Neuroinflammation and the Glial Endocannabinoid System

  • Cristina Benito
  • Rosa María Tolón
  • Estefanía Núñez
  • María Ruth Pazos
  • Julián Romero

The remarkable density and wide distribution of cannabinoid CB1 receptors in the central nervous system served to explain many of the well-known pharmacological effects of natural, synthetic and endogenous cannabinoids. This receptor type is one of the most abundant cerebral receptors so far described. Its presynaptic location in neurons allows its participation in a myriad of cerebral functions, such as those controlling motor activity or memory and to mediate cannabinoid-induced neuroprotection. At the same time, the psychoactive effects derived from CB1 activation limited the development of novel therapeutic approaches on the use of cannabinoids. However, recent data have raised the possible interest of the endocannabinoid system in neuroinflammation. These new perspectives can be summarized mostly at two levels: (1) the participation of other components of the endocannabinoid system, mainly CB2 receptors and fatty acid amide hydrolase (FAAH), in neuroinflammatory processes; and (2) the predominance of the glial endocannabinoid system over the neuronal endocannabinoid system under pathological conditions. We now know that dramatic changes take place in the endocannabinoid system in the human brain, suggesting its possible involvement in several prevalent diseases, such as Alzheimer's disease, multiple sclerosis or viral encephalitis. This is the subject of the present review.


Multiple Sclerosis Microglial Cell Fatty Acid Amide Hydro Fatty Acid Amide Hydro Inhibition Fatty Acid Amide Hydro Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abood ME, Rizvi G, Sallapudi N, McAllister S (2001) Activation of the CB1 cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci Lett 309:197–201.PubMedCrossRefGoogle Scholar
  2. Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2:734–744.PubMedCrossRefGoogle Scholar
  3. Arevalo-Martin A, Vela JM, Molina-Holgado E, Borrell J, Guaza C (2003) Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J Neurosci 23:2511–2516.PubMedGoogle Scholar
  4. Back SA, Gan X, Li Y, Rosenberg PA, Volpe JJ (1998) Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J Neurosci 18:6241–6253.PubMedGoogle Scholar
  5. Barres BA, Hart IK, Coles HS, Burne JF, Voyvodic JT, Richardson WD, Raff MC (1992) Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70:31–46.PubMedCrossRefGoogle Scholar
  6. Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A, Piomelli D (1997) Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277:1094–1097.PubMedCrossRefGoogle Scholar
  7. Benito C, Nunez E, Tolon RM, Carrier EJ, Rabano A, Hillard CJ, Romero J (2003) Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J Neurosci 23:11136–11141.PubMedGoogle Scholar
  8. Benito C, Kim WK, Chavarria I, Hillard CJ, Mackie K, Tolon RM, Williams K, Romero J (2005) A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis. J Neurosci 25:2530–2536.PubMedCrossRefGoogle Scholar
  9. Benito C, Romero JP, Tolón RM, Clemente D, Docagne F, Hillard CJ, Guaza C, Romero J (2007) Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci 27:2396–2402.PubMedCrossRefGoogle Scholar
  10. Bisogno T, Maccarrone M, De Petrocellis L, Jarrahian A, Finazzi-Agrò A, Hillard C, Di Marzo V (2001) The uptake by cells of 2-arachidonyglycerol, an endogenous agonist of cannabinoid receptors. Eur J Biochem 268:1982–1989.PubMedCrossRefGoogle Scholar
  11. Boje KM, Arora PK (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 587:250–256.PubMedCrossRefGoogle Scholar
  12. Bouaboula M, Bourrié B, Rinaldi-Carmona M, Shire D, Le fur G, Casellas P (1995) Stimulation of cannabinoid receptor CB1 induces krox-24 espression in human astrocytoma cells. J Biol Chem 270:13973–13980.PubMedCrossRefGoogle Scholar
  13. Butt AM, Ransom BR (1993) Morphology of astrocytes and oligodendrocytes during development in the intact rat optic nerve. J Comp Neurol 338:141–158.PubMedCrossRefGoogle Scholar
  14. Cabral GA, Harmon KN, Carlisle SJ (2001) Cannabinoid-mediated inhibition of inducible nitric oxide production by rat microglial cells: evidence for CB1 receptor participation. Adv Exp Med Biol 493:207–214.PubMedCrossRefGoogle Scholar
  15. Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA (2002) Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol 2:69–82.PubMedCrossRefGoogle Scholar
  16. Carracedo A, Geelen MJ, Diez M, Hanada K, Guzman M, Velasco G (2004) Ceramide sensitizes astrocytes to oxidative stress: protective role of cannabinoids. Biochem J 380:435–440.PubMedCrossRefGoogle Scholar
  17. Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, Pfister SL, Campbell WB, Hillard CJ (2004) Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 65:999–1007.PubMedCrossRefGoogle Scholar
  18. Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173.PubMedCrossRefGoogle Scholar
  19. Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK (1992) Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol 149:2736–2741.PubMedGoogle Scholar
  20. Chen Y, Swanson RA 2003. Astrocytes and brain injury. J Cereb Blood Flow Metab 23:137–149.PubMedCrossRefGoogle Scholar
  21. Chopp M, Zhang RL, Chen H, Li Y, Jiang N, Rusche JR (1994) Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25:869–875.PubMedGoogle Scholar
  22. Costa B, Colleoni M, Conti S, Parolaro D, Franke C, Trovato AE, Giagnoni G (2004) Oral antiinflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Nauyn-Schmiedebergs Arch Pharmacol 369:74–79.Google Scholar
  23. Croxford JL, Miller SD (2003) Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R + WIN55, 212. J Clin Invest 111:1231–1240.PubMedGoogle Scholar
  24. Curran NM, Griffin BD, O’Toole D, Brady KJ, Fitzgerald SN, Moynagh PN (2005) The synthetic cannabinoid R(+) WIN55, 212–2 inhibits the interleukin-1 signaling pathway in human astrocytes in a cannabinoid receptor-independent manner. J Biol Chem 280:35797–35805.PubMedCrossRefGoogle Scholar
  25. Daaka Y, Friedman H, Klein TW (1996) Cannabinoid receptor proteins are increased in jurkat, human T-cell line after mitogen activation. J Pharmacol Exp Ther 276:776–783.PubMedGoogle Scholar
  26. Davies CA, Loddick SA, Toulmond S, Stroemer RP, Hunt J, Rothwell NJ (1999) The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 19(1):87–98.PubMedCrossRefGoogle Scholar
  27. Deutsch DG, Glaser ST, Howell JM, Kunz JS, Puffenbarger RA, Hillard CJ, Abumrad N (2000) The cellular uptake of anandamide is coupled to its breakdown by fatty acid amide hydrolase (FAAH). J Biol Chem 276:6967–6973.PubMedCrossRefGoogle Scholar
  28. Di Marzo V, Fontana A, Cadas H, Shimelli S, Cimino G, Schwart JC, Piommelli D (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686–619.PubMedCrossRefGoogle Scholar
  29. Dinarello CA, Thompson RC (1991) Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor. J Biol Chem 266:14147–14150.PubMedGoogle Scholar
  30. Di Tomaso E, Cadas H, Gaillet S, Beltramo M, Desarnaud F, Venance L, Piomelli D (1997) Endogenous lipids that activate cannabinoid receptors. Formation and inactivation. Adv Exp Med Biol 407:335–340.PubMedGoogle Scholar
  31. Docagne F, Muneton V, Clemente D, Ali C, Loria F, Correa F, Hernangomez M, Mestre L, Vivien D, Guaza C (2007) Excitotoxicity in a chronic model of multiple sclerosis: neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation. Mol Cell Neurosci 34:551–561.PubMedCrossRefGoogle Scholar
  32. Dusart I, Schwab ME (1994) Secondary cell death and the inmflammatory reaction after dorsal hemisction of the rat spinal cord. Eur J Neurosci 6:712–724.PubMedCrossRefGoogle Scholar
  33. Egertova M, Cravatt BF, Elphick MR (2003) Comparative analysis of fatty acid amide hydrolase and cb1 cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling. Neuroscience 119:481–496.PubMedCrossRefGoogle Scholar
  34. Ellis RJ, Deutsch R, Heaton RK, Marcotte TD, McCutchan JA, Nelson JA, Abramson I, Thal LJ, Atkinson JH, Wallace MR, Grant I (1997) Neurocognitive impairment is an independent risk factor for death in HIV infection. Arch Neurol 54:416–424.PubMedGoogle Scholar
  35. Esposito G, Izzo AA, Di Rosa M, and Iuvone T (2001) Selective cannabinoid CB1 receptor-mediated inhibition of inducible nitric oxide synthase protein expression in C6 rat glioma cells. J Neurochem 78:835–841.PubMedCrossRefGoogle Scholar
  36. Facchinetti F, Del Giudice E, Furegato S, Passarotto M, Leon A (2003) Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia 41:161–168.PubMedCrossRefGoogle Scholar
  37. Fernandez PA, Tang DG, Cheng L, Prochiantz A, Mudge AW, Raff MC (2000) Evidence that axon-derived neuregulin promotes oligodendrocyte survival in the developing rat optic nerve. Neuron 28:81–90.PubMedCrossRefGoogle Scholar
  38. Fernandez-Lopez D, Martinez-Orgado J, Nunez E, Romero J, Lorenzo P, Moro MA, Lizasoain I (2006) Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res 60:169–73.PubMedCrossRefGoogle Scholar
  39. Fernandez-Ruiz J, Gonzalez S (2005) Cannabinoid control of motor function at the basal ganglia. Handb Exp Pharmacol 168:479–507.PubMedCrossRefGoogle Scholar
  40. Fernandez-Ruiz JJ, Gonzalez S, Romero J, Ramos JA (2005) Cannabinoids in neurodegeneration and neuroprotection. In Cannabinoids as Therapeutics, Mechoulam R, ed., Birkhäuser Verlag/Switzerland, pp. 79–109.CrossRefGoogle Scholar
  41. Fowler CJ (2003) Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents. Non-psychoactive cannabinoids, “entourage” compounds and inhibitors of N-acyl ethanolamine brakdown as therapeutic strategies to avoid pyschotropic effects. Brain res Rev 41:26–43.PubMedCrossRefGoogle Scholar
  42. Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA, Stella N (2003) Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility. J Neurosci 23:7767–7775.PubMedGoogle Scholar
  43. Frei K, Malipiero Uv, Leist TP, Zinkernagel RM, Schwab ME, Fontana A (1989) On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol 19:689–694.PubMedCrossRefGoogle Scholar
  44. Frohman EM, Racke MK, Raine CS (2006) Multiple Sclerosis. The plaque and its pathogenesis. New Eng J Med 354:942–955.PubMedCrossRefGoogle Scholar
  45. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61.PubMedCrossRefGoogle Scholar
  46. Galve-Roperh I, Sánchez C, Cortés M, Gómez del Pulgar T, Izquierdo M, Guzmán 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
  47. Gard AL, Burrell MR, Pfeiffer SR, Rudge JS, Williams II WC (1995) Astroglial control of oligodendrocyte survival mediated by PDGF and leukemia inhibitory factor-like protein. Development 121:2187–2197.PubMedGoogle Scholar
  48. Gendelman HE, Genis P, Jett M, Zhai QH, Nottet HS (1994) An experimental model sustem for HIV-1-inudced brain injury. Adv Neuroimmunol 4:189–193.PubMedCrossRefGoogle Scholar
  49. Glass M, Dragunow M, Faull RL (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299–318.PubMedCrossRefGoogle Scholar
  50. Gómez del Pulgar T, de CeballoS ML, Guzmán M, Velasco G (2002a) Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase B pathway. J Biol Chem 277:36527–36533.PubMedCrossRefGoogle Scholar
  51. Gómez del Pulgar T, Velasco G, Sánchez C, Haro A, Gumán M (2002b) De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J 363:183–188.PubMedCrossRefGoogle Scholar
  52. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23.PubMedCrossRefGoogle Scholar
  53. Graeber MB, Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumors. Glia 40:252–259.PubMedCrossRefGoogle Scholar
  54. Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, Whote CL, Araoz C (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci 86:7611–7615.PubMedCrossRefGoogle Scholar
  55. Grundy RI (2002) The therapeutic potential of the cannabinoids in neuroprotection. Expert Opin Investig Drugs 11:1–10.CrossRefGoogle Scholar
  56. Grundy RI, Rabuffetti M, Beltramo M (2001) Cannabinoids and neuroprotection. Mol Neurobiol 24:29–51.PubMedCrossRefGoogle Scholar
  57. Gubellini P, Picconi B, Bari M, Battista N, Calabresi P, Centonze D, Bernardi G, Finazzi-Agro A, Maccarrone M (2002) Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J Neurosci 22:6900–6907.PubMedGoogle Scholar
  58. Guzmán M, Sanchez C, Galve-Roperh I (2001) Control of the cell survival/death decision by cannabinoids. J Mol Med 78:613–625.PubMedCrossRefGoogle Scholar
  59. Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (−))9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 95:8268–8273.PubMedCrossRefGoogle Scholar
  60. Hansen HH, Schmid PC, Bittigau P, Lastres-Becker I, Berrendero F, Manzanares J, Ikonomidou C, Schmid HH, Fernandez-Ruiz JJ, Hansen HS (2001) Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J Neurochem 78:1415–1427.PubMedCrossRefGoogle Scholar
  61. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, De Costa BR, Rice KC (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci 87:1932–1936.PubMedCrossRefGoogle Scholar
  62. Herkenham M, Lynn AB, Johnson MR, Melvin LS, De Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583.PubMedGoogle Scholar
  63. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R and Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202.PubMedCrossRefGoogle Scholar
  64. Ishibashi T, Dakin K, Stevens B, Lee P, Kozlov S, Stewart C, Fields R (2006) Astrocytes promote myelination in response to electrical impulses. Neuron 49:823–832.PubMedCrossRefGoogle Scholar
  65. Jonsson K-O, Vandevoorde S, Lambert DM, Tiger G, Fowler CJ (2001) Effects of homologues and analogues of pamitoylethanolamide upon the inactivation of the endocannabinoid anandamide. Br J Pharmacol 133:1263–1275.PubMedCrossRefGoogle Scholar
  66. Josephs MD, Solorzano CC, Taylor M, Rosenberg JJ, Topping D, Abouhamze A, Mackay SL, Hirsch E, Hirsh D, Labow M, Moldawer LL (2000) Modulation of the acute phase response by altered expression of the IL-1 type 1 receptor or IL-1ra. Am J Physiol Regul Integr Comp Physiol 278:R824–R830.PubMedGoogle Scholar
  67. Karanian DA, Brown QB, Makriyannis A, Kosten TA, Bahr BA (2005) Dual modulation of endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity. J Neurosci 25:7813–7820.PubMedCrossRefGoogle Scholar
  68. Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994.PubMedCrossRefGoogle Scholar
  69. Keirstead HS, Blakemore WF (1999) The role of oligodendrocytes and oligodendrocyte progenitors in CNS remyelination. Adv Exp Med Biol 468:183–197.PubMedGoogle Scholar
  70. Klein TW, Lane B, Newton CA, Friedman H (2000) The cannabinoid system and cytokine network. Proc Soc Exp Biol Med 225:1–8.PubMedCrossRefGoogle Scholar
  71. Köfalvi A, Pereira MF, Rebola N, Rodrigues RJ, Oliveira CR, Cunha RA (2007) Anandamide and NADA bi-directionally modulate presynaptic Ca2+ levels and transmitter release in the hippocampus. Br J Pharmacol doi:10.1038/sj.bjp. 0707252.Google Scholar
  72. Levine JM, Reynolds R, Fawcett JW (2001) The oligodendrocyte precursor cell in health and disease. Trends Neurosci 24:39–47.PubMedCrossRefGoogle Scholar
  73. Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative deseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7.PubMedCrossRefGoogle Scholar
  74. Loddick SA, Wong ML, Bongiorno PB, Gold PW, Licinio J, Rothwell NJ (1997) Endogenous interleukin-1 receptor antagonist is neuroprotective. Biochem Biophys Res Commun 234:211–215.PubMedCrossRefGoogle Scholar
  75. Lynn AB, Herkenham M (1994) Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther 268:1612–1623.PubMedGoogle Scholar
  76. Mackie K, Hille B (1992) Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci USA 89:3825–3829.PubMedCrossRefGoogle Scholar
  77. Magistretti P (2000) Cellular bases of functional bran imaging: insights from neuron-glia metabolic coupling. Brain Res 886:108–112.PubMedCrossRefGoogle Scholar
  78. Mailleux P, Vanderhaeghen JJ (1992) Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48:655–668.PubMedCrossRefGoogle Scholar
  79. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88.PubMedCrossRefGoogle Scholar
  80. Martino G, Adorini L, Rieckmann P, Hillert J, Kallmann B, Comi G, Filippi M. (2002) Inflammation in multiple sclerosis the good, the bad, and the complex. Lancet Neuro 1:499–509.CrossRefGoogle Scholar
  81. McCoy KL, Matveyeva M, Carlisle SJ, Cabral GA (1999) Cannabinoid inhibition of the processing of intact lysozyme by macrophages: evidence for CB2 receptor participation. J Pharmacol Exp Ther 289:1620–1625.PubMedGoogle Scholar
  82. McGeer PL, Yasojima K, McGeer EG (2001) Inflammation in Parkinson’s disease. Adv Neuro 86:83–89.Google Scholar
  83. Mc Guire SO, Ling ZD, Lipton JW, Sortwell CE, Collier TJ, Carvey P (2001) Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons. Exp Neurol 169:219–230.CrossRefGoogle Scholar
  84. Mechoulam R, Lichtman AH (2003) Neuroscience. Stout guards of the central nervous system. Science 302:65–67.PubMedCrossRefGoogle Scholar
  85. Mechoulam R, Panikashivili A, Shohami E (2002) Cannabinoids and brain injury: therapeutic implications. Trend Mol Med 8:58–61.CrossRefGoogle Scholar
  86. Mestre L, Correa F, Arevalo-Martin A, Molina-Holgado E, Valenti M, Ortar G, Di Marzo V, Guaza C (2005) Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis. J Neurochem 92:1327–1339.PubMedCrossRefGoogle Scholar
  87. Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C (2002) The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 202:13–23.PubMedCrossRefGoogle Scholar
  88. Moldrich G, Wenger T (2000) Localization of the CB1 cannabinoid recptor in the rat brain. An immunohistochemical study. Peptides 21:1735–1742.PubMedCrossRefGoogle Scholar
  89. Molina-Holgado F, Lledo A, Guaza C (1997) Anandamide suppresses nitric oxide and TNF-alpha responses to Theiler’s virus or endotoxin in astrocytes. Neuroreport 8:1929–1933.PubMedCrossRefGoogle Scholar
  90. Molina-Holgado F, Molina-Holgado E, Guaza C (1998) The endogenous cannabinoid anandamide potentiates interleukin-6 production by astrocytes infected with Theiler’s murine encephalomyelitis virus by a receptor-mediated pathway. FEBS Lett 433:139–142.PubMedCrossRefGoogle Scholar
  91. Molina-Holgado F, Molina-Holgado E, Guaza C, Rothwell NJ (2002a) Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharde-induced nitric oxide release in astrocytes cultures. J Neurosci Res 67:829–836.PubMedCrossRefGoogle Scholar
  92. Molina-Holgado E, Vela JM, Arevalo-Martin A, Almazan G, Molina-Holgado F, Borrell J, Guaza C (2002b) Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci 22:9742–9753.PubMedGoogle Scholar
  93. Molina-Holgado F, Pinteaux E, Moore JD, Molina-Holgado E, Guaza C, Gibson RM, Rothwell NJ (2003) Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J Neurosci 23:6470–6474.PubMedGoogle Scholar
  94. Mosley K, Cuzner ML (1996) Receptor-mediated phagocytosis of myelin by macrophages and microglia: effect of opsonization and receptor blocking agents. Neurochem Res 21:481–487.PubMedCrossRefGoogle Scholar
  95. Muthian S, Nithipatikom K, Campbell WB, Hillard CJ (2000) Synthesis and characterization of a fluorescent substrate for the N-arachidonoylethanolamine (anandamide) transmembrane carrier. J Pharmacol Exp Ther 293:289–295.PubMedGoogle Scholar
  96. Nadler V, Mechoulam R, Sokolovsky M (1993) Blockade of 45Ca2+ influx through the N-methyl-D-aspartate receptor ion channel by the non-psychoactive cannabinoid HU-211. Brain Res 622:79–85.PubMedCrossRefGoogle Scholar
  97. Nimmerjahn A, Kirchhoff F, Helmchen F (2005)Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318.PubMedCrossRefGoogle Scholar
  98. Noe SN, Newton C, Widen R, Friedman H, Klein TW (2000) Anti-CD40, anti-CD3, and IL-2 stimulation induce contrasting changes in CB1 mRNA expression in mouse splenocytes. J Neroimmunol 110:161–167.CrossRefGoogle Scholar
  99. Nunez E, Benito C, Pazos MR, Barbachano A, Fajardo O, Gonzalez S, Tolon RM, Romero J (2004) Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse 53:208–213.PubMedCrossRefGoogle Scholar
  100. Ortega-Gutierrez S, Molina-Holgado E, Guaza C (2005) Effect of anandamide uptake inhibition in the production of nitric oxide and in the release of cytokines in astrocyte cultures. Glia 52:163–168.PubMedCrossRefGoogle Scholar
  101. 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
  102. Parri R, Crunelli V (2003) An astrocyte bridge from synapse to blood flow. Nat Neurosci 6:5–6.PubMedCrossRefGoogle Scholar
  103. Pearlman RJ, Aubrey KR, Vandenberg RJ (2003) Arachidonic acid and anandamide have opposite modulatory actions at the glycine transporter, GLYT1a. J Neurochem 84:592–601.PubMedCrossRefGoogle Scholar
  104. Persidsky Y, Gendelman HE (2003) Mononuclear phagocyte immunity and the neuropathogenesis of HIV-1 infection. J Leukoc Biol 74:691–701.PubMedCrossRefGoogle Scholar
  105. Pertwee RG (1999) Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors. Life Sciences 65:597–605.PubMedCrossRefGoogle Scholar
  106. Piet R, Vargová L, Syková E, Poulain D, Oliet S (2004) Physiological contribution of the astrocytic environment of neurons to intersynaptic crosstalk. Proc Natl Acad Sci USA 101:2151–2155.PubMedCrossRefGoogle Scholar
  107. Pryce G, Baker D (2005) Emerging properties of cannabinoid medicines in management of multiple sclerosis. Trends Neurosci 28:272–276.PubMedCrossRefGoogle Scholar
  108. Puffenbarger RA, Boothe AC, Cabral GA (2000) Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69.PubMedCrossRefGoogle Scholar
  109. Ramirez BG, Blazquez C, Gomez GP, Guzman M, De Ceballos ML (2005) Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25:1904–1913.PubMedCrossRefGoogle Scholar
  110. Rodriguez JJ, Mackie K, Pickel VM (2001) Ultrastructural localization of the CB1 cannabinoid recptor in opioid recptor patches of the rat caudate putamen nucleus. J Neurosci 21:823–833.PubMedGoogle Scholar
  111. Rog DJ, Nurmikko TJ, Friede T, Young CA (2005) Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 65:812–819.PubMedCrossRefGoogle Scholar
  112. Rogers J, Luber-Narod J, Styren SD, Civin WH (1988) Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging 9:339–349.PubMedCrossRefGoogle Scholar
  113. Romero J, Hillard CJ, Calero M, Rabano A (2002) Fatty acid amide hydrolase localization in the human central nervous system: an immunohistochemical study. Brain Res Mol Brain Res 100:85–93.PubMedGoogle Scholar
  114. Sagan S, Venance L, Torrens Y, Cordier J, Glowinski J, Giaume C (1999) Anandamide and WIN 55212–2 inhibit cyclic AMP formation through G-protein-coupled recptors distinct from CB1 cannabinoid receptors in cultured astrocytes. Eur J Neurosci 11:691–699.PubMedCrossRefGoogle Scholar
  115. Salio C, Doly S, Fischer J, Franzoni MF, Conrath M (2002) Neuronal and astrocytic localization of the cannabinoid recptor-1 in the dorsal horn of the rat spinal cord. Neurosci Lett 329:13–16.PubMedCrossRefGoogle Scholar
  116. Sánchez C, Galve-Roperh I, Canova C, Brachet P, Guzmán M (1998a) Delta 9-tetrahydrocannabinol induces apoptosis in a C6 glioma cells. FEBS Lett 436:6–10.PubMedCrossRefGoogle Scholar
  117. Sánchez C, Galve-Roperh I, Rueda D, Guzmán M (1998b) Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. Mol Pharmacol 54:834–843.PubMedGoogle Scholar
  118. Sánchez C, de Ceballos ML, Gómez del Pulgar T, Rueda D, Corbacho C, velasco G, Galve-Roperh I, Huffman JWH, Ramón y Cajal S, Guzmán M (2001a) Inhibition of glioma growth in vivo by selective activation of the CB2 cannabinoid receptor. Cancer Res 61:5784–5789.Google Scholar
  119. Sánchez C, Rueda D, Segui B, Galve-Roperh I, Levade T, Guzmán M (2001b) The CB1 cannabinoid receptor of astrocytes in coupled to sphingomyelin hydrolysis through the adaptor protein Fan. Mol Pharmacol 59:955–959.PubMedGoogle Scholar
  120. Sapp E, kegel KB, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, Bhide PG, Vonsattel JP, DiFiglia M (2001) Early and progressive accumulation of reactive microglia in the Huntington disease brain. J Neuropathol Exp Neurol 60:161–172.PubMedGoogle Scholar
  121. Shen M, Thayer SA (1998) The cannabinoid agonist Win55, 212–2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons. Brain Res 783:77–84.PubMedCrossRefGoogle Scholar
  122. Sheng WS, Hu S, min X, Cabral GA, Lokensgard JR, Peterson P (2005) Synthetic cannabinoid WIN55, 212–2 inhibits generation of inflammatory mediators by IL-1beta stimulated human astrocytes. Glia 49:211–219.PubMedCrossRefGoogle Scholar
  123. Shivachar AC, Martin BR, Ellis EF (1996) Anandamide- and delta9-tetrahydrocannabinol-evoked arachidonic acid mobilization and blockade by SR141716A [N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride]. Biochem Pharmacol 51:669–676.PubMedCrossRefGoogle Scholar
  124. Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T (1997) Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant. J Neuroimmuno 72:169–177.CrossRefGoogle Scholar
  125. Stefano GB, Liu Y, Goligorsky MS (1996) Cannabinoid receptors are coupled to nitric oxide release in invertebrate immunocytes, microglia, and human monocytes. J Biol Chem 271:19238–19242.PubMedCrossRefGoogle Scholar
  126. Stella N (2004) Cannabinoid signaling in glial cells. Glia 48:267–277.PubMedCrossRefGoogle Scholar
  127. Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778.PubMedCrossRefGoogle Scholar
  128. Streit WJ (2005) Microglia and neuroprotection: implications for Alzheimer’s disease. Brain Res Rev 48:234–239.PubMedCrossRefGoogle Scholar
  129. Streit WJ, Mrak RE, Griffin WS (2004) Microglia and neuroinflammation: a pathological perspective. J Neuoinflammation 1:14.CrossRefGoogle Scholar
  130. Suárez I, Bodega G, Ramos JA, Fernández-Ruiz JJ, Fernández B (2000) Neuronal and astroglial response to pre- and perinatal exposure to delta-9-tetrahydrocannabinol in the rat substantia nigra. Dev Neurosci 22:253–263.PubMedCrossRefGoogle Scholar
  131. Suárez I, Bodega G, Fernández-Ruiz JJ, Ramos JA, Rubio M, Fernández B (2002) Reduced glial fibrillary acidic protein and glutamine synthase expression in astrocytes and Bergmann glial cells in the rat cerebellum caused by delta-9-tetrahydrocannabinol administration during development. Dev Neurosci 24:300–312.PubMedCrossRefGoogle Scholar
  132. Sun GY, Xu J, Jensen MD, Yu S, Wood WG, Gonzalez FA, Simonyi A, Sun AY, Weisman GA. (2005) Phospholipase A2 in astrocytes: responses to oxidative stress, inflammation, and G protein-coupled receptor agonists. Mol Neurobiol 31:27–41.PubMedCrossRefGoogle Scholar
  133. Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM (1998a) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous sytem. Neuroscience 83:393–411.PubMedCrossRefGoogle Scholar
  134. Tsou K, Nogueron MI, Muthian S, Sanudo-Pena MC, Hillard CJ, Deutsch DG, Walker JM (1998b) Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci Lett 254:137–140.PubMedCrossRefGoogle Scholar
  135. Van der Laan LJ, Ruuls SR, Weber KS, Lodder IJ, Dopp EA, Dijkstra CD (1996) Macrophage phagocytosis of myelin in vitro determined by flow cytometry: phagocytosis is mediated by CR3 and induces production of tumor necrosis factor-alpha and nitric oxide. J Neuroimmunol 70:145–152.PubMedCrossRefGoogle Scholar
  136. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332.PubMedCrossRefGoogle Scholar
  137. Venance L, Piomelli D, Glowinski J, Giaume C (1995) Inhibition by anandamide of gap junctions and intercellular calcium signalling in striatal astrocytes. Nature 376:590–594.PubMedCrossRefGoogle Scholar
  138. Voutsinos-Porche B, Bonvento G, Tanaka K, Steiner P, Welker E, Chatton J-Y, Magistretti PJ, Pellerin L (2003) Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Neuron 37:275–286.PubMedCrossRefGoogle Scholar
  139. Waksman Y, Olson J.M, Carlisle SJ, Cabral GA (1999) The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J Pharmacol Exp Ther 288:1357–1366.PubMedGoogle Scholar
  140. Walter L, Stella N (2003) Endothelin-1 increases 2-arachidonyl glycerol (2-AG) production in astrocytes. Glia 44:85–90.PubMedCrossRefGoogle Scholar
  141. Walter L, Franklin A, Witting A, Moller T, Stella N (2002) Astrocytes in culture produce anandamide and other acylethanolamides. J Biol Chem 277:20869–20876.PubMedCrossRefGoogle Scholar
  142. Walter L, Franklin A, Witting A, Wade C, Xie Y, Kunos G, Mackie K, Stella N (2003) Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci 23:1398–1405.PubMedGoogle Scholar
  143. Weber A, Ni J, Ling KH, Acheampong A, Tang-Liu DD, Burk R, Cravatt BF, Woodward D (2004) Formation of prostamides from anandamide in FAAH knockout mice analyzed by HPLC with tandem mass spectrometry. J Lipid Res 45:757–763.PubMedCrossRefGoogle Scholar
  144. Westlake TM, Howlett AC, Bonner TI, Matsuda LA, Herkenham M (1994) Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer’s brains. Neuroscience 63:637–652.PubMedCrossRefGoogle Scholar
  145. Williams K, Ulvestad E, Waage A, Antel JP, McLaurin J (1994) Activation of adult human derived microglia by myelin phagocytosis in vitro. J Neurosci Res 38:433–443.PubMedCrossRefGoogle Scholar
  146. Williams KC, Hickey WF (2002) Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS. Annu Rev Neurosci 25:537–562.PubMedCrossRefGoogle Scholar
  147. Witting A, Stella N (2004) Cannabinoid signaling in glial cells in health and disease. Current Neuropharmacol 2.Google Scholar
  148. Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P (2006) COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol 6:12.PubMedCrossRefGoogle Scholar
  149. Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Thompson A (2003) Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362:1517–1526.PubMedCrossRefGoogle Scholar
  150. Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, Nunn AJ, Teare LJ, Fox PJ, Thompson AJ (2005) Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 76:1664–1669.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Cristina Benito
  • Rosa María Tolón
  • Estefanía Núñez
  • María Ruth Pazos
  • Julián Romero
    • 1
  1. 1.Laboratorio de Apoyo a la InvestigaciónFundación Hospital AlcorcónAlcorcónSpain

Personalised recommendations