar]
  • 30.Rao AM, Hatcher JF, Dempsey RJ. Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection. J Neurochem. 2000;75:2528–2535. doi: 10.1046/j.1471-4159.2000.0752528.x. [DOI] [PubMed] [Google Scholar]
  • 31.Rao AM, Hatcher JF, Dempsey RJ. Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res. 2001;893:268–272. doi: 10.1016/S0006-8993(00)03280-7. [DOI] [PubMed] [Google Scholar]
  • 32.Sastry PS, Rao KS. A poptosis and the nervous system. J Neurochem. 2000;74:1–20. doi: 10.1046/j.1471-4159.2000.0740001.x. [DOI] [PubMed] [Google Scholar]
  • 33.Adibhatla RM, Hatcher JF. Cytidine 5′-diphosphocholine (CDP-choline) in stroke and other CNS disorders. Neurochem Res. 2005;30:15–23. doi: 10.1007/s11064-004-9681-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Ter Horst GJ, Korf J, editors. Clinical Pharmacology of Cerebral Ischemia. Totowa, NJ: Humana; 1997. [Google Scholar]
  • 35.Choi DW. Methods for antagonizing glutamate neurotoxicity. Cerebrovasc Brain Metab Rev. 1990;2:105–147. [PubMed] [Google Scholar]
  • 36.Bazan NG. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J Lipid Res. 2003;44:2221–2233. doi: 10.1194/jlr.R300013-JLR200. [DOI] [PubMed] [Google Scholar]
  • 37.Bazan NG. Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. Brain Pathol. 2005;15:159–166. doi: 10.1111/j.1750-3639.2005.tb00513.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Bazan NG, Marcheselli VL, Cole-Edwards K. Brain response to injury and neurodegeneration: endogenous neuroprotective signaling. Ann NY Acad Sci. 2005;1053:137–147. doi: 10.1196/annals.1344.011. [DOI] [PubMed] [Google Scholar]
  • 39.Lukiw WJ, Cui J-G, Marcheselli VL, et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest. 2005;115:2774–2783. doi: 10.1172/JCI25420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci USA. 2004;101:8491–8496. doi: 10.1073/pnas.0402531101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Cui Z, Houweling M. Phosphatidylcholine and cell death. Biochim Biophys Acta. 2002;1585:87–96. doi: 10.1016/s1388-1981(02)00328-1. [DOI] [PubMed] [Google Scholar]
  • 42.Freeman EJ, Terrian DM, Dorman RV. Presynaptic facilitation of glutamate release from isolated hippocampal mossy fiber nerve endings by arachidonic acid. Neurochem Res. 1990;15:743–750. doi: 10.1007/BF00973656. [DOI] [PubMed] [Google Scholar]
  • 43.Ruehr ML, Zhang L, Dorman RV. Lipid-dependent modulation of Ca2+ availability in isolated mossy fiber nerve endings. Neurochem Res. 1997;22:1215–1222. doi: 10.1023/A:1021976828513. [DOI] [PubMed] [Google Scholar]
  • 44.Jayadev S, Linardic CM, Hannun YA. Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to TNF-α. J Biol Chem. 1994;269:5757–5763. [PubMed] [Google Scholar]
  • 45.Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci. 1995;20:73–77. doi: 10.1016/S0968-0004(00)88961-6. [DOI] [PubMed] [Google Scholar]
  • 46.Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309–1312. doi: 10.1126/science.281.5381.1309. [DOI] [PubMed] [Google Scholar]
  • 47.Perry DK, Hannun YA. The role of ceramide in cell signaling. Biochim Biophys Acta. 1998;1436:233–243. doi: 10.1016/s0005-2760(98)00145-3. [DOI] [PubMed] [Google Scholar]
  • 48.Kinloch RA, Treherne JM, Furness LM. Hajimohamadreza I. The pharmacology of apoptosis. Trends Pharmacol Sci. 1999;20:35–42. doi: 10.1016/S0165-6147(98)01277-2. [DOI] [PubMed] [Google Scholar]
  • 49.Goswami R, Dawson G. Does ceramide play a role in neural cell apoptosis? J Neurosci Res. 2000;60:141–149. doi: 10.1002/(SICI)1097-4547(20000415)60:2<141::AID-JNR2>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
  • 50.Garcia-Ruiz C, Colell A, Mari M, Morales A, Fernandezcheca JC. Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species—role of mitochondrial glutathione. J Biol Chem. 1997;272:11369–11377. doi: 10.1074/jbc.272.17.11369. [DOI] [PubMed] [Google Scholar]
  • 51.Ghafourifar P, Klein SD, Schucht O, et al. Ceramide induces cytochrome c release from isolated mitochondria. Importance of mitochondrial redox state. J Biol Chem. 1999;274:6080–6084. doi: 10.1074/jbc.274.10.6080. [DOI] [PubMed] [Google Scholar]
  • 52.Cai J, Yang J, Jones DP. Mitochondrial control of apoptosis—the role of cytochrome c. Biochim Biophys Acta. 1998;1366:139–149. doi: 10.1016/S0005-2728(98)00109-1. [DOI] [PubMed] [Google Scholar]
  • 53.Cai J, Jones DP. Superoxide in apoptosis—mitochondrial generation triggered by cytochrome c loss. J Biol Chem. 1998;273:11401–11404. doi: 10.1074/jbc.273.19.11401. [DOI] [PubMed] [Google Scholar]
  • 54.Hoch FL. Cardiolipins and biomembrane function. Biochim Biophys Acta. 1992;1113:71–133. doi: 10.1016/0304-4157(92)90035-9. [DOI] [PubMed] [Google Scholar]
  • 55.Nakahara I, Kikuchi H, Taki W, et al. Degradation of mitochondrial phospholipids during experimental cerebral ischemia in rats. J Neurochem. 1991;57:839–844. doi: 10.1111/j.1471-4159.1991.tb08227.x. [DOI] [PubMed] [Google Scholar]
  • 56.Nakahara I, Kikuchi H, Taki W, et al. Changes in major phospholipids of mitochondria during postischemic reperfusion in rat brain. J Neurosurg. 1992;76:244–250. doi: 10.3171/jns.1992.76.2.0244. [DOI] [PubMed] [Google Scholar]
  • 57.Rimon G, Bazenet CE, Philpott KL, Rubin LL. Increased surface phosphatidylserine is an early marker of neuronal apoptosis. J Neurosci Res. 1997;48:563–570. doi: 10.1002/(SICI)1097-4547(19970615)48:6<563::AID-JNR9>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  • 58.Suzuki S, Furushiro M, Takahashi M, Sakai M, Kudo S. Oral administration of soybean lecithin transphosphatidylated phosphatidylserine (SB-tPS) reduces ischemic damage in the gerbil hippocampus. Jpn J Pharmacol. 1999;81:237–239. doi: 10.1254/jjp.81.237. [DOI] [PubMed] [Google Scholar]
  • 59.Katsuki H, Okuda S. Arachidonic acid as a neurotoxic and neurotrophic substance. Prog Neurobiol. 1995;46:607–636. doi: 10.1016/0301-0082(95)00016-O. [DOI] [PubMed] [Google Scholar]
  • 60.Kruman I, Brucekeller AJ, Bredesen D, Waeg G, Mattson MP. Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J Neurosci. 1997;17:5089–5100. doi: 10.1523/JNEUROSCI.17-13-05089.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Uchida K, Kanematsu M, Sakai K, et al. Protein-bound acrolein—potential markers for oxidative stress. Proc Natl Acad Sci USA. 1998;95:4882–4887. doi: 10.1073/pnas.95.9.4882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Calingasan NY, Uchida K, Gibson GE. Protein-bound acrolein: a novel marker of oxidative stress in Alzheimer's disease. J Neurochem. 1999;72:751–756. doi: 10.1046/j.1471-4159.1999.0720751.x. [DOI] [PubMed] [Google Scholar]
  • 63.Adibhatla RM, Hatcher JF. Citicoline mechanisms and clinical efficacy in cerebral ischemia. J Neurosci Res. 2002;70:133–139. doi: 10.1002/jnr.10403. [DOI] [PubMed] [Google Scholar]
  • 64.Adibhatla RM, Hatcher JF, Dempsey RJ. Cytidine-5′-diphosphocholine (CDP-choline) affects CTP-phosphocholine cytidylyltransferase and lyso-phosphatidylcholine after transient brain ischemia. J Neurosci Res. 2004;76:390–396. doi: 10.1002/jnr.20078. [DOI] [PubMed] [Google Scholar]
  • 65.Kudo I. Diversity of phospholipase A2 enzymes. Foreword. Biol. Pharm Bull. 2004;27:1157–1157. doi: 10.1248/bpb.27.1157. [DOI] [PubMed] [Google Scholar]
  • 66.Williams TI, Lynn BC, Markesbery WR, Lovell MA. Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in mild cognitive impairment and early Alzheimer's disease.Neurobiol Aging. In press. [DOI] [PubMed]
  • 67.Urabe T, Hattori N, Yoshikawa M, Yoshino H, Uchida K, Mizuno Y. Colocalization of Bcl-2 and 4-hydroxynomenal modified proteins in microglial cells and neurons of rat brain following transient focal ischemia. Neurosci Lett. 1998;247:159–162. doi: 10.1016/S0304-3940(98)00311-5. [DOI] [PubMed] [Google Scholar]
  • 68.Urabe T, Yamasaki Y, Hattori N, Yoshikawa M, Uchida K, Mizuno Y. Accumulation of 4-hydroxynonenal-modified proteins in hippocampal CA1 pyramidal neurons precedes delayed neuronal damage in the gerbil brain. Neuroscience. 2000;100:241–250. doi: 10.1016/S0306-4522(00)00264-5. [DOI] [PubMed] [Google Scholar]
  • 69.Uchida K, Kanematsu M, Morimitsu Y, Osawa T, Noguchi N, Niki E. Acrolein is a product of lipid peroxidation reaction—formation of free acrolein and its conjugate with lysine residues in oxidized low density lipoproteins. J Biol Chem. 1998;273:16058–16066. doi: 10.1074/jbc.273.26.16058. [DOI] [PubMed] [Google Scholar]
  • 70.Tomitori H, Usui T, Saeki N, et al. Polyamine oxidase and acrolein as novel biochemical markers for diagnosis of cerebral stroke. Stroke. 2005;36:2609–2613. doi: 10.1161/01.STR.0000190004.36793.2d. [DOI] [PubMed] [Google Scholar]
  • 71.Liu X, Lovell MA, Lynn BC. Development of a method for quantification of acrolein-deoxyguanosine adducts in DNA using isotope dilution-capillary LC/MS/MS and its application to human brain tissue. Anal Chem. 2005;77:5982–5989. doi: 10.1021/ac050624t. [DOI] [PubMed] [Google Scholar]
  • 72.Cejka D, Losert D, Wacheck V. Short interfering RNA (siRNA): tool or therapeutic? Clin Sci (Lond) 2006;110:47–58. doi: 10.1042/CS20050162. [DOI] [PubMed] [Google Scholar]
  • 73.Dykxhoorn DM, Palliser D, Lieberman J. The silent treatment siRNAs as small molecule drugs. Gene Ther. 2006;13:541–552. doi: 10.1038/sj.gt.3302703. [DOI] [PubMed] [Google Scholar]
  • 74.Wang L, Magdaleno S, Tabas I, Jackowski S. Early embryonic lethality in mice with targeted deletion of the CTP:phosphocholine cytidylyltransferase alpha gene (Pcytla) Mol Cell Biol. 2005;25:3357–3363. doi: 10.1128/MCB.25.8.3357-3363.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Klein J. Functions and pathophysiological roles of phospholipase D in the brain. J Neurochem. 2005;94:1473–1487. doi: 10.1111/j.1471-4159.2005.03315.x. [DOI] [PubMed] [Google Scholar]
  • 76.Pettus BJ, Bielawski J, Porcelli AM, et al. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-α. FASEB J. 2003;17:1411–1421. doi: 10.1096/fj.02-1038com. [DOI] [PubMed] [Google Scholar]

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