Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis

Neuropharmacology

Volumn 113, Issue , 2017, Pages 618-626

  Fitzpatrick, John Mark K ^a   Downer, Eric J ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

Cannabinoids; Cell signalling; Innate immunity; Multiple sclerosis; Therapeutics; Toll like receptor

Indexed keywords

CANNABINOID; CANNABINOID RECEPTOR; NABIXIMOLS; TOLL LIKE RECEPTOR; CANNABINOID RECEPTOR AFFECTING AGENT;

ASTROCYTE; DISEASE COURSE; DRUG ACTIVITY; HUMAN; INNATE IMMUNITY; MICROGLIA; MOLECULAR INTERACTION; MULTIPLE SCLEROSIS; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; METABOLISM;

ANIMALS; CANNABINOID RECEPTOR MODULATORS; CANNABINOIDS; HUMANS; MULTIPLE SCLEROSIS; TOLL-LIKE RECEPTORS;

EID: 84996615478     PISSN: 00283908     EISSN: 18737064     Source Type: Journal    
DOI: 10.1016/j.neuropharm.2016.04.009     Document Type: Review

References (132)

1. Achiron, A., Miron, S., Lavie, V., Margalit, R., Biegon, A., Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis: implications for the treatment of acute relapses of multiple sclerosis. J. Neuroimmunol. 102 (2000), 26–31.
2. Andersson, A., Covacu, R., Sunnemark, D., Danilov, A.I., Dal Bianco, A., Khademi, M., Wallstrom, E., Lobell, A., Brundin, L., Lassmann, H., Harris, R.A., Pivotal advance: HMGB1 expression in active lesions of human and experimental multiple sclerosis. J. Leukoc. Biol. 84 (2008), 1248–1255.
3. Arevalo-Martin, A., Vela, J.M., Molina-Holgado, E., Borrell, J., Guaza, C., Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J. Neurosci. 23 (2003), 2511–2516.
4. Baker, D., Pryce, G., Croxford, J.L., Brown, P., Pertwee, R.G., Huffman, J.W., Layward, L., Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404 (2000), 84–87.
5. Baker, D., Pryce, G., Croxford, J.L., Brown, P., Pertwee, R.G., Makriyannis, A., Khanolkar, A., Layward, L., Fezza, F., Bisogno, T., Di Marzo, V., Endocannabinoids control spasticity in a multiple sclerosis model. Faseb J. 15 (2001), 300–302.
6. Block, M.L., Hong, J.S., Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol. 76 (2005), 77–98.
7. Bruck, W., The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage. J. Neurol. 252:Suppl. 5 (2005), v3–9.
8. Bsibsi, M., Ravid, R., Gveric, D., van Noort, J.M., Broad expression of Toll-like receptors in the human central nervous system. J. Neuropathol. Exp. Neurol. 61 (2002), 1013–1021.
9. Cabranes, A., Pryce, G., Baker, D., Fernandez-Ruiz, J., Changes in CB1 receptors in motor-related brain structures of chronic relapsing experimental allergic encephalomyelitis mice. Brain Res. 1107 (2006), 199–205.
10. Carlisle, S.J., Marciano-Cabral, F., Staab, A., Ludwick, C., Cabral, G.A., Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int. Immunopharmacol. 2 (2002), 69–82.
11. Centonze, D., Bari, M., Rossi, S., Prosperetti, C., Furlan, R., Fezza, F., De Chiara, V., Battistini, L., Bernardi, G., Bernardini, S., Martino, G., Maccarrone, M., The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. Brain 130 (2007), 2543–2553.
12. Chearwae, W., Bright, J.J., 15-deoxy-Delta(12,14)-prostaglandin J(2) and curcumin modulate the expression of toll-like receptors 4 and 9 in autoimmune T lymphocyte. J. Clin. Immunol. 28 (2008), 558–570.
13. Chiurchiu, V., Cencioni, M.T., Bisicchia, E., De Bardi, M., Gasperini, C., Borsellino, G., Centonze, D., Battistini, L., Maccarrone, M., Distinct modulation of human myeloid and plasmacytoid dendritic cells by anandamide in multiple sclerosis. Ann. Neurol. 73 (2013), 626–636.
14. Chiurchiu, V., Lanuti, M., De Bardi, M., Battistini, L., Maccarrone, M., The differential characterization of GPR55 receptor in human peripheral blood reveals a distinctive expression in monocytes and NK cells and a proinflammatory role in these innate cells. Int. Immunol. 27 (2015), 153–160.
15. Chung, E.S., Bok, E., Chung, Y.C., Baik, H.H., Jin, B.K., Cannabinoids prevent lipopolysaccharide-induced neurodegeneration in the rat substantia nigra in vivo through inhibition of microglial activation and NADPH oxidase. Brain Res. 1451 (2012), 110–116.
16. Coffey, R.G., Snella, E., Johnson, K., Pross, S., Inhibition of macrophage nitric oxide production by tetrahydrocannabinol in vivo and in vitro. Int. J. Immunopharmacol. 18 (1996), 749–752.
17. Compston, A., Coles, A., Multiple sclerosis. Lancet 359 (2002), 1221–1231.
18. Compston, A., Coles, A., Multiple sclerosis. Lancet 372 (2008), 1502–1517.
19. Correale, J., Farez, M.F., The role of astrocytes in multiple sclerosis progression. Front. Neurol., 6, 2015, 180.
20. Crowley, T., Fitzpatrick, J.M., Kuijper, T., Cryan, J.F., O'Toole, O., O'Leary, O.F., Downer, E.J., Modulation of TLR3/TLR4 inflammatory signaling by the GABAB receptor agonist baclofen in glia and immune cells: relevance to therapeutic effects in multiple sclerosis. Front. Cell Neurosci., 9, 2015, 284.
21. Croxford, J.L., Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 17 (2003), 179–202.
22. Croxford, J.L., Miller, S.D., Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212. J. Clin. Invest. 111 (2003), 1231–1240.
23. Croze, E., Yamaguchi, K.D., Knappertz, V., Reder, A.T., Salamon, H., Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis. Pharmacogenomics J. 13 (2013), 443–451.
24. Cua, D.J., Sherlock, J., Chen, Y., Murphy, C.A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S.A., Gorman, D., Kastelein, R.A., Sedgwick, J.D., Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421 (2003), 744–748.
25. de Lago, E., Moreno-Martet, M., Cabranes, A., Ramos, J.A., Fernandez-Ruiz, J., Cannabinoids ameliorate disease progression in a model of multiple sclerosis in mice, acting preferentially through CB1 receptor-mediated anti-inflammatory effects. Neuropharmacology 62 (2012), 2299–2308.
26. Demuth, D.G., Molleman, A., Cannabinoid signalling. Life Sci. 78 (2006), 549–563.
27. Devinsky, O., Cilio, M.R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., Katz, R., Di Marzo, V., Jutras-Aswad, D., Notcutt, W.G., Martinez-Orgado, J., Robson, P.J., Rohrback, B.G., Thiele, E., Whalley, B., Friedman, D., Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55 (2014), 791–802.
28. Downer, E.J., Cannabinoids and innate immunity: taking a toll on neuroinflammation. ScientificWorldJournal 11 (2011), 855–865.
29. Downer, E.J., Clifford, E., Amu, S., Fallon, P.G., Moynagh, P.N., The synthetic cannabinoid R(+)WIN55,212-2 augments interferon-beta expression via peroxisome proliferator-activated receptor-alpha. J. Biol. Chem. 287 (2012), 25440–25453.
30. Downer, E.J., Clifford, E., Gran, B., Nel, H.J., Fallon, P.G., Moynagh, P.N., Identification of the synthetic cannabinoid R(+)WIN55,212-2 as a novel regulator of IFN regulatory factor 3 activation and IFN-beta expression: relevance to therapeutic effects in models of multiple sclerosis. J. Biol. Chem. 286 (2011), 10316–10328.
31. Duncan, M., Galic, M.A., Wang, A., Chambers, A.P., McCafferty, D.M., McKay, D.M., Sharkey, K.A., Pittman, Q.J., Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305 (2013), R224–R231.
32. Echigo, R., Sugimoto, N., Yachie, A., Ohno-Shosaku, T., Cannabinoids inhibit peptidoglycan-induced phosphorylation of NF-kappaB and cell growth in U87MG human malignant glioma cells. Oncol. Rep. 28 (2012), 1176–1180.
33. Eljaschewitsch, E., Witting, A., Mawrin, C., Lee, T., Schmidt, P.M., Wolf, S., Hoertnagl, H., Raine, C.S., Schneider-Stock, R., Nitsch, R., Ullrich, O., The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron 49 (2006), 67–79.
34. Facchinetti, F., Del Giudice, E., Furegato, S., Passarotto, M., Leon, A., Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia 41 (2003), 161–168.
35. Feliu, A., Moreno-Martet, M., Mecha, M., Carrillo-Salinas, F.J., de Lago, E., Fernandez-Ruiz, J., Guaza, C., A Sativex((R)) -like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis. Br. J. Pharmacol. 172 (2015), 3579–3595.
36. Feng, X., Petraglia, A.L., Chen, M., Byskosh, P.V., Boos, M.D., Reder, A.T., Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1. J. Neuroimmunol. 129 (2002), 205–215.
37. Fitzgerald, D.C., O'Brien, K., Young, A., Fonseca-Kelly, Z., Rostami, A., Gran, B., Interferon regulatory factor (IRF) 3 is critical for the development of experimental autoimmune encephalomyelitis. J. Neuroinflammation, 11, 2014, 130.
38. Fitzgerald, K.A., McWhirter, S.M., Faia, K.L., Rowe, D.C., Latz, E., Golenbock, D.T., Coyle, A.J., Liao, S.M., Maniatis, T., IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4 (2003), 491–496.
39. Gaby, A., Multiple sclerosis. Glob. Adv. Health Med. 2 (2013), 50–56.
40. Galiegue, S., Mary, S., Marchand, J., Dussossoy, D., Carriere, D., Carayon, P., Bouaboula, M., Shire, D., Le Fur, G., Casellas, P., Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur. J. Biochem. 232 (1995), 54–61.
41. Galligan, C.L., Pennell, L.M., Murooka, T.T., Baig, E., Majchrzak-Kita, B., Rahbar, R., Fish, E.N., Interferon-beta is a key regulator of proinflammatory events in experimental autoimmune encephalomyelitis. Mult. Scler. 16 (2010), 1458–1473.
42. Gandhi, R., Laroni, A., Weiner, H.L., Role of the innate immune system in the pathogenesis of multiple sclerosis. J. Neuroimmunol. 221 (2010), 7–14.
43. Gold, R., Kappos, L., Arnold, D.L., Bar-Or, A., Giovannoni, G., Selmaj, K., Tornatore, C., Sweetser, M.T., Yang, M., Sheikh, S.I., Dawson, K.T., Investigators, D.S., Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N. Engl. J. Med. 367 (2012), 1098–1107.
44. Granja, A.G., Carrillo-Salinas, F., Pagani, A., Gomez-Canas, M., Negri, R., Navarrete, C., Mecha, M., Mestre, L., Fiebich, B.L., Cantarero, I., Calzado, M.A., Bellido, M.L., Fernandez-Ruiz, J., Appendino, G., Guaza, C., Munoz, E., A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis. J. Neuroimmune Pharmacol. 7 (2012), 1002–1016.
45. Guo, B., Chang, E.Y., Cheng, G., The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J. Clin. Invest. 118 (2008), 1680–1690.
46. Guo, X., Harada, C., Namekata, K., Matsuzawa, A., Camps, M., Ji, H., Swinnen, D., Jorand-Lebrun, C., Muzerelle, M., Vitte, P.A., Ruckle, T., Kimura, A., Kohyama, K., Matsumoto, Y., Ichijo, H., Harada, T., Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO Mol. Med. 2 (2010), 504–515.
47. Harrison, D.M., Calabresi, P.A., Promising treatments of tomorrow for multiple sclerosis. Ann. Indian Acad. Neurology 12 (2009), 283–290.
48. Hasseldam, H., Johansen, F.F., Cannabinoid treatment renders neurons less vulnerable than oligodendrocytes in experimental autoimmune encephalomyelitis. Int. J. Neurosci. 121 (2011), 510–520.
49. Hayashi, T., Yao, S., Crain, B., Chan, M., Tawatao, R.I., Gray, C., Vuong, L., Lao, F., Cottam, H.B., Carson, D.A., Corr, M., Treatment of autoimmune inflammation by a TLR7 ligand regulating the innate immune system. PLoS One, 7, 2012, e45860.
50. Henry, R.J., Kerr, D.M., Finn, D.P., Roche, M., FAAH-mediated modulation of TLR3-induced neuroinflammation in the rat hippocampus. J. Neuroimmunol. 276 (2014), 126–134.
51. Henry, R.J., Kerr, D.M., Finn, D.P., Roche, M., For whom the endocannabinoid tolls: modulation of innate immune function and implications for psychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 64 (2016), 167–180.
52. Hernangomez, M., Carrillo-Salinas, F.J., Mecha, M., Correa, F., Mestre, L., Loria, F., Feliu, A., Docagne, F., Guaza, C., Brain innate immunity in the regulation of neuroinflammation: therapeutic strategies by modulating CD200-CD200R interaction involve the cannabinoid system. Curr. Pharm. Des. 20 (2014), 4707–4722.
53. Hoffmann, O., Braun, J.S., Becker, D., Halle, A., Freyer, D., Dagand, E., Lehnardt, S., Weber, J.R., TLR2 mediates neuroinflammation and neuronal damage. J. Immunol. 178 (2007), 6476–6481.
54. Howlett, A.C., Barth, F., Bonner, T.I., Cabral, G., Casellas, P., Devane, W.A., Felder, C.C., Herkenham, M., Mackie, K., Martin, B.R., Mechoulam, R., Pertwee, R.G., International union of pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol. Rev. 54 (2002), 161–202.
55. Iversen, L., The Science of Marijuana. 2000, Oxford University Press, New York.
56. Jean-Gilles, L., Feng, S., Tench, C.R., Chapman, V., Kendall, D.A., Barrett, D.A., Constantinescu, C.S., Plasma endocannabinoid levels in multiple sclerosis. J. Neurol. Sci. 287 (2009), 212–215.
57. Jefferies, C.A., Fitzgerald, K.A., Interferon gene regulation: not all roads lead to tolls. Trends Mol. Med. 11 (2005), 403–411.
58. Juknat, A., Pietr, M., Kozela, E., Rimmerman, N., Levy, R., Gao, F., Coppola, G., Geschwind, D., Vogel, Z., Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells. PLoS One, 8, 2013, e61462.
59. Kawai, T., Akira, S., The roles of TLRs, RLRs and NLRs in pathogen recognition. Int. Immunol. 21 (2009), 317–337.
60. Killestein, J., Uitdehaag, B.M., Polman, C.H., Cannabinoids in multiple sclerosis: do they have a therapeutic role?. Drugs 64 (2004), 1–11.
61. Klegeris, A., Bissonnette, C.J., McGeer, P.L., Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br. J. Pharmacol. 139 (2003), 775–786.
62. Kong, W., Li, H., Tuma, R.F., Ganea, D., Selective CB2 receptor activation ameliorates EAE by reducing Th17 differentiation and immune cell accumulation in the CNS. Cell Immunol. 287 (2014), 1–17.
63. Kozela, E., Lev, N., Kaushansky, N., Eilam, R., Rimmerman, N., Levy, R., Ben-Nun, A., Juknat, A., Vogel, Z., Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br. J. Pharmacol. 163 (2011), 1507–1519.
64. Kozela, E., Pietr, M., Juknat, A., Rimmerman, N., Levy, R., Vogel, Z., Cannabinoids delta(9)-tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide-activated NF-kappaB and interferon-beta/STAT proinflammatory pathways in BV-2 microglial cells. J. Biol. Chem. 285 (2010), 1616–1626.
65. Lampropoulou, V., Hoehlig, K., Roch, T., Neves, P., Calderon Gomez, E., Sweenie, C.H., Hao, Y., Freitas, A.A., Steinhoff, U., Anderton, S.M., Fillatreau, S., TLR-activated B cells suppress T cell-mediated autoimmunity. J. Immunol. 180 (2008), 4763–4773.
66. Lehnardt, S., Lehmann, S., Kaul, D., Tschimmel, K., Hoffmann, O., Cho, S., Krueger, C., Nitsch, R., Meisel, A., Weber, J.R., Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia. J. Neuroimmunol. 190 (2007), 28–33.
67. Li, B., Baylink, D.J., Deb, C., Zannetti, C., Rajaallah, F., Xing, W., Walter, M.H., Lau, K.H., Qin, X., 1,25-Dihydroxyvitamin D3 suppresses TLR8 expression and TLR8-mediated inflammatory responses in monocytes in vitro and experimental autoimmune encephalomyelitis in vivo. PLoS One, 8, 2013, e58808.
68. Ligresti, A., Cascio, M.G., Pryce, G., Kulasegram, S., Beletskaya, I., De Petrocellis, L., Saha, B., Mahadevan, A., Visintin, C., Wiley, J.L., Baker, D., Martin, B.R., Razdan, R.K., Di Marzo, V., New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis. Br. J. Pharmacol. 147 (2006), 83–91.
69. Liu, Y., Teige, I., Ericsson, I., Navikas, V., Issazadeh-Navikas, S., Suppression of EAE by oral tolerance is independent of endogenous IFN-beta whereas treatment with recombinant IFN-beta ameliorates EAE. Immunol. Cell Biol. 88 (2010), 468–476.
70. Loria, F., Petrosino, S., Mestre, L., Spagnolo, A., Correa, F., Hernangomez, M., Guaza, C., Di Marzo, V., Docagne, F., Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide. Eur. J. Neurosci. 28 (2008), 633–641.
71. Lou, Z.Y., Yu, W.B., Chen, J., Li, L., Jiang, L.S., Xiao, B.G., Liu, Z.G., Neuroprotective effect is driven through the upregulation of CB1 receptor in experimental autoimmune encephalomyelitis. J. Mol. Neurosci. 58:2 (2016), 193–200.
72. Lucchinetti, C.F., Popescu, B.F., Bunyan, R.F., Moll, N.M., Roemer, S.F., Lassmann, H., Bruck, W., Parisi, J.E., Scheithauer, B.W., Giannini, C., Weigand, S.D., Mandrekar, J., Ransohoff, R.M., Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med. 365 (2011), 2188–2197.
73. Lyman, W.D., Sonett, J.R., Brosnan, C.F., Elkin, R., Bornstein, M.B., Delta 9-tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J. Neuroimmunol. 23 (1989), 73–81.
74. Ma, L., Jia, J., Liu, X., Bai, F., Wang, Q., Xiong, L., Activation of murine microglial N9 cells is attenuated through cannabinoid receptor CB2 signaling. Biochem. Biophys. Res. Commun. 458 (2015), 92–97.
75. Mailleux, P., Vanderhaeghen, J.J., Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48 (1992), 655–668.
76. Marchalant, Y., Rosi, S., Wenk, G.L., Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation. Neuroscience 144 (2007), 1516–1522.
77. Marta, M., Toll-like receptors in multiple sclerosis mouse experimental models. Ann. N. Y. Acad. Sci. 1173 (2009), 458–462.
78. Marta, M., Andersson, A., Isaksson, M., Kampe, O., Lobell, A., Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur. J. Immunol. 38 (2008), 565–575.
79. Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., Bonner, T.I., Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346 (1990), 561–564.
80. Mecha, M., Feliu, A., Inigo, P.M., Mestre, L., Carrillo-Salinas, F.J., Guaza, C., Cannabidiol provides long-lasting protection against the deleterious effects of inflammation in a viral model of multiple sclerosis: a role for A2A receptors. Neurobiol. Dis. 59 (2013), 141–150.
81. Medzhitov, R., Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1 (2001), 135–145.
82. Medzhitov, R., Preston-Hurlburt, P., Kopp, E., Stadlen, A., Chen, C., Ghosh, S., Janeway, C.A. Jr., MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2 (1998), 253–258.
83. Mellanby, R.J., Cambrook, H., Turner, D.G., O'Connor, R.A., Leech, M.D., Kurschus, F.C., MacDonald, A.S., Arnold, B., Anderton, S.M., TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis. J. Neuroinflammation, 9, 2012, 248.
84. Mestre, L., Docagne, F., Correa, F., Loria, F., Hernangomez, M., Borrell, J., Guaza, C., A cannabinoid agonist interferes with the progression of a chronic model of multiple sclerosis by downregulating adhesion molecules. Mol. Cell Neurosci. 40 (2009), 258–266.
85. Miller, D.H., Chard, D.T., Ciccarelli, O., Clinically isolated syndromes. Lancet Neurol. 11 (2012), 157–169.
86. Minagar, A., Current and future therapies for multiple sclerosis. Scientifica, 2013, 2013, 249101.
87. Minagar, A., Maghzi, A.H., McGee, J.C., Alexander, J.S., Emerging roles of endothelial cells in multiple sclerosis pathophysiology and therapy. Neurological Res. 34 (2012), 738–745.
88. Molina-Holgado, F., Lledo, A., Guaza, C., Anandamide suppresses nitric oxide and TNF-alpha responses to Theiler's virus or endotoxin in astrocytes. Neuroreport 8 (1997), 1929–1933.
89. Molina-Holgado, F., Molina-Holgado, E., Guaza, C., Rothwell, N.J., Role of CB1 and CB2 receptors in the inhibitory effects of cannabinoids on lipopolysaccharide-induced nitric oxide release in astrocyte cultures. J. Neurosci. Res. 67 (2002), 829–836.
90. More, S.V., Park, J.Y., Kim, B.W., Kumar, H., Lim, H.W., Kang, S.M., Koppula, S., Yoon, S.H., Choi, D.K., Anti-neuroinflammatory activity of a novel cannabinoid derivative by inhibiting the NF-kappaB signaling pathway in lipopolysaccharide-induced BV-2 microglial cells. J. Pharmacol. Sci. 121 (2013), 119–130.
91. Mowry, E.M., Natural history of multiple sclerosis: early prognostic factors. Neurol. Clin. 29 (2011), 279–292.
92. Moynagh, P.N., TLR signalling and activation of IRFs: revisiting old friends from the NF-kappaB pathway. Trends Immunol. 26 (2005), 469–476.
93. Murumalla, R., Bencharif, K., Gence, L., Bhattacharya, A., Tallet, F., Gonthier, M.P., Petrosino, S., di Marzo, V., Cesari, M., Hoareau, L., Roche, R., Effect of the cannabinoid receptor-1 antagonist SR141716A on human adipocyte inflammatory profile and differentiation. J. Inflamm. (Lond.), 8, 2011, 33.
94. Nishimura, M., Naito, S., Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol. Pharm. Bull. 28 (2005), 886–892.
95. O'Brien, K., Fitzgerald, D., Rostami, A., Gran, B., The TLR7 agonist, imiquimod, increases IFN-beta production and reduces the severity of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 221 (2010), 107–111.
96. O'Brien, K., Fitzgerald, D.C., Naiken, K., Alugupalli, K.R., Rostami, A.M., Gran, B., Role of the innate immune system in autoimmune inflammatory demyelination. Curr. Med. Chem. 15 (2008), 1105–1115.
97. O'Connell, K., Kelly, S.B., Fogarty, E., Duggan, M., Buckley, L., Hutchinson, M., McGuigan, C., Tubridy, N., Economic costs associated with an MS relapse. Multiple Scler. Relat. Disord. 3 (2014), 678–683.
98. Ortega-Gutierrez, S., Molina-Holgado, E., Arevalo-Martin, A., Correa, F., Viso, A., Lopez-Rodriguez, M.L., Di Marzo, V., Guaza, C., Activation of the endocannabinoid system as therapeutic approach in a murine model of multiple sclerosis. FASEB J. 19 (2005), 1338–1340.
99. Palazuelos, J., Davoust, N., Julien, B., Hatterer, E., Aguado, T., Mechoulam, R., Benito, C., Romero, J., Silva, A., Guzman, M., Nataf, S., Galve-Roperh, I., The CB(2) cannabinoid receptor controls myeloid progenitor trafficking: involvement in the pathogenesis of an animal model of multiple sclerosis. J. Biol. Chem. 283 (2008), 13320–13329.
100. Pertwee, R.G., Cannabinoids and multiple sclerosis. Pharmacol. Ther. 95 (2002), 165–174.
101. Popescu, C.D., Multiple sclerosis and pregnancy. Rev. medico-chirurgicala Soc. Medici si Nat. din Iasi 118 (2014), 28–32.
102. Porter, A.C., Felder, C.C., The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol. Ther. 90 (2001), 45–60.
103. Prinz, M., Garbe, F., Schmidt, H., Mildner, A., Gutcher, I., Wolter, K., Piesche, M., Schroers, R., Weiss, E., Kirschning, C.J., Rochford, C.D., Bruck, W., Becher, B., Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J. Clin. Invest. 116 (2006), 456–464.
104. Pryce, G., Ahmed, Z., Hankey, D.J., Jackson, S.J., Croxford, J.L., Pocock, J.M., Ledent, C., Petzold, A., Thompson, A.J., Giovannoni, G., Cuzner, M.L., Baker, D., Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126 (2003), 2191–2202.
105. Pryce, G., Baker, D., Control of spasticity in a multiple sclerosis model is mediated by CB1, not CB2, cannabinoid receptors. Br. J. Pharmacol. 150 (2007), 519–525.
106. Puffenbarger, R.A., Boothe, A.C., Cabral, G.A., Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29 (2000), 58–69.
107. Rahimi, A., Faizi, M., Talebi, F., Noorbakhsh, F., Kahrizi, F., Naderi, N., Interaction between the protective effects of cannabidiol and palmitoylethanolamide in experimental model of multiple sclerosis in C57BL/6 mice. Neuroscience 290 (2015), 279–287.
108. Rekand, T., THC: CBD spray and MS spasticity symptoms: data from latest studies. Eur. Neurol. 71:Suppl. 1 (2014), 4–9.
109. Reynolds, J.M., Pappu, B.P., Peng, J., Martinez, G.J., Zhang, Y., Chung, Y., Ma, L., Yang, X.O., Nurieva, R.I., Tian, Q., Dong, C., Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity 32 (2010), 692–702.
110. Ribeiro, R., Wen, J., Li, S., Zhang, Y., Involvement of ERK1/2, cPLA2 and NF-kappaB in microglia suppression by cannabinoid receptor agonists and antagonists. Prostagl. Other Lipid Mediat. 100–101 (2013), 1–14.
111. Richard, K.L., Filali, M., Prefontaine, P., Rivest, S., Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J. Neurosci. Official J. Soc. Neurosci. 28 (2008), 5784–5793.
112. Rock, F.L., Hardiman, G., Timans, J.C., Kastelein, R.A., Bazan, J.F., A family of human receptors structurally related to drosophila toll. Proc. Natl. Acad. Sci. U. S. A. 95 (1998), 588–593.
113. Rossi, S., Furlan, R., De Chiara, V., Muzio, L., Musella, A., Motta, C., Studer, V., Cavasinni, F., Bernardi, G., Martino, G., Cravatt, B.F., Lutz, B., Maccarrone, M., Centonze, D., Cannabinoid CB1 receptors regulate neuronal TNF-alpha effects in experimental autoimmune encephalomyelitis. Brain Behav. Immun. 25 (2011), 1242–1248.
114. Sanchez Lopez, A.J., Roman-Vega, L., Ramil Tojeiro, E., Giuffrida, A., Garcia-Merino, A., Regulation of cannabinoid receptor gene expression and endocannabinoid levels in lymphocyte subsets by interferon-beta: a longitudinal study in multiple sclerosis patients. Clin. Exp. Immunol. 179 (2015), 119–127.
115. Serpell, M.G., Notcutt, W., Collin, C., Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J. Neurol. 260:1 (2013), 285–295.
116. Shao, B.Z., Wei, W., Ke, P., Xu, Z.Q., Zhou, J.X., Liu, C., Activating cannabinoid receptor 2 alleviates pathogenesis of experimental autoimmune encephalomyelitis via activation of autophagy and inhibiting NLRP3 inflammasome. CNS Neurosci. Ther. 20 (2014), 1021–1028.
117. Stasiolek, M., Bayas, A., Kruse, N., Wieczarkowiecz, A., Toyka, K.V., Gold, R., Selmaj, K., Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis. Brain 129 (2006), 1293–1305.
118. Szafran, B., Borazjani, A., Lee, J.H., Ross, M.K., Kaplan, B.L., Lipopolysaccharide suppresses carboxylesterase 2g activity and 2-arachidonoylglycerol hydrolysis: a possible mechanism to regulate inflammation. Prostagl. Other Lipid Mediat. 121:Pt B (2015), 199–206.
119. Takeda, S., Delta(9)-tetrahydrocannabinol targeting estrogen receptor signaling: the possible mechanism of action coupled with endocrine disruption. Biol. Pharm. Bull. 37 (2014), 1435–1438.
120. Thoma-Uszynski, S., Stenger, S., Takeuchi, O., Ochoa, M.T., Engele, M., Sieling, P.A., Barnes, P.F., Rollinghoff, M., Bolcskei, P.L., Wagner, M., Akira, S., Norgard, M.V., Belisle, J.T., Godowski, P.J., Bloom, B.R., Modlin, R.L., Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291 (2001), 1544–1547.
121. Thompson, A.J., Polman, C.H., Miller, D.H., McDonald, W.I., Brochet, B., Filippi, M.M.X., De Sa, J., Primary progressive multiple sclerosis. Brain 120:Pt 6 (1997), 1085–1096.
122. Touil, T., Fitzgerald, D., Zhang, G.X., Rostami, A., Gran, B., Cutting edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. J. Immunol. 177 (2006), 7505–7509.
123. Trapp, B.D., Nave, K.A., Multiple sclerosis: an immune or neurodegenerative disorder?. Annu. Rev. Neurosci. 31 (2008), 247–269.
124. Van Sickle, M.D., Duncan, M., Kingsley, P.J., Mouihate, A., Urbani, P., Mackie, K., Stella, N., Makriyannis, A., Piomelli, D., Davison, J.S., Marnett, L.J., Di Marzo, V., Pittman, Q.J., Patel, K.D., Sharkey, K.A., Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310 (2005), 329–332.
125. Vosoughi, R., Freedman, M.S., Therapy of MS. Clin. Neurol. Neurosurg. 112 (2010), 365–385.
126. Walter, L., Stella, N., Cannabinoids and neuroinflammation. Br. J. Pharmacol. 141 (2004), 775–785.
127. Weiner, H.L., A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J. Neurol. 255:Suppl. 1 (2008), 3–11.
128. Wilhelmsen, K., Khakpour, S., Tran, A., Sheehan, K., Schumacher, M., Xu, F., Hellman, J., The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells. J. Biol. Chem. 289 (2014), 13079–13100.
129. Xu, J.J., Diaz, P., Bie, B., Astruc-Diaz, F., Wu, J., Yang, H., Brown, D.L., Naguib, M., Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy. Neuroscience 260 (2014), 185–194.
130. Zajicek, J., Fox, P., Sanders, H., Wright, D., Vickery, J., Nunn, A., Thompson, A., Group, U.M.R., Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362 (2003), 1517–1526.
131. Zhang, H., Hilton, D.A., Hanemann, C.O., Zajicek, J., Cannabinoid receptor and N-acyl phosphatidylethanolamine phospholipase D–evidence for altered expression in multiple sclerosis. Brain Pathol. 21 (2011), 544–557.
132. Zhu, W., Friedman, H., Klein, T.W., Delta9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1. J. Pharmacol. Exp. Ther. 286 (1998), 1103–1109.