Molecular Neurobiology

, 31:219 | Cite as

Synaptic signaling by lipids in the life and death of neurons

  • Nicolas G. BazanEmail author


Synaptic activity promotes the regulated formation of lipid messengers through phospholipase-mediated cleavage of specific phospholipid reservoirs from membranes. Multiple effectors trigger the formation of lipid messengers, including neurotransmitters, membrane depolarization, ion channels, cytokines, and neurotrophic factors. Lipid messengers in turn modulate and interact with other signaling cascades, contributing to the development, differentiation, function (e.g., long-term potentiation [LTP] and memory), protection, and repair of cells in the nervous system. These relationships with other signaling cascades remain largely to be investigated. Oxidative stress disrupts lipid signaling, enhances lipid peroxidation, and initiates and propagates neurodegeneration. There is growing evidence that lipid messengers participate in the extensive interactions among neurons, astrocytes, oligodendrocytes, microglia, cells of the microvasculature, and other cells. This article provides an example of how signaling by lipids regulates critical events essential for neuronal survival and reviews the recent identification of a novel endogenous neuroprotective signaling pathway involving a docosahexaneoic acid-derived mediator.

Index Entries

Docosahexaenoic acid ischemia-reperfusion neurodegeneration neuroprotectin D1 neuroprotection oxidative stress retinal degeneration retinal pigment epithelial cells stroke 


  1. 1.
    Lo E. H., Dalkara T., and Moskowitz M. A. (2003) Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4, 399–415.PubMedCrossRefGoogle Scholar
  2. 2.
    Iadecola C. (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat. Rev. Neurosci. 5, 347–360.PubMedCrossRefGoogle Scholar
  3. 3.
    del Zoppo G. J., and Mabuchi T. (2003) Cerebral microvessel responses to focal ischemia. J. Cereb. Blood Flow Metab. 23, 879–894.PubMedCrossRefGoogle Scholar
  4. 4.
    Dirnagl U., Simon R. P., and Hallenbeck J. M. (2003) Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 26, 248–254.PubMedCrossRefGoogle Scholar
  5. 5.
    Bazan N. G., Birkle D. L., and Reddy T. S. (1984) Docosahexaenoic acid (22:6, n-3) is metabolized to lipoxygenase reaction products in the retina. Biochem. Biophys. Res. Commun. 125, 741–747.PubMedCrossRefGoogle Scholar
  6. 6.
    Bazan N. G. (1990) Supply of n-3 polyunsaturated fatty acids and their significance in the central nervous system, in Nutrition and the Brain, Wurtman R. J., and Wurtman J. J., eds., Raven Press, New York, NY, pp. 1–24.Google Scholar
  7. 7.
    Bazan N. G. and Allan, G. (1998) Platelet-activating factor and other bioactive lipids, in Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management, Ginsberg M. D., and Bogousslavsky J., eds., Blackwell Science Inc., Malden, MA, pp. 532–555.Google Scholar
  8. 8.
    Yoshida S., Harik S. I., Busto R., Santiso M., Martinez E., and Ginsberg M. D. (1984) Free fatty acids and energy metabolites in ischemic cerebral cortex with noradrenaline depletion. J. Neurochem. 42, 711–717.PubMedCrossRefGoogle Scholar
  9. 9.
    Horrocks L. A. and Farooqui A. A. (1994) NMDA receptor-stimulated release of arachidonic acid: mechanisms for the Bazan effect, in Cell Signal Transduction, Second Messengers, and Protein Phosphorylation in Health and Disease, Municio A. M., and Miras-Portugal M. T., eds. Plenum Press, New York, NY, pp. 113–128.Google Scholar
  10. 10.
    Sun G. Y., Xu J., Jensen M. D., and Simonyi A. (2004) Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases. J. Lipid Res. 45, 205–213.PubMedCrossRefGoogle Scholar
  11. 11.
    Hong S., Gronert K., Devchand P. R., Moussignac R. L., and Serhan C. N. (2003) Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J. Biol. Chem. 278, 14,677–14,687.Google Scholar
  12. 12.
    Serhan C. N., Clish C. B., Brannon J., Colgan S. P., Chiang N., and Gronert K. (2000) Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J. Exp. Med. 192, 1197–1204.PubMedCrossRefGoogle Scholar
  13. 13.
    Marcheselli V. L., Hong S., Lukiw W. J., Tian X. H., Gronert K., Musto A., Hardy M., Gimenez J. M., Chiang N., Serhan C. N., and Bazan N. G. (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278, 43,807–43,817 [erratum in: J. Biol. Chem. (2003) 278, 51974].CrossRefGoogle Scholar
  14. 14.
    Serhan C. N., Hong S., Gronert K., Colgan S. P., Devchand P. R., Mirick G., and Moussignac R. L. (2002) Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025–1037.PubMedCrossRefGoogle Scholar
  15. 15.
    Matsuo Y., Onodera H., Shiga Y., Nakamura M., Ninomiya M., Kihara T., and Kogure K. (1994) Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 25, 1469–1475.PubMedGoogle Scholar
  16. 16.
    Royo N. C., Wahl F., and Stutzmann J. M. (1999) Kinetics of polymorphonuclear neutrophil infiltration after a traumatic brain injury in rat. Neuroreport 10, 1363–1367.PubMedCrossRefGoogle Scholar
  17. 17.
    Chopp M., Li Y., Jiang N., Zhang R. L., and Prostak J. (1996) Antibodies against adhesion molecules reduce apoptosis after transient middle cerebral artery occlusion in rat brain. J. Cereb. Blood Flow Metab. 16, 578–584.PubMedCrossRefGoogle Scholar
  18. 18.
    Chatzipanteli K., Alonso O. F., Kraydieh S., and Dietrich W. D. (2000) Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: biochemical and immunocytochemical studies. J. Cereb. Blood Flow Metab. 20, 531–542.PubMedCrossRefGoogle Scholar
  19. 19.
    Huang J., Choudhri T. F., Winfree C. J., McTaggart R. A., Kiss S., Mocco J., Kim L. J., Protopsaltis T. S., Zhang Y., Pinsky D. J., and Connolly E. S., Jr. (2000) Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke. Stroke 31, 3047–3053.PubMedGoogle Scholar
  20. 20.
    Mattson M. P., Culmsee C., Yu Z., and Camandola S. (2000) Roles of nuclear factor kappaB in neuronal survival and plasticity. J. Neurochem. 74, 443–456.PubMedCrossRefGoogle Scholar
  21. 21.
    Schneider A., Martin-Villalba A., Weih F., Vogel J., Wirth T., and Schwaninger M. (1999) NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat. Med. 5, 554–559.PubMedCrossRefGoogle Scholar
  22. 22.
    Bazan N. G. (2005) Eicosanoids, docosanoids, platelet-activating factor, and inflammation, in Basic Neurochemistry, 7th ed., Siegel G., Albers R.W., Brady S., and Price D., eds., Elsevier, London, U.K., in press.Google Scholar
  23. 23.
    Lukiw W. J., and Bazan N. G. (1998) Strong nuclear factor-kappaB-DNA binding parallels cyclooxygenase-2 gene transcription in aging and in sporadic Alzheimer’s disease superior temporal lobe neocortex. J. Neurosci. Res. 53, 583–592.PubMedCrossRefGoogle Scholar
  24. 24.
    Mukherjee P. K., DeCoster M. A., Campbell F. Z., Davis R. J., and Bazan N. G. (1999) Glutamate receptor signaling interplay modulates stress-sensitive mitogen-activated protein kinases and neuronal cell death. J. Biol. Chem. 274, 6493–6498.PubMedCrossRefGoogle Scholar
  25. 25.
    Mukherjee P. K., Marcheselli V. L., Serhan C. N., and Bazan N. G. (2004) Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc. Natl. Acad. Sci. U.S.A. 101, 8491–8496.PubMedCrossRefGoogle Scholar
  26. 26.
    Mattson M. P., and Bazan N. G. (2005) Apoptosis and necrosis, in Basic Neurochemistry, 7th ed., Siegel G., Albers R.W., Brady S., and Price D., eds., Elsevier, London, U.K., in press.Google Scholar
  27. 27.
    Rodriguez de Turco E. B., Belayev L., Liu Y., Busto R., Parkins N., Bazan N. G., and Ginsberg M. D. (2002) Systemic fatty acid responses to transient focal cerebral ischemia: influence of neuroprotectant therapy with human albumin. J. Neurochem. 83, 515–524.PubMedCrossRefGoogle Scholar
  28. 28.
    Rodriguez de Turco E. B., Belayev L., Liu Y., Busto R., Parkins N., Bazan N. G., and Ginsberg M. D. (2002) Synaptic signaling and mitochondrial dysfunction in ischemia-reperfusion damage: pharmacologic targets in intracellular lipid signaling, in Pharmacology of Cerebral Ischemia, Krieglstein J. and Klumpp S., eds., medpharm Scientific Publishers, Stuttgart, Germany, pp. 431–439.Google Scholar
  29. 29.
    Belayev L., Marcheselli V. L., Khoutorova L., Rodriguez de Turco E. B., Busto R., Ginsberg M. D., and Bazan N. G. (2005) Docosahexanenoic acid complexed to albumin elicits high-grade ischemic neuroprotection. Stroke 36, 118–123.PubMedCrossRefGoogle Scholar
  30. 30.
    Scott B. L., and Bazan N. G. (1989) Membrane docosahexenoate is supplied to the developing brain and retina by the liver. Proc. Natl. Acad. Sci. U.S.A. 86, 2903–2907.PubMedCrossRefGoogle Scholar
  31. 31.
    Remmers M., Schmidt-Kastner R., Belayev L., Lin B., Busto R., and Ginsberg M. D. (1999) Protein extravasation and cellular uptake after high-dose human-albumin treatment of transient focal cerebral ischemia in rats. Brain Res. 827, 237–242.PubMedCrossRefGoogle Scholar
  32. 32.
    Ginsberg M. D. (2003) Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture. Stroke 34, 214–223.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  1. 1.LSU Neuroscience Center and Department of OphthalmologyLouisiana State University Health Sciences Center School of Medicine in New OrleansNew Orleans

Personalised recommendations