Molecular Neurobiology

, Volume 26, Issue 2–3, pp 317–346 | Cite as

Acute neuronal injury, excitotoxicity, and the endocannabinoid system

  • Mario van der Stelt
  • Wouter B. Veldhuis
  • Mauro Maccarrone
  • Peter R. Bär
  • Klaas Nicolay
  • Gerrit A. Veldink
  • Vincenzo Di Marzo
  • Johannes F. G. Vliegenthart
Article

Abstract

The endocannabinoid system is a valuable target for drug discovery, because it is involved in the regulation of many cellular and physiological functions. The endocannabinoid system constitutes the endogenous lipids anandamide, 2-arachidonoylglycerol and noladin ether, and the cannabinoid CB1 and CB2 receptors as well as the proteins for their inactivation. It is thought that (endo)cannabinoid-based drugs may potentially be useful to reduce the effects of neurodegeneration. This paper reviews recent developments in the endocannabinoid system and its involvement in neuroprotection.

Exogenous (endo)cannabinoids have been shown to exert neuroprotection in a variety of in vitro and in vivo models of neuronal injury via different mechanisms, such as prevention of excitotoxicity by CB1-mediated inhibition of glutamatergic transmission, reduction of calcium influx, and subsequent inhibition of deleterious cascades, TNF-α formation, and anti-oxidant activity. It has been suggested that the release of endogenous endocannabinoids during neuronal injury might be a protective response. However, several observations indicate that the role of the endocannabinoid system as a general endogenous protection system is questionable. The data are critically reviewed and possible explanations are given.

Index Entries

Cannabinoid anandamide 2-arachidonoylglycerol excitotoxicity neuroprotection neurodegeneration 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Di Marzo, V. (1998) ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim. Biophys. Acta. 1392, 153–175.PubMedGoogle Scholar
  2. 2.
    Hanus, L., Gopher, A., Almog, S, and Mechoulam, R. (1993) Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J. Med. Chem. 36, 3032–3034.PubMedCrossRefGoogle Scholar
  3. 3.
    Devane, W. A., Hanus, L., Breuer, A., et al. (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949.PubMedCrossRefGoogle Scholar
  4. 4.
    Mechoulam, R., Ben-Shabat, S., Hanus, L., et al. (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Sugiura, T., Kondo, S., Sukagawa, A., et al. (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97.PubMedCrossRefGoogle Scholar
  6. 6.
    Hanus, L., Abu-Lafi, S., Fride, E., et al. (2001) 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl. Acad. Sci. USA 98, 3662–3665.PubMedCrossRefGoogle Scholar
  7. 7.
    Lambert, D. M. and Di Marzo, V. (1999) The palmitoylethanolamide and oleamide enigmas: are these two fatty acid amides cannabimimetic? Curr. Med. Chem. 6, 757–737.PubMedGoogle Scholar
  8. 8.
    Lambert, D. M., Vandevoorde, S., Jonsson, K. O., and Fowler, C. J. (2002) The palmitoylethanolamide family: a new class of anti-inflammatory agents? Curr. Med. Chem. 9, 663–676.PubMedGoogle Scholar
  9. 9.
    Di Marzo, V., Melck, D., Bisogno, T., and De Petrocellis, L. (1998) Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21, 521–528.PubMedCrossRefGoogle Scholar
  10. 10.
    Hansen, H. S., Moesgaard, B., Hansen, H. H., and Petersen, G. (2000) N-Acylethanolamines and precursor phospholipids—relation to cell injury. Chem. Phys. Lipids 108, 135–150.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    Hansen, H. S., Moesgaard, B., Hansen, H. H., Schousboe, A., and Petersen, G. (1999) Formation of N-acyl-phosphatidylethanolamine and N-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity. Lipids 34, S327-S330.PubMedCrossRefGoogle Scholar
  13. 13.
    Ueda, N., Liu, Q., and Yamanaka, K. (2001) Marked activation of the N-acylphosphatidylethanolamine-hydrolyzing phosphodiesterase by divalent cations. Biochim. Biophys. Acta. 1532, 121–127.PubMedGoogle Scholar
  14. 14.
    Schmid, H. H. (2000) Pathways and mechanisms of N-acylethanolamine biosynthesis: can anandamide be generated selectively? Chem. Phys. Lipids 108, 71–87.PubMedCrossRefGoogle Scholar
  15. 15.
    Di Marzo, V., De Petrocellis, L., Sugiura, T., and Waku, K. (1996) Potential biosynthetic connections between the two cannabimimetic eicosanoids, anandamide and 2-arachidonoylglycerol, in mouse neuroblastoma cells. Biochem. Biophys. Res. Commun. 227, 281–288.PubMedCrossRefGoogle Scholar
  16. 16.
    Stella, N., Schweitzer, P., and Piomelli, D. (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778.PubMedCrossRefGoogle Scholar
  17. 17.
    Bisogno, T., Melck, D., De Petrocellis, L., and Di Marzo, V. (1999) Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin. J. Neurochem. 72, 2113–2119.PubMedCrossRefGoogle Scholar
  18. 18.
    Pertwee, R. G. (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther. 74, 129–180.PubMedCrossRefGoogle Scholar
  19. 19.
    Gonsiorek, W., Lunn, C., Fan, X., Narula, S., Lundell, D., and Hipkin, R. W. (2000) Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. Mol. Pharmacol. 57, 1045–1050.PubMedGoogle Scholar
  20. 20.
    Herkenham, M., Lynn, A. B., Johnson, M. R., Melvin, L. S., de Costa, B. R., and Rice, K. C. (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci. 11, 563–583.PubMedGoogle Scholar
  21. 21.
    Grundy, R. I., Rabuffetti, M., and Beltramo, M. (2001) Cannabinoids and neuroprotection. Mol. Neurobiol. 24, 29–51.PubMedCrossRefGoogle Scholar
  22. 22.
    Sagan, S., Venance, L., Torrens, Y., Cordier, J., Glowinski, J., and Giaume, C. (1999) Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G- protein-coupled receptors distinct from CB1 cannabinoid receptors in cultured astrocytes. Eur. J. Neurosci. 11, 691–699.PubMedCrossRefGoogle Scholar
  23. 23.
    Venance, L., Piomelli, D., Glowinski, J., and Giaume, C. (1995) Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes. Nature 376, 590–594.PubMedCrossRefGoogle Scholar
  24. 24.
    Di Marzo, V., Breivogel, C. S., Tao, Q., et al. (2000) Levels, metabolism, and pharmacological activity of anandamide in CB(1) cannabinoid receptor knockout mice: evidence for non-CB(1), non-CB(2) receptor-mediated actions of anandamide in mouse brain. J. Neurochem. 75, 2434–2444.PubMedCrossRefGoogle Scholar
  25. 25.
    Breivogel, C. S., Griffin, G., Di Marzo, V., and Martin, B. R. (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol. Pharmacol. 60, 155–163.PubMedGoogle Scholar
  26. 26.
    Jarai, Z., Wagner, J. A., Varga, K., et al. (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc. Natl. Acad. Sci. USA 96, 14,136–14,141.CrossRefGoogle Scholar
  27. 27.
    Howlett, A. C. and Mukhopadhyay, S. (2000) Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem. Phys. Lipids 108, 53–70.PubMedCrossRefGoogle Scholar
  28. 28.
    Maingret, F., Patel, A. J., Lazdunski, M., and Honore, E. (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1. Embo. J. 20, 47–54.PubMedCrossRefGoogle Scholar
  29. 29.
    Chemin, J., Monteil, A., Perez-Reyes, E., Nargeot, J., and Lory, P. (2001) Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. Embo. J. 20, 7033–7040.PubMedCrossRefGoogle Scholar
  30. 30.
    Zygmunt, P. M., Petersson, J., Andersson, D. A., et al. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457.PubMedCrossRefGoogle Scholar
  31. 31.
    Smart, D. and Jerman, J. C. (2000) Anandamide: an endogenous activator of the vanilloid receptor. Trends Pharmacol. Sci. 21, 134.PubMedCrossRefGoogle Scholar
  32. 32.
    Di Marzo, V., Bisogno, T., and De Petrocellis, L. (2001) Anandamide: some like it hot. Trends Pharmacol. Sci. 22, 346–349.PubMedCrossRefGoogle Scholar
  33. 33.
    De Petrocellis, L., Bisogno, T., Maccarrone, M., Davis, J. B., Finazzi-Agro, A., and Di Marzo, V. (2001) The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J. Biol. Chem. 276, 12,856–12,863.CrossRefGoogle Scholar
  34. 34.
    Di Marzo, V., Bisogno, T., Sugiura, T., Melck, D., and De Petrocellis, L. (1998) The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal- and basophillike cells: connections with anandamide. Biochem. J. 331, 15–19.PubMedGoogle Scholar
  35. 35.
    Bisogno, T., MacCarrone, M., De Petrocellis, L., et al. (2001) The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors. Eur. J. Biochem. 268, 1982–1989.PubMedCrossRefGoogle Scholar
  36. 36.
    Jarrahian, A., Manna, S., Edgemond, W. S., Campbell, W. B., and Hillard, C. J. (2000) Structure-activity relationships among N-arachidonylethanolamine (Anandamide) head group analogues for the anandamide transporter. J. Neurochem. 74, 2597–2606.PubMedCrossRefGoogle Scholar
  37. 37.
    Fezza, F., Bisogno, T., Minassi, A., Appendino, G., Mechoulam, R., and Di Marzo, V. (2002) Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues. FEBS Lett. 513, 294–298.PubMedCrossRefGoogle Scholar
  38. 38.
    Hillard, C. J., Edgemond, W. S., Jarrahian, A., and Campbell, W. B. (1997) Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via faciliated diffusion. J. Neurochem. 69, 631–638.PubMedGoogle Scholar
  39. 39.
    Cravatt, B. F., Giang, D. K., Mayfield, S. P., Boger, D. L., Lerner, R. A., and Gilula, N. B. (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87.PubMedCrossRefGoogle Scholar
  40. 40.
    Ueda, N. and Yamamoto, S. (2000) Anandamide amidohydrolase (fatty acid amide hydrolase). Prostaglandins Other Lipid Mediat. 61, 19–28.PubMedCrossRefGoogle Scholar
  41. 41.
    Cravatt, B. F., Demarest, K., Patricelli, M. P., et al. (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl. Acad. Sci. USA 98, 9371–9376.PubMedCrossRefGoogle Scholar
  42. 42.
    Di Marzo, V., Bisogno, T., De Petrocellis, L., et al. (1999) Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. Eur. J. Biochem. 264, 258–267.PubMedCrossRefGoogle Scholar
  43. 43.
    Goparaju, S. K., Ueda, N., Taniguchi, K., and Yamamoto, S. (1999) Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. Biochem. Pharmacol. 57, 417–423.PubMedCrossRefGoogle Scholar
  44. 44.
    Ueda, N., Yamanaka, K., and Yamamoto, S. (2001) Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J. Biol. Chem. 276, 35,552–35,527.Google Scholar
  45. 45.
    Burstein, S. H., Rossetti, R. G., Yagen, B., and Zurier, R. B. (2000) Oxidative metabolism of anandamide. Prostaglandins Other Lipid Mediat. 61, 29–41.PubMedCrossRefGoogle Scholar
  46. 46.
    Maccarrone, M., De Petrocellis, L., Bari, M., Fezza, F., Salvati, S., Di Marzo, V., and Finazzi-Agro, A. (2001) Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes. Arch. Biochem. Biophys. 393, 321–328.PubMedCrossRefGoogle Scholar
  47. 47.
    Maccarrone, M., Fiorucci, L., Erba, F., Bari, M., Finazzi-Agro, A., and Ascoli, F. (2000) Human mast cells take up and hydrolyze anandamide under the control of 5-lipoxygenase and do not express cannabinoid receptors. FEBS Lett. 468, 176–180.PubMedCrossRefGoogle Scholar
  48. 48.
    Mechoulam, R., Fride, E., Hanus, L., Sheskin, T., Bisogno, T., Di Marzo, V., Bayewitch, M., and Vogel, Z. (1997) Anandamide may mediate sleep induction. Nature 389, 25–26.PubMedCrossRefGoogle Scholar
  49. 49.
    Ben-Shabat, S., Fride, E., Sheskin, T., et al. (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol. 353, 23–31.PubMedCrossRefGoogle Scholar
  50. 50.
    Maurelli, S., Bisogno, T., De Petrocellis, L., Di Luccia, A., Marino, G., and Di Marzo, V. (1995) Two novel classes of neuroactive fatty acid amides are substrates for mouse neuroblastoma ‘anandamide amidohydrolase’. FEBS Lett. 377, 82–86.PubMedCrossRefGoogle Scholar
  51. 51.
    Maccarrone, M., van der Stelt, M., Rossi, A., Veldink, G. A., Vliegenthart, J. F., and Agro, A. F. (1998) Anandamide hydrolysis by human cells in culture and brain. J. Biol. Chem. 273, 32,332–32,339.CrossRefGoogle Scholar
  52. 52.
    Maccarrone, M., Bari, M., Lorenzon, T., Bisogno, T., Di Marzo, V., and Finazzi-Agro, A. (2000) Anandamide uptake by human endothelial cells and its regulation by nitric oxide. J. Biol. Chem. 275, 13,484–13,492.Google Scholar
  53. 53.
    Deadwyler, S. A., Hampson, R. E., Mu, J., Whyte, A., and Childers, S. (1995) Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process. J. Pharmacol. Exp. Ther. 273, 734–743.PubMedGoogle Scholar
  54. 54.
    Deadwyler, S. A., Hampson, R. E., Bennett, B. A., et al. (1993) Cannabinoids modulate potassium current in cultured hippocampal neurons. Receptors Channels 1, 121–134.PubMedGoogle Scholar
  55. 55.
    Glass, M. and Felder, C. C. (1997) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J. Neurosci. 17, 5327–5333.PubMedGoogle Scholar
  56. 56.
    Sugiura, T., Kodaka, T., Nakane, S., et al. (1999) Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, either-linked analogues, and related compounds. J. Biol. Chem. 274, 2794–2801.PubMedCrossRefGoogle Scholar
  57. 57.
    Sugiura, T., Kondo, S., Kishimoto, S., et al. (2000) Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J. Biol. Chem. 275, 605–612.PubMedCrossRefGoogle Scholar
  58. 58.
    Felder, C. C., Briley, E. M., Axelrod, J., Simpson, J. T., Mackie, K., and Devane, W. A. (1993) Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. Proc. Natl. Acad. Sci. USA 90, 7656–7660.PubMedCrossRefGoogle Scholar
  59. 59.
    Felder, C. C., Joyce, K. E., Briley, E. M., et al. (1995) Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol. Pharmacol. 48, 443–450.PubMedGoogle Scholar
  60. 60.
    Hampson, A. J., Bornheim, L. M., Scanziani, M., et al. (1998) Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission. J. Neurochem. 70, 671–676.PubMedGoogle Scholar
  61. 61.
    Akinshola, B. E., Taylor, R. E., Ogunseitan, A. B., and Onaivi, E. S. (1999) Anandamide inhibition of recombinant AMPA receptor subunits in Xenopus oocytes is increased by forskolin and 8-bromo-cyclic AMP. Naunyn. Schmiedebergs Arch. Pharmacol. 360, 242–248.PubMedCrossRefGoogle Scholar
  62. 62.
    Netzeband, J. G., Conroy, S. M., Parsons, K. L., and Gruol, D. L. (1999) Cannabinoids enhance NMDA-elicited Ca2+ signals in cerebellar granule neurons in culture. J. Neurosci. 19, 8765–8777.PubMedGoogle Scholar
  63. 63.
    Schlicker, E. and Kathmann, M. (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22, 565–572.PubMedCrossRefGoogle Scholar
  64. 64.
    Logan, W. J. and Snyder, S. H. (1971) Unique high affinity uptake systems for glycine, glutamic and aspartic acids in central nervous tissue of the rat. Nature 234, 297–299.PubMedCrossRefGoogle Scholar
  65. 65.
    Shen, M., 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.PubMedGoogle Scholar
  66. 66.
    Al-Hayani, A. and Davies, S. N. (2000) Cannabinoid receptor mediated inhibition of excitatory synaptic transmission in the rat hippocampal slice is developmentally regulated. Br. J. Pharmacol. 131, 663–665.PubMedCrossRefGoogle Scholar
  67. 67.
    Terranova, J. P., Michaud, J. C., Le Fur, G., and Soubrie, P. (1995) Inhibition of long-term potentiation in rat hippocampal slices by anandamide and WIN55212-2: reversal by SR141716 A, a selective antagonist of CB1 cannabinoid receptors. Naunyn. Schmiedebergs Arch. Pharmacol. 352, 576–579.PubMedCrossRefGoogle Scholar
  68. 68.
    Hajos, N., Ledent, C., and Freund, T. F. (2001) Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106, 1–4.PubMedCrossRefGoogle Scholar
  69. 69.
    Huang, C. C., Lo, S. W., and Hsu, K. S. (2001) Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J. Physiol. 532, 731–748.PubMedCrossRefGoogle Scholar
  70. 70.
    Gerdeman, G. and Lovinger, D. M. (2001) CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J. Neurophysiol. 85, 468–471.PubMedGoogle Scholar
  71. 71.
    Levenes, C., Daniel, H., Soubrie, P., and Crepel, F. (1998) Cannabinoids decrease excitatory synaptic transmission and impair long- term depression in rat cerebellar Purkinje cells. J. Physiol. 510, 867–879.PubMedCrossRefGoogle Scholar
  72. 72.
    Szabo, B., Wallmichrath, I., Mathonia, P., and Pfreundtner, C. (2000) Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience 97, 89–97PubMedCrossRefGoogle Scholar
  73. 73.
    Morisset, V. and Urban, L. (2001) Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substantia gelatinosa neurons of the rat spinal cord. J. Neurophysiol. 86, 40–48.PubMedGoogle Scholar
  74. 74.
    Robbe, D., Alonso, G., Duchamp, F., Bockaert, J., and Manzoni, O. J. (2001) Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J. Neurosci. 21, 109–116.PubMedGoogle Scholar
  75. 75.
    Vaughan, C. W., Connor, M., Bagley, E. E., and Christie, M. J. (2000) Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol. Pharmacol. 57, 288–295.PubMedGoogle Scholar
  76. 76.
    Auclair, N., Otani, S., Soubrie, P., and Crepel, F. (2000) cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons. J. Neurophysiol. 83, 3287–3293.PubMedGoogle Scholar
  77. 77.
    Ferraro, L., Tomasini, M. C., Gessa, G. L., Bebe, B. W., Tanganelli, S., and Antonelli, T. (2001) The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study. Cereb. Cortex 11, 728–733.PubMedCrossRefGoogle Scholar
  78. 78.
    Wilson, R. I., Kunos, G., and Nicoll, R. A. (2001) Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 453–462.PubMedCrossRefGoogle Scholar
  79. 79.
    Wilson, R. I. and Nicoll, R. A. (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592.PubMedCrossRefGoogle Scholar
  80. 80.
    Maejima, T., Hashimoto, K., Yoshida, T., Aiba, A., and Kano, M. (2001) Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31, 463–475.PubMedCrossRefGoogle Scholar
  81. 81.
    Maejima, T., Ohno-Shosaku, T., and Kano, M. (2001) Endogenous cannabinoid as a retrograde messenger from depolarized postsynaptic neurons to presynaptic terminals. Neurosci. Res. 40, 205–210.PubMedCrossRefGoogle Scholar
  82. 82.
    Kreitzer, A. C. and Regehr, W. G. (2001) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29, 717–727.PubMedCrossRefGoogle Scholar
  83. 83.
    Kreitzer, A. C. and Regehr, W. G. (2001) Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J. Neurosci. 21, RC174.Google Scholar
  84. 84.
    Ohno-Shosaku, T., Maejima, T., and Kano, M. (2001) Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738.PubMedCrossRefGoogle Scholar
  85. 85.
    Gerdeman, G. L., Ronesi, J., and Lovinger, D. M. (2002) Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat. Neurosci. 5, 446–451.PubMedGoogle Scholar
  86. 86.
    Lucas, D. R. and Newhouse, J. P. (1957) The toxic activity of sodium-L-glutamate on the inner layers of the retina. Arch. Opthalmol. 58, 192–201.Google Scholar
  87. 87.
    Olney, J. W. (1971) Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. An electron microscopic study. J. Neuropathol. Exp. Neurol. 30, 75–90.PubMedCrossRefGoogle Scholar
  88. 88.
    Lee, J. M., Zipfel, G. J., and Choi, D. W. (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399, A7–14.PubMedGoogle Scholar
  89. 89.
    Kermer, P., Klocker, N., and Bahr, M. (1999) Neuronal death after brain injury. Models, mechanisms, and therapeutic strategies in vivo. Cell Tissue Res. 298, 383–395.PubMedCrossRefGoogle Scholar
  90. 90.
    Ishimaru, M. J., Ikonomidou, C., Tenkova, T. I., et al. (1999) Distinguishing excitotoxic from apoptotic neurodegeneration in the developing rat brain. J. Comp. Neurol. 408, 461–476.PubMedCrossRefGoogle Scholar
  91. 91.
    Faden, A. I., Demediuk, P., Panter, S. S., and Vink, R. (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244, 798–800.PubMedCrossRefGoogle Scholar
  92. 92.
    Rothman, S. M. and Olney, J. W. (1986) Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19, 105–111.PubMedCrossRefGoogle Scholar
  93. 93.
    Siesjo, B. K. (1992) Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J. Neurosurg. 77, 169–184.PubMedGoogle Scholar
  94. 94.
    Doble, A. (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol. Ther. 81, 163–221.PubMedCrossRefGoogle Scholar
  95. 95.
    Rossi, D. J., Oshima, T., and Attwell, D. (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403, 316–321.PubMedCrossRefGoogle Scholar
  96. 96.
    Koch, R. A. and Barish, M. E. (1994) Perturbation of intracellular calcium and hydrogen ion regulation in cultured mouse hippocampal neurons by reduction of the sodium ion concentration gradient. J. Neurosci. 14, 2585–2593.PubMedGoogle Scholar
  97. 97.
    Rothman, S. M. (1985) The neurotoxicity of excitatory amino acids is produced by passive chloride influx. J. Neurosci. 5, 1483–1489.PubMedGoogle Scholar
  98. 98.
    Choi, D. W. (1995) Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci. 18, 58–60.PubMedCrossRefGoogle Scholar
  99. 99.
    Stout, A. K., Raphael, H. M., Kanterewicz, B. I., Klann, E., and Reynolds, I. J. (1998) Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat. Neurosci. 1, 366–373.PubMedCrossRefGoogle Scholar
  100. 100.
    Pang, Z. and Geddes, J. W. (1997) Mechanisms of cell death induced by the mitochondrial toxin 3-nitropropionic acid: acute excitotoxic necrosis and delayed apoptosis. J. Neurosci. 17, 3064–3073.PubMedGoogle Scholar
  101. 101.
    Dijkhuizen, R. M., van Lookeren Campagne, M., Niendorf, T., et al. (1996) Status of the neonatal rat brain after NMDA-induced excitotoxic injury as measured by MRI, MRS and metabolic imaging. NMR Biomed. 9, 84–92.PubMedCrossRefGoogle Scholar
  102. 102.
    Zeevalk, G. D. and Nicklas, W. J. (1992) Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-d-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J. Neurochem. 59, 1211–1220.PubMedCrossRefGoogle Scholar
  103. 103.
    Velasco, I., Tapia, R., and Massieu, L. (1996) Inhibition of glutamate uptake induces progressive accumulation of extracellular glutamate and neuronal damage in rat cortical cultures. J. Neurosci. Res. 44, 551–561.PubMedCrossRefGoogle Scholar
  104. 104.
    Pellegrini-Giampietro, D. E., Cherici, G., Alesiani, M., Carla, V., and Moroni, F. (1990) Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemia-induced neuronal damage. J. Neurosci. 10, 1035–1041.PubMedGoogle Scholar
  105. 105.
    Goldberg, M. P. and Choi, D. W. (1993) Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J. Neurosci. 13, 3510–3524.PubMedGoogle Scholar
  106. 106.
    Abdel-Hamid, K. M. and Tymianski, M. (1997) Mechanisms and effects of intracellular calcium buffering on neuronal survival in organotypic hippocampal cultures exposed to anoxia/aglycemia or to excitotoxins. J. Neurosci. 17, 3538–3553.PubMedGoogle Scholar
  107. 107.
    Choi, D. W., Maulucci-Gedde, M., and Kriegstein, A. R. (1987) Glutamate neurotoxicity in cortical cell culture. J. Neurosci. 7, 357–368.PubMedGoogle Scholar
  108. 108.
    Abood, M. E., Rizvi, G., Sallapudi, N., and McAllister, S. D. (2001) Activation of the CB(1) cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci. Lett. 309, 197–201.PubMedCrossRefGoogle Scholar
  109. 109.
    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.PubMedCrossRefGoogle Scholar
  110. 110.
    Shen, M. and Thayer, S. A. (1998) Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol. Pharmacol. 54, 459–462.PubMedGoogle Scholar
  111. 111.
    Hampson, A. J., Grimaldi, M., Axelrod, J., and Wink, D. (1998) Cannabidiol and (−) Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc. Natl. Acad. Sci. USA 95, 8268–8273.PubMedCrossRefGoogle Scholar
  112. 112.
    Sinor, A. D., Irvin, S. M., and Greenberg, D. A. (2000) Endocannabinoids protect cerebral cortical neurons from in vitro ischemia in rats. Neurosic. Lett. 278, 157–160.CrossRefGoogle Scholar
  113. 113.
    Hampson, A. J. and Grimaldi, M. (2001) Cannabinoid receptor activation and elevated cyclic AMP reduce glutamate neurotoxicity. Eur. J. Neurosci. 13, 1529–1536.PubMedCrossRefGoogle Scholar
  114. 114.
    Nagayama, T., Sinor, A. D., Simon, R. P., Chen, J., Graham, S. H., Jin, K., and Greenberg, D. A. (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J. Neurosci. 19, 2987–2995.PubMedGoogle Scholar
  115. 115.
    Marsicano, G., Moosmann, B., Hermann, H., Lutz, B., and Behl, C. (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J. Neurochem. 80, 448–456.PubMedCrossRefGoogle Scholar
  116. 116.
    Gallily, R., Breuer, A., and Mechoulam, R. (2000) 2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factoralpha production in murine macrophages, and in mice. Eur. J. Pharmacol. 406, R5–7.PubMedCrossRefGoogle Scholar
  117. 117.
    Smith, M. L., Bendek, G., Dahlgren, N., Rosen, I., Wieloch, T., and Siesjo, B. K. (1984) Models for studying long-term recovery following forebrain ischemia in the rat. 2. A 2-vessel occlusion model. Acta. Neurol. Scand. 69, 385–401.PubMedGoogle Scholar
  118. 118.
    Pulsinelli, W. A. and Brierley, J. B. (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10, 267–272.PubMedGoogle Scholar
  119. 119.
    Kameyama, M., Suzuki, J., Shirane, R., and Ogawa, A. (1985) A new model of bilateral hemispheric ischemia in the rat—three vessel occlusion model. Stroke 16, 489–493.PubMedGoogle Scholar
  120. 120.
    Ito, U., Spatz, M., Walker, J. T., Jr., and Klatzo, I. (1975) Experimental cerebral ischemia in mongolian gerbils. I. Light microscopic observations. Acta. Neuropathol. (Berl.). 32, 209–223.CrossRefGoogle Scholar
  121. 121.
    Garcia, J. H., Wagner, S., Liu, K. F., and Hu, X. J. (1995) Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke 26, 627–635.PubMedGoogle Scholar
  122. 122.
    Dixon, C. E., Lyeth, B. G., Povlishock, J. T., et al. (1987) A fluid percussion model of experimental brain injury in the rat. J. Neurosurg. 67, 110–119.PubMedCrossRefGoogle Scholar
  123. 123.
    Shapira, Y., Shohami, E., Sidi, A., Soffer, D., Freeman, S., and Cotev, S. (1988) Experimental closed head injury in rats: mechanical, pathophysiologic, and neurologic properties. Cri. Car. Med. 16, 258–265.Google Scholar
  124. 124.
    Lighthall, J. W. (1988) Controlled cortical impact: a new experimental brain injury model. J. Neurotrauma 5, 1–15.PubMedGoogle Scholar
  125. 125.
    Louw, D. F., Yang, F. W., and Sutherland, G. R. (2000) The effect of delta-9-tetrahydrocannabinol on forebrain ischemia in rat. Brain Res. 857, 183–187.PubMedCrossRefGoogle Scholar
  126. 126.
    Muthian, S. and Hillard, C. J. (2000) CB1 receptor antagonists are neuroprotective in focal cerebral ischemia-reperfusion injury, in Symposium on the Cannabinoids 107 (ICRS, Burlington, Vermont, 2000).Google Scholar
  127. 127.
    Braida, D., Pozzi, M., and Sala, M. (2000) CP 55,940 protects against ischemia-induced electroencephalographic flattening and hyperlocomotion in Mongolian gerbils. Neurosci. Lett. 296, 69–72.PubMedCrossRefGoogle Scholar
  128. 128.
    Wagner, J. A., Hu, K., Bauersachs, J., et al. (2001) Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J. Am. Coll. Cardiol. 38, 2048–2054.PubMedCrossRefGoogle Scholar
  129. 129.
    van der Stelt, M., Veldhuis, W. B., Bar, P. R., Veldink, G. A., Vliegenthart, J. F., and Nicolay, K. (2001) Neuroprotection by Delta 9-tetrahy-drocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J. Neurosci. 21, 6475–6479.PubMedGoogle Scholar
  130. 130.
    Mechoulam, R., Panikashvili, D., and Shohami, E. (2002) Cannabinoids and brain injury: therapeutic implications Trends Mol. Med. 8, 58–61.PubMedCrossRefGoogle Scholar
  131. 131.
    Schmid, H. H., Schmid, P. C., and Natarajan, V. (1990) N-acylated glycerophospholipids and their derivatives. Prog. Lipid. Res. 29, 1–43.PubMedCrossRefGoogle Scholar
  132. 132.
    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, 17,287–17,295.Google Scholar
  133. 133.
    Hansen, H. S., Moesgaard, B., Hansen, H. H., Schousboe, A., and Petersen, G. (1999) Formation of N-acyl-phosphatidylethanolamine and N-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity. Lipids 34, S327-S330.PubMedCrossRefGoogle Scholar
  134. 134.
    Hansen, H. H., Hansen, S. H., Schousboe, A., and Hansen, H. S. (2000) Determination of the phospholipid precursor of anandamide and other N-acylethanolamine phospholipids before and after sodium azide-induced toxicity in cultured neocortical neurons. J. Neurochem. 75, 861–871.PubMedCrossRefGoogle Scholar
  135. 135.
    Hansen, H. H., Ikonomidou, C., Bittigau, P., Hansen, S. H., and Hansen, H. S. (2001) Accumulation of the anandamide precursor and other N-acylethanolamine phospholipids in infant rat models of in vivo necrotic and apoptotic neuronal death. J. Neurochem. 76, 39–46.PubMedCrossRefGoogle Scholar
  136. 136.
    Hansen, H. S., Lauritzen, L., Strand, A. M., Vinggaard, A. M., Frandsen, A., and Schousboe, A. (1997) Characterization of glutamate-induced formation of N-acylphosphatidylethanolamine and N-acylethanolamine in cultured neocortical neurons. J. Neurochem. 69, 753–761.PubMedGoogle Scholar
  137. 137.
    Hansen, H. H., Schmid, P. C., Bittigau, P. (2001) et al. Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J. Neurochem. 78, 1415–1427.PubMedCrossRefGoogle Scholar
  138. 138.
    Panikashvili, D., Simeonidou, C., Ben-Shabat, S., Hanus, L., Breuer, A., Mechoulam, R., and Shohami, E. (2001) An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature 413, 527–531.PubMedCrossRefGoogle Scholar
  139. 139.
    Sugiura, T., Yoshinaga, N., Kondo, S., Waku, K., and Ishima, Y. (2000) Generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in picrotoxinin-administered rat brain. Biochem. Biophys. Res. Commun. 271, 654–658.PubMedCrossRefGoogle Scholar
  140. 140.
    Jin, K. L., Mao, X. O., Goldsmith, P. C., and Greenberg, D. A. (2000) CB1 cannabinoid receptor induction in experimental stroke. Ann. Neurol. 48, 257–261.PubMedCrossRefGoogle Scholar
  141. 141.
    van der Stelt, M., Veldhuis, W. B., van Haaften, G. W., et al. (2001) Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J. Neurosci. 21, 8765–8771.PubMedGoogle Scholar
  142. 142.
    Andersson, M., Jacobsson, S. O., Jonsson, K. O., Tiger, G., and Fowler, C. J. (2000) Neurotoxicity of glutamate in chick telencephalon neurons: reduction of toxicity by preincubation with carbachol, but not by the endogenous fatty acid amides anandamide and palmitoylethanolamide. Arch. Toxicol. 74, 161–164.PubMedCrossRefGoogle Scholar
  143. 143.
    Chan, G. C., Hinds, T. R., Impey, S., and Storm, D. R. (1998) Hippocampal neurotoxicity of Delta9-tetrahydrocannabinol. J. Neurosci. 18, 5322–5332.PubMedGoogle Scholar
  144. 144.
    Stella, N, and Piomelli, D. (2001) Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur. J. Pharmacol. 425, 189–196.PubMedCrossRefGoogle Scholar
  145. 145.
    Shen, M. and Thayer, S. A. (1998) The cannabinoid agaonist Win55,212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons. Brain Res. 783, 77–84.PubMedCrossRefGoogle Scholar
  146. 146.
    Denovan-Wright, E. M. and Robertson, H. A. (2000) Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington’s disease mice. Neuroscience 98, 705–713.PubMedCrossRefGoogle Scholar
  147. 147.
    Lastres-Becker, I., Fezza, F., Cebeira, M., et al. (2001) Changes in endocannabinoid transmission in the basal ganglia in a rat model of Huntington’s disease. Neuroreport 12, 2125–2129.PubMedCrossRefGoogle Scholar
  148. 148.
    Zimmer, A., Zimmer, A. M., Hohmann, A. G., Herkenham, M., and Bonner, T. I. (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 5780–5785.PubMedCrossRefGoogle Scholar
  149. 149.
    Lambert, D. M., Vandevoorde, S., Diependaele, G., Govaerts, S. J., and Robert, A. R. (2001) Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice. Epilepsia 42, 321–327.PubMedCrossRefGoogle Scholar
  150. 150.
    Johnson, D. E., Heald, S. L., Dally, R. D., and Janis, R. A. (1993) Isolation, identification and synthesis of an endogenous arachidonic amide that inhibits calcium channel antagonist 1,4-dihydropyridine binding. Prostaglandins Leukot. Essent. Fatty Acids 48, 429–437.PubMedCrossRefGoogle Scholar
  151. 151.
    Sasamura, T. and Kuraishi, Y. (1999) Peripheral and central actions of capsaicin and VR1 receptor. Jpn. J. Pharmacol. 80, 275–280.PubMedCrossRefGoogle Scholar
  152. 152.
    Grant, E. R., Dubin, A. E., Zhang, S. P., Zivin, R. A., and Zhong, Z. (2002) Simultaneous intracellular calcium and sodium flux imaging in human vanilloid receptor 1 (VR1)-transfected human embryonic kidney cells: a method to resolve ionic dependence of VR1-mediated cell death. J. Pharmacol. Exp. Ther. 300, 9–17.PubMedCrossRefGoogle Scholar
  153. 153.
    Premkumar, L. S. and Ahern, G. P. (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature 408, 985–990.PubMedCrossRefGoogle Scholar
  154. 154.
    De Petrocellis, L., Harrison, S., Bisogno, T., et al. (2001) The vanilloid receptor (VR1)-mediated effects of anandamide are potently enhanced by the cAMP-dependent protein kinase. J. Neurochem. 77, 1660–1663.PubMedCrossRefGoogle Scholar
  155. 155.
    Mattson, M. P., Culmsee, C., and Yu, Z. F. (2000) Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res. 301, 173–187.PubMedCrossRefGoogle Scholar
  156. 156.
    Mattson, M. P. (2000) Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell. Biol. 1, 120–129.PubMedCrossRefGoogle Scholar
  157. 157.
    Schwarz, H., Blanco, F. J., and Lotz, M. (1994) Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. J. Neuroimmunol, 55, 107–115.PubMedCrossRefGoogle Scholar
  158. 158.
    Sarker, K. P., Obara, S., Nakata, M., Kitajima, L., and Maruyama, I. (2000) Anandamide induces apoptosis of PC-12 cells: involvement of superoxide and caspase-3, FEBS Lett. 472, 39–44.PubMedCrossRefGoogle Scholar
  159. 159.
    Galve-Roperh, I., Sanchez, C., Cortes, M. L., del Pulgar, T. G., Izquierdo, M., and Guzman, M. (2000) Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat. Med. 6, 313–319.PubMedCrossRefGoogle Scholar
  160. 160.
    Guzman, M., Sanchez, C., and Galve-Roperh, I. (2001) Control of the cell survival/death decision by cannabinoids. J. Mol. Med. 78, 613–625.PubMedCrossRefGoogle Scholar
  161. 161.
    Sanchez, C., Galve-Roperh, I., Canova, C., Brachet, P., and Guzman, M. (1998) Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett. 436, 6–10.PubMedCrossRefGoogle Scholar
  162. 162.
    Ruiz, L., Miguel, A., and Diaz-Laviada, I. (1999) Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Lett. 458, 400–404.PubMedCrossRefGoogle Scholar
  163. 163.
    De Petrocellis, L., Melck, D., Palmisano, A., Bisogno, T., Laezza, C., Bifulco, M., and Di Marzo, V. (1998) The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc. Natl. Acad. Sci. USA 95, 8375–8380.PubMedCrossRefGoogle Scholar
  164. 164.
    Melck, D., Rueda, D., Galve-Roperh, I., De Petrocellis, L., Guzman, M., and Di Marzo, V. (1999) Involvement of the cAMP/protein kinase A pathway and of mitogen- activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells. FEBS Lett. 463, 235–240.PubMedCrossRefGoogle Scholar
  165. 165.
    Melck, D., De Petrocellis, L., Orlando, P., Bisogno, T., Laezza, C., Bifulco, M., and Di Marzo, V. (2000) Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation. Endocrinology 141, 118–126.PubMedCrossRefGoogle Scholar
  166. 166.
    Bifulco, M., Laezza, C., Portella, G., Vitale, M., Orlando, P., De Petrocellis, L., and Di Marzo, V. (2001) Control by the endogenous cannabinoid system of ras oncogene-dependent tumor growth. FASEB. J. 15, 2745–2747.PubMedGoogle Scholar
  167. 167.
    Guzman, M., Galve-Roperh, I, and Sanchez, C. (2001) Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol. Sci. 22, 19–22.PubMedCrossRefGoogle Scholar
  168. 168.
    Sanchez, C., de Ceballos, M. L., del Pulgar, T. G., et al. (2001) Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 61, 5784–5789.PubMedGoogle Scholar
  169. 169.
    Sanchez, C., Rueda, D., Segui, B., Galve-Roperh, I., Levade, T., and Guzman, M. (2001) The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan. Mol. Pharmacol. 59, 955–959.PubMedGoogle Scholar
  170. 170.
    Rueda, D., Galve-Roperh, I., Haro, A., and Guzman, M. (2000) The CB(1) cannabinoid receptor is coupled to the activation of c-Jun N-terminal kinase. Mol. Pharmacol. 58, 814–820.PubMedGoogle Scholar
  171. 171.
    Gomez del Pulgar, T., Velasco, G., and Guzman, M. (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem. J. 347, 369–373.PubMedCrossRefGoogle Scholar
  172. 172.
    Maccarrone, M., Lorenzon, T., Bari, M., Melino, G., and Finazzi-Agro, A. (2000) Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J. Biol. Chem. 275, 31,938–31,945.Google Scholar
  173. 173.
    Wahl, G. M. and Carr, A. M. (2001) The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nat. Cell. Biol. 3, E277-E286.PubMedCrossRefGoogle Scholar
  174. 174.
    Jacobsson, S. O., Wallin, T., and Fowler, C. J. (2001) Inhibition of Rat C6 Glioma Cell Proliferation by Endogenous and Synthetic Cannabinoids. Relative Involvement of Cannabinoid and Vanilloid Receptors. J. Pharmacol. Exp. Ther. 299, 951–959.PubMedGoogle Scholar
  175. 175.
    Klein, M., Calderon, S., and Hayes, B. (1999) Abuse liability assessment of neuroprotectants. Ann. NY Acad. Sci. 890, 515–525.PubMedCrossRefGoogle Scholar
  176. 176.
    Shohami, E. and Mechoulam, R. (2000) A non-psychotropic cannabinoid with neuroprotective properties. Drug Dev. Res. 50, 211–215.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2002

Authors and Affiliations

  • Mario van der Stelt
    • 1
  • Wouter B. Veldhuis
    • 2
    • 3
  • Mauro Maccarrone
    • 4
  • Peter R. Bär
    • 3
  • Klaas Nicolay
    • 2
  • Gerrit A. Veldink
    • 1
  • Vincenzo Di Marzo
    • 5
  • Johannes F. G. Vliegenthart
    • 1
  1. 1.Department of Bio-Organic Chemistry, Bijvoet Center for Biomolecular ResearchUtrecht UniversityCH UtrechtThe Netherlands
  2. 2.Department of Experimental in vivo NMR, Image Sciences Institute, UtrechtUniversity Medical Center UtrechtThe Netherlands
  3. 3.Department of Experimental NeurologyUniversity Medical Center UtrechtUtrechtThe Netherlands
  4. 4.Department of Experimental Medicine and Biochemical SciencesUniversity of Rome “Tor Vergata”RomeItaly
  5. 5.Endocannabinoid Research GroupInstitute of Biomolecular Chemistry—Consiglio Nazionale delle RicerchePozzuoli (Naples)Italy

Personalised recommendations