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Lipids and lipidomics in brain injury and diseases

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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.

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References

  1. Piomelli D. The challenge of brain lipidomics.Prostaglandins Other Lipid Mediat. 2003;77:23–34.

    Article  CAS  Google Scholar 

  2. Fahy E, Subramaniam S, Brown HA, et al. A comprehensive classification system for lipids.J Lipid Res. 2005;46:839–862.

    Article  PubMed  CAS  Google Scholar 

  3. Wenk MR. The emerging field of lipidomics.Nat Rev Drug Discov. 2005;4:594–610.

    Article  PubMed  CAS  Google Scholar 

  4. Hannun YA, Luberto C, Argraves KM. Enzymes of sphingolipid metabolism: from modular to integrative signaling.Biochemistry. 2001;40:4893–4903.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  6. Balazy M. Eicosanomics: targeted lipidomics of eicosanoids in biological systems.Prostaglandins Other Lipid Mediat. 2004;73:173–180.

    Article  PubMed  CAS  Google Scholar 

  7. Hillard CJ. Lipids and drugs of abuse.Life Sci. 2005;77:1531–1542.

    Article  PubMed  CAS  Google Scholar 

  8. van Meer G. Cellular lipidomics.EMBO J. 2005;24:3159–3165.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  17. Pulfer M, Murphy RC. Electrospray mass spectrometry of phospholipids.Mass Spectrom Rev. 2003:22:332–364.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  19. Fisher M, Brott TG. Emerging therapies for acute ischemic stroke: new therapies on trial.Stroke. 2003;34:359–361.

    Article  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.

    PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  26. Lipton P. Ischemic cell death in brain neurons.Physiol Rev. 1999;79:1431–1568.

    PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  29. Rao AM, Hatcher JF, Dempsey RJ. Lipid metabolism in ischemic neuronal death.Recent Res Develop Neurochem. 1999;2:533–549.

    CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  32. Sastry PS, Rao KS. A poptosis and the nervous system.J Neurochem. 2000;74:1–20.

    Article  PubMed  CAS  Google Scholar 

  33. Adibhatla RM, Hatcher JF. Cytidine 5′-diphosphocholine (CDP-choline) in stroke and other CNS disorders.Neurochem Res. 2005;30:15–23.

    Article  PubMed  CAS  Google Scholar 

  34. Ter Horst GJ, Korf J, eds.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  CAS  Google Scholar 

  36. Bazan NG. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor.J Lipid Res. 2003;44:2221–2233.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  41. Cui Z, Houweling M. Phosphatidylcholine and cell death.Biochim Biophys Acta. 2002;1585:87–96.

    PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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  CAS  Google Scholar 

  45. Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis.Trends Biochem Sci. 1995;20:73–77.

    Article  PubMed  CAS  Google Scholar 

  46. Green DR, Reed JC. Mitochondria and apoptosis.Science. 1998;281:1309–1312.

    Article  PubMed  CAS  Google Scholar 

  47. Perry DK, Hannun YA. The role of ceramide in cell signaling.Biochim Biophys Acta. 1998;1436:233–243.

    PubMed  CAS  Google Scholar 

  48. Kinloch RA, Treherne JM, Furness LM, Hajimohamadreza I. The pharmacology of apoptosis.Trends Pharmacol Sci. 1999;20:35–42.

    Article  PubMed  CAS  Google Scholar 

  49. Goswami R, Dawson G. Does ceramide play a role in neural cell apoptosis?J Neurosci Res. 2000;60:141–149.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  53. Cai J, Jones DP. Superoxide in apoptosis—mitochondrial generation triggered by cytochrome c loss.J Biol Chem. 1998;273:11401–11404.

    Article  PubMed  CAS  Google Scholar 

  54. Hoch FL. Cardiolipins and biomembrane function.Biochim Biophys Acta. 1992;1113:71–133.

    PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  59. Katsuki H, Okuda S. Arachidonic acid as a neurotoxic and neurotrophic substance.Prog Neurobiol., 1995;46:607–636.

    Article  PubMed  CAS  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.

    PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  63. Adibhatla RM, Hatcher JF. Citicoline mechanisms and clinical efficacy in cerebral ischemia.J Neurosci Res. 2002;70:133–139.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  65. Kudo I. Diversity of phospholipase A2 enzymes. Foreword.Biol. Pharm Bull. 2004;27:1157.

    Article  PubMed  CAS  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.

  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  72. Cejka D, Losert D, Wacheck V. Short interfering RNA (siRNA): tool or therapeutic?Clin Sci (Lond). 2006;110:47–58.

    Article  CAS  Google Scholar 

  73. Dykxhoorn DM, Palliser D, Lieberman J. The silent treatment siRNAs as small molecule drugs.Gene Ther. 2006;13:541–552.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

  75. Klein J. Functions and pathophysiological roles of phospholipase D in the brain.J Neurochem. 2005;94:1473–1487.

    Article  PubMed  CAS  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.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Rao Muralikrishna Adibhatla.

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Published: May 5, 2006

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Adibhatla, R.M., Hatcher, J.F. & Dempsey, R.J. Lipids and lipidomics in brain injury and diseases. AAPS J 8, 36 (2006). https://doi.org/10.1007/BF02854902

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