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Formation ofN-acyl-phosphatidylethanolamine andN-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity

  • Anandamides And Covalent Modification By Lipids
  • Published:
Lipids

Abstract

N-Acyl-phosphatidylethanolamine (NAPE) is present in very small amounts in mammalian tissues (less than 0.1% of total phospholipids). However, NAPE as well as its degradation product,N-acylethanolamine (NAE), can be formed in certain neuronal tissues in response to increased [Ca2+]i. A high [Ca2+]i will activate the NAPE-formingN-acyl-transferase using thesn-1 acyl group of a donor phospholipid as substrate in the transfer reaction. This membrane-bound enzyme seems to have no substrate specificity with respect to transfer of acyl groups; thus the fatty acids in theN-acyl group of NAPE are mainly 16:0 and 18:1, corresponding to the fatty acids in thesn-1 acyl group of the donor phospholipids. The NAPE-hydrolyzing phospholipase D also seems not to be acyl-group specific. In mouse neocortical neurons in primary culture, formation of NAPE and NAE is stimulated by glutamatevia activation of theN-methyl-d-aspartate-receptor. Both NAPE and, to a lesser extent, NAE accumulate in a linear fashion for many hours while at the same time the neurons are dying. Likewise, in neurons prelabeled with14C-arachidonic acid,14C-arachidonic acid-labeled NAPE, and anandamide (=N-arachi-donoylethanolamine) are accumulating. The formation of NAPE and NAE may represent a cytoprotective response in relation to various forms of neurotoxicity.

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Abbreviations

NAE:

N-acylethanolamine

NAPE:

N-acyl-phosphatidylethanolamine

NMDA:

N-methyl-d-aspartate

PLD:

phospholipase D

Ptd-Etn:

phosphatidylethanolamine

References

  1. Chapman, K.D., and Sprinkle, W.B. (1996) Developmental, Tissue-Specific, and Environmental Factors Regulate the Biosynthesis ofN-Acylphosphatidylethanolamine in Cotton (Gossypium hirsutum L.),J. Plant Physiol. 149, 277–284.

    CAS  Google Scholar 

  2. Schmid, H.H.O., Schmid, P.C., and Natarajan, V. (1990)N-Acylated Glycerolipids and Their Derivatives,Prog. Lipid Res. 29, 1–43.

    Article  PubMed  CAS  Google Scholar 

  3. Natarajan, V., Schmid, P.C., Reddy, P.V., Zuarte-Augustin, M.L., and Schmid, H.H.O. (1983) Biosynthesis ofN-Acylethanolamine Phospholipids by Dog Brain Preparations,J. Neurochem. 41, 1303–1312.

    Article  PubMed  CAS  Google Scholar 

  4. Natarajan, V., Schmid, P.C., and Schmid, H.H.O. (1986)N-Acylethanolamine Phospholipid Metabolism in Normal and Ischemic Rat Brain,Biochim. Biophys. Acta 878, 32–41.

    PubMed  CAS  Google Scholar 

  5. Hansen, H.S., Lauritzen, L., Moesgaard, B., Strand, A.M., and Hansen, H.H. (1998) Formation ofN-Acyl-phosphatidylethanolamines andN-Acylethanolamines—Proposed Role in Neurotoxicity,Biochem. Pharmacol. 55, 719–725.

    Article  PubMed  CAS  Google Scholar 

  6. Chilton, F.H., Fonteh, A.N., Surette, M.E., Triggiani, M., and Winkler, J.D. (1996) Control of Arachidonate Levels Within Inflammatory Cells,Biochim. Biophys. Acta Lipids Lipid Metab. 1299, 1–15.

    Article  Google Scholar 

  7. Di Marzo, V., Fontana, A., Cadas, H., Schinelli, S., Cimino, G., Schwartz, J.-C., and Piomelli, D. (1994) Formation and Inactivation of Endogenous Cannabinoid Anandamide in Central Neurons,Nature 372, 686–691.

    Article  PubMed  Google Scholar 

  8. Sugiura, T., Kondo, S., Sukagawa, A., Tonegawa, T., Nakane, S., Yamashita, A., and Waku, K. (1996) Enzymatic Synthesis of Anandamide, an Endogenous Cannabinoid Receptor Ligand, ThroughN-Acylphosphatidylethanolamine Pathway in Testis: Involvement of Ca2+-Dependent Transacylase and Phosphodiesterase Activities,Biochem. Biophys. Res. Commun. 218, 113–117.

    Article  PubMed  CAS  Google Scholar 

  9. Deutsch, D.G., Goligorsky, M.S., Schmid, P.C., Krebsbach, R.J., Schmid, H.H.O., Das, S.K., Dey, S.K., Arreaza, G., Thorup, C., Stefano, G., and Moore, L.C. (1997) Production and Physiological Actions of Anandamide in the Vasculature of the Rat Kidney,J. Clin. Invest. 100, 1538–1546.

    Article  PubMed  CAS  Google Scholar 

  10. Kempe, K., Hsu, F.F., Bohrer, A., and Turk, J. (1996) Isotope Dilution Mass Spectrometric Measurements Indicate That Arachidonylethanolamide, the Proposed Endogenous Ligand of the Cannabinoid Receptor, Accumulates in Rat Brain Tissue Post Mortem But Is Contained at Low Levels in or Is Absent from Fresh Tissue,J. Biol. Chem. 271, 17287–17295.

    Article  PubMed  CAS  Google Scholar 

  11. Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A., and Mechoulam, R. (1992) Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor,Science 258, 1946–1949.

    Article  PubMed  CAS  Google Scholar 

  12. Devane, W.A. (1994) New Dawn of Cannabinoid Pharmacology,Trends Pharmacol. Sci. 15, 40–41.

    Article  PubMed  CAS  Google Scholar 

  13. Hillard, C.J., and Campbell, W.B. (1997) Biochemistry and Pharmacology of Arachidonylethanolamide, a Putative Endogenous Cannabinoid,J. Lipid Res. 38, 2383–2398.

    PubMed  CAS  Google Scholar 

  14. Hansen, H.S., Lauritzen, L., Strand, A.M., Moesgaard, B., and Frandsen, A. (1995) Glutamate Stimulates the Formation ofN-Acylphosphatidylethanolamine andN-Acylethanolamine in Cortical Neurons in Culture,Biochim. Biophys. Acta Lipids Lipid Metab. 1258, 303–308.

    Article  Google Scholar 

  15. Chapman, K.D., Lin, I., and DeSouza, A.D. (1995) Metabolism of Cottonseed MicrosomalN-Acylphosphatidylethanolamine,Arch. Biochem. Biophys. 318, 401–407.

    Article  PubMed  CAS  Google Scholar 

  16. Schmid, P.C., Reddy, P.V., Natarajan, V., and Schmid, H.H.O. (1983) Metabolism ofN-Acylethanolamine Phospholipids by Mammalian Phosphodiesterase of the Phospholipase D Type,J. Biol. Chem. 258, 9302–9306.

    PubMed  CAS  Google Scholar 

  17. Sugiura, T., Kondo, S., Sukagawa, A., Tonegawa, T., Nakane, S., Yamashita, A., Ishima, Y., and Waku, K. (1996) Transacylase-Mediated and Phosphodiesterase-Mediated Synthesis ofN-Arachidonoylethanolamine, an Endogenous Cannabinoid-Receptor Ligand, in Rat Brain Microsomes—Comparison with Synthesis from Free Arachidonic Acid and Ethanolamine,Eur. J. Biochem. 240, 53–62.

    Article  PubMed  CAS  Google Scholar 

  18. Hansen, H.S., Lauritzen, L., Strand, A.M., Vinggaard, A.M., Frandsen, A., and Schousboe, A. (1997) Characterization of Glutamate-Induced Formation ofN-Acylphosphatidylethanolamine andN-Acylethanolamine in Cultured Neocortical Neurons,J. Neurochem. 69, 753–761.

    Article  PubMed  CAS  Google Scholar 

  19. Schmid, P.C., Krebsbach, R.J., Perry, S.R., Dettmer, T.M., Maasson, J.L., and Schmid, H.H.O. (1995) Occurrence and Post-mortem Generation of Anandamide and Other Long-ChainN-Acylethanolamines in Mammalian Brain,FEBS Lett. 375, 117–120.

    Article  PubMed  CAS  Google Scholar 

  20. Felder, C.C., Nielsen, A., Briley, E.M., Palkovits, M., Priller, J., Axelrod, J., Nguyen, D.N., Richardson, J.M., Riggin, R.M., Koppel, G.A., Paul, S.M., and Becker, G.W. (1996) Isolation and Measurement of the Endogenous Cannabinoid Receptor Agonist, Anandamide, in Brain and Peripheral Tissues of Human and Rat,FEBS Lett. 393, 231–235.

    Article  PubMed  CAS  Google Scholar 

  21. Frandsen, A., and Schousboe, A. (1993) Excitatory Amino Acid-Mediated Cytotoxicity and Calcium Homeostasis in Cultured Neurons,J. Neurochem. 60, 1202–1211.

    Article  PubMed  CAS  Google Scholar 

  22. Frandsen, A., and Schousboe, A. (1990) Development of Excitatory Amino Acid Induced Cytotoxicity in Cultured Neurons,Int. J. Dev. Neurosci. 8, 209–216.

    Article  PubMed  CAS  Google Scholar 

  23. Schmid, P.C., Kuwae, T., Krebsbach, R.J., and Schmid, H.H.O. (1997) Anandamide and OtherN-Acylethanolamines in Mouse Peritoneal Macrophages,Chem. Phys. Lipids 87, 103–110.

    Article  PubMed  CAS  Google Scholar 

  24. Sugiura, T., Kodaka, T., Kondo, S., Nakane, S., Kondo, H., Waku, K., Ishima, Y., Watanabe, K., and Yamamoto, I. (1997) Is the Cannabinoid CB1 Receptor a 2-Arachidonoylglycerol Receptor? Structural Requirements for Triggering a Ca2+ Transient in NG108-15 Cells,J. Biochem. (Tokyo) 122, 890–895.

    CAS  Google Scholar 

  25. Sugiura, T., Kondo, S., Sukagawa, A., Nakane, S., Shinoda, A., Itoh, K., Yamashita, A., and Waku, K. (1995) 2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain,Biochem. Biophys. Res. Commun. 215, 89–97.

    Article  PubMed  CAS  Google Scholar 

  26. Sugiura, T., Kodaka, T., Kondo, S., Tonegawa, T., Nakane, S., Kishimoto, S., Yamashita, A., and Waku, K. (1997) Inhibition by 2-Arachidonoylglycerol, a Novel Type of Possible Neuromodulator, of the Depolarization-Induced Increase in Intracellular Free Calcium in Neuroblastoma × Glioma Hybrid NG108-15 Cells,Biochem. Biophys. Res. Commun. 233, 207–210.

    Article  PubMed  CAS  Google Scholar 

  27. Mechoulam, R., Ben-Shabat, S., Hanus, L., Ligumsky, M., Kaminski, N.E., Schatz, A.R., Gopher, A., Almog, S., Martin, B.R., Compton, D.R., Pertwee, R.G., Griffin, G., Bayewitch, M., Barg, J., and Vogel, Z. (1995) Identification of an Endogenous 2-Monoglyceride, Present in Canine Gut, That Binds to Cannabinoid Receptors,Biochem. Pharmacol. 50, 83–90.

    Article  PubMed  CAS  Google Scholar 

  28. Bisogno, T., Sepe, N., Melck, D., Maurelli, S., De Petrocellis, L., and Di Marzo, V. (1997) Biosynthesis, Release and Degradation of the Novel Endogenous Cannabimimetic Metabolite 2-Arachidonoylglycerol in Mouse Neuroblastoma Cells,Biochem. J. 322, 671–677.

    PubMed  CAS  Google Scholar 

  29. Goparaju, S.K., Ueda, N., Yamaguchi, H., and Yamamoto, S. (1998) Anandamide Amidohydrolase Reacting with 2-Arachidonoylglycerol, Another Cannabinoid Receptor Ligand,FEBS Lett. 422, 69–73.

    Article  PubMed  CAS  Google Scholar 

  30. Stella, N., Schweitzer, P., and Piomelli, D. (1997) A Second Endogenous Cannabinoid That Modulates Long-Term Potentiation,Nature 388, 773–778

    Article  PubMed  CAS  Google Scholar 

  31. Mercadal, M., Domingo, J.C., Bermudez, M., Mora, M., and De Madariaga, M.A. (1995)N-Palmitoylphosphatidylethanolamine Stabilizes Liposomes in the Presence of Human Serum: Effect of Lipidic Composition and System Characterization,Biochim. Biophys. Acta Bio-Membr. 1235, 281–288.

    Article  Google Scholar 

  32. Newman, J.L., Stiers, D.L., Anderson, W.H., and Schmid, H.H.O. (1986) Phase Behaviour of SyntheticN-Acylethanolamine Phospholipids,Chem. Phys. Lipids 42, 249–260.

    Article  PubMed  CAS  Google Scholar 

  33. Epps, D.E., Palmer, J.W., Schmid, H.H.O., and Pfeiffer, D.R. (1982) Inhibition of Permeability-Dependent Ca2+ Release from Mitochondria byN-Acylethanolamines, a Class of Lipids Synthesized in Ischemic Heart Tissue,J. Biol. Chem. 257, 1383–1391.

    PubMed  CAS  Google Scholar 

  34. Skaper, S.D., Buriani, A., Dal Toso, R., Petrelli, L., Romanello, S., Facci, L., and Leon, A. (1996) The ALIAmide Palmitoylethanolamide and Cannabinoids, but Not Anandamide, Are Protective in a Delayed Postglutamate Paradigm of Excitotoxic Death in Cerebellar Granule Neurons,Proc. Natl. Acad. Sci. USA 93, 3984–3989.

    Article  PubMed  CAS  Google Scholar 

  35. Mazzari, S., Canella, R., Petrelli, L., Marcolongo, G., and Leon, A. (1996)N-(2-Hydroxyethyl)Hexadecanamide Is Orally Active in Reducing Edema Formation and Inflammatory Hyperalgesia by Down-Modulating Mast Cell Activation,Eur. J. Pharmacol. 300, 227–236.

    Article  PubMed  CAS  Google Scholar 

  36. Shen, M.X., Piser, T.M., Seybold, V.S., and Thayer, S.A. (1996) Cannabinoid Receptor Agonists Inhibit Glutamatergic Synaptic Transmission in Rat Hippocampal Cultures,J. Neurosci. 16, 4322–4334.

    PubMed  CAS  Google Scholar 

  37. Wiesner, D.A., and Dawson, G. (1996) Staurosporine Induces Programmed Cell Death in Embryonic Neurons and Activation of the Ceramide Pathway,J. Neurochem. 66, 1418–1425.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Harald S. Hansen.

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Hansen, H.S., Moesgaard, B., Hansen, H.H. et al. Formation ofN-acyl-phosphatidylethanolamine andN-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity. Lipids 34 (Suppl 1), S327–S330 (1999). https://doi.org/10.1007/BF02562333

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