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Acute neuronal injury, excitotoxicity, and the endocannabinoid system

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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.

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References

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  14. Schmid, H. H. (2000) Pathways and mechanisms of N-acylethanolamine biosynthesis: can anandamide be generated selectively? Chem. Phys. Lipids 108, 71–87.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  16. 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 

  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.

    Article  PubMed  CAS  Google Scholar 

  18. Pertwee, R. G. (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol. Ther. 74, 129–180.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  21. Grundy, R. I., Rabuffetti, M., and Beltramo, M. (2001) Cannabinoids and neuroprotection. Mol. Neurobiol. 24, 29–51.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  27. Howlett, A. C. and Mukhopadhyay, S. (2000) Cellular signal transduction by anandamide and 2-arachidonoylglycerol. Chem. Phys. Lipids 108, 53–70.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  31. Smart, D. and Jerman, J. C. (2000) Anandamide: an endogenous activator of the vanilloid receptor. Trends Pharmacol. Sci. 21, 134.

    Article  PubMed  CAS  Google Scholar 

  32. Di Marzo, V., Bisogno, T., and De Petrocellis, L. (2001) Anandamide: some like it hot. Trends Pharmacol. Sci. 22, 346–349.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  40. Ueda, N. and Yamamoto, S. (2000) Anandamide amidohydrolase (fatty acid amide hydrolase). Prostaglandins Other Lipid Mediat. 61, 19–28.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  63. Schlicker, E. and Kathmann, M. (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22, 565–572.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  72. Szabo, B., Wallmichrath, I., Mathonia, P., and Pfreundtner, C. (2000) Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience 97, 89–97

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  78. Wilson, R. I., Kunos, G., and Nicoll, R. A. (2001) Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 453–462.

    Article  PubMed  CAS  Google Scholar 

  79. Wilson, R. I. and Nicoll, R. A. (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. Olney, J. W. (1971) Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. An electron microscopic study. J. Neuropathol. Exp. Neurol. 30, 75–90.

    Article  PubMed  CAS  Google Scholar 

  88. Lee, J. M., Zipfel, G. J., and Choi, D. W. (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399, A7–14.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  92. Rothman, S. M. and Olney, J. W. (1986) Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19, 105–111.

    Article  PubMed  CAS  Google Scholar 

  93. Siesjo, B. K. (1992) Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J. Neurosurg. 77, 169–184.

    PubMed  CAS  Google Scholar 

  94. Doble, A. (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol. Ther. 81, 163–221.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  97. Rothman, S. M. (1985) The neurotoxicity of excitatory amino acids is produced by passive chloride influx. J. Neurosci. 5, 1483–1489.

    PubMed  CAS  Google Scholar 

  98. Choi, D. W. (1995) Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci. 18, 58–60.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  107. Choi, D. W., Maulucci-Gedde, M., and Kriegstein, A. R. (1987) Glutamate neurotoxicity in cortical cell culture. J. Neurosci. 7, 357–368.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  110. Shen, M. and Thayer, S. A. (1998) Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol. Pharmacol. 54, 459–462.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  113. Hampson, A. J. and Grimaldi, M. (2001) Cannabinoid receptor activation and elevated cyclic AMP reduce glutamate neurotoxicity. Eur. J. Neurosci. 13, 1529–1536.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  118. Pulsinelli, W. A. and Brierley, J. B. (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10, 267–272.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  124. Lighthall, J. W. (1988) Controlled cortical impact: a new experimental brain injury model. J. Neurotrauma 5, 1–15.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  130. Mechoulam, R., Panikashvili, D., and Shohami, E. (2002) Cannabinoids and brain injury: therapeutic implications Trends Mol. Med. 8, 58–61.

    Article  PubMed  CAS  Google Scholar 

  131. Schmid, H. H., Schmid, P. C., and Natarajan, V. (1990) N-acylated glycerophospholipids and their derivatives. Prog. Lipid. Res. 29, 1–43.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  143. Chan, G. C., Hinds, T. R., Impey, S., and Storm, D. R. (1998) Hippocampal neurotoxicity of Delta9-tetrahydrocannabinol. J. Neurosci. 18, 5322–5332.

    PubMed  CAS  Google Scholar 

  144. Stella, N, and Piomelli, D. (2001) Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur. J. Pharmacol. 425, 189–196.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  151. Sasamura, T. and Kuraishi, Y. (1999) Peripheral and central actions of capsaicin and VR1 receptor. Jpn. J. Pharmacol. 80, 275–280.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  153. Premkumar, L. S. and Ahern, G. P. (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature 408, 985–990.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  155. Mattson, M. P., Culmsee, C., and Yu, Z. F. (2000) Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res. 301, 173–187.

    Article  PubMed  CAS  Google Scholar 

  156. Mattson, M. P. (2000) Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell. Biol. 1, 120–129.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  167. Guzman, M., Galve-Roperh, I, and Sanchez, C. (2001) Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol. Sci. 22, 19–22.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  175. Klein, M., Calderon, S., and Hayes, B. (1999) Abuse liability assessment of neuroprotectants. Ann. NY Acad. Sci. 890, 515–525.

    Article  PubMed  CAS  Google Scholar 

  176. Shohami, E. and Mechoulam, R. (2000) A non-psychotropic cannabinoid with neuroprotective properties. Drug Dev. Res. 50, 211–215.

    Article  CAS  Google Scholar 

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van der Stelt, M., Veldhuis, W.B., Maccarrone, M. et al. Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol Neurobiol 26, 317–346 (2002). https://doi.org/10.1385/MN:26:2-3:317

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