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Current Bioactive Compounds

Editor-in-Chief

ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Review Article

Cannabis sativa L. Constituents and Their Role in Neuroinflammation

Author(s): Vittoria Borgonetti, Paolo Governa*, Monica Montopoli and Marco Biagi

Volume 15, Issue 2, 2019

Page: [147 - 158] Pages: 12

DOI: 10.2174/1573407214666180703130525

Price: $65

Open Access Journals Promotions 2
Abstract

The interest in Cannabis sativa L. phytocomplex as a medicinal tool is a recently-emerging topic. Neurodegenerative diseases represent a promising field of application for cannabis and its preparations, as most of this pathologic conditions relies on an inflammatory etiology. Several cannabis constituents display anti-inflammatory effects targeting multiple pathways. In this review, a comprehensive overview of the available literature on C. sativa constituents activities in neuroinflammation is given. On the basis that the anti-inflammatory activity of cannabis is not attributable to only a single constituent, we discuss the possible advantages of administering the whole phytocomplex in order to fully exploit the “entourage effect” in neuroinflammatory-related conditions.

Keywords: Cannabis sativa L., neuroinflammation, cannabinoids, caryophyllene, apigenin, microglia, endocannabinoid system, phytotherapy.

Graphical Abstract
[1]
Gertsch, J. Botanical drugs, synergy, and network pharmacology: forth and back to intelligent mixtures. Planta Med., 2011, 77(11), 1086-1098.
[2]
Andre, C.M.; Hausman, J-F.; Guerriero, G. Cannabis sativa: The Plant of the Thousand and One Molecules. Front. Plant Sci., 2016, 7, 19.
[3]
Kendall, D.A.; Yudowski, G.A. Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Front. Cell. Neurosci., 2017, 10, 294.
[4]
Ligresti, A.; De Petrocellis, L.; Di Marzo, V. From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology. Physiol. Rev., 2016, 96(4), 1593-1659.
[5]
Hazekamp, A.; Fischedick, J.T. Cannabis - from cultivar to chemovar. Drug Test. Anal., 2012, 4(7-8), 660-667.
[6]
Hazekamp, A.; Tejkalová, K.; Papadimitriou, S. Cannabis: From Cultivar to Chemovar II-A Metabolomics Approach to Cannabis Classification. Cannabis Cannabinoid Res., 2016, 1, 202-215.
[7]
McPartland, J.M.; Russo, E.B. Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? J. Cannabis Ther., 2001, 1, 103-132.
[8]
Elsohly, M.A.; Slade, D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci., 2005, 78(5), 539-548.
[9]
Mediavilla, V.; Steinemann, S. Essential Oil of Cannabis Sativa L. Strains. J. Int. Hemp Assoc., 1997, 1997, 80-82.
[10]
Ross, S.A.; ElSohly, M.A. The volatile oil composition of fresh and air-dried buds of Cannabis sativa. J. Nat. Prod., 1996, 59(1), 49-51.
[11]
Di Paola, E.; Tsioutsiou, E.E.; Miraldi, E. Preparazioni Innovative a Base Di Cannabis Non Psicotropa. Piante Med., 2016, 15, 82.
[12]
Bahi, A.; Al Mansouri, S.; Al Memari, E.; Al Ameri, M.; Nurulain, S.M.; Ojha, S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol. Behav., 2014, 135, 119-124.
[13]
Carlini, E.A.; Karniol, I.G.; Renault, P.F.; Schuster, C.R. Effects of marihuana in laboratory animals and in man. Br. J. Pharmacol., 1974, 50(2), 299-309.
[14]
Leocani, L.; Nuara, A.; Houdayer, E.; Schiavetti, I.; Del Carro, U.; Amadio, S.; Straffi, L.; Rossi, P.; Martinelli, V.; Vila, C.; Sormani, M.P.; Comi, G. Sativex(®) and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis. J. Neurol., 2015, 262(11), 2520-2527.
[15]
Vermersch, P.; Trojano, M. Tetrahydrocannabinol:Cannabidiol Oromucosal Spray for Multiple Sclerosis-Related Resistant Spasticity in Daily Practice. Eur. Neurol., 2016, 76(5-6), 216-226.
[16]
Sastre-Garriga, J.; Vila, C.; Clissold, S.; Montalban, X. THC and CBD oromucosal spray (Sativex®) in the management of spasticity associated with multiple sclerosis. Expert Rev. Neurother., 2011, 11(5), 627-637.
[17]
Parmar, J.R.; Forrest, B.D.; Freeman, R.A. Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis-based pharmaceutical drugs. Res. Social Adm. Pharm., 2016, 12(4), 638-654.
[18]
Graham, E.S.; Angel, C.E.; Schwarcz, L.E.; Dunbar, P.R.; Glass, M. Detailed characterisation of CB2 receptor protein expression in peripheral blood immune cells from healthy human volunteers using flow cytometry. Int. J. Immunopathol. Pharmacol., 2010, 23(1), 25-34.
[19]
Koudriavtseva, T.; Mainero, C. Neuroinflammation, neurodegeneration and regeneration in multiple sclerosis: intercorrelated manifestations of the immune response. Neural Regen. Res., 2016, 11(11), 1727-1730.
[20]
Naegele, M.; Martin, R. The good and the bad of neuroinflammation in multiple sclerosis. Handb. Clin. Neurol., 2014, 122, 59-87.
[21]
Moll, N.M.; Rietsch, A.M.; Thomas, S.; Ransohoff, A.J.; Lee, J-C.; Fox, R.; Chang, A.; Ransohoff, R.M.; Fisher, E. Multiple sclerosis normal-appearing white matter: pathology-imaging correlations. Ann. Neurol., 2011, 70(5), 764-773.
[22]
Mecha, M.; Carrillo-Salinas, F.J.; Feliú, A.; Mestre, L.; Guaza, C. Microglia activation states and cannabinoid system: Therapeutic implications. Pharmacol. Ther., 2016, 166, 40-55.
[23]
Gowran, A.; Noonan, J.; Campbell, V.A. The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci. Ther., 2011, 17(6), 637-644.
[24]
Di Marzo, V.; Melck, D.; Bisogno, T.; De Petrocellis, L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci., 1998, 21(12), 521-528.
[25]
O’Callaghan, J.P.; Sriram, K.; Miller, D.B. Defining “neuroinflammation”. Ann. N. Y. Acad. Sci., 2008, 1139, 318-330.
[26]
Mackie, K.; Lai, Y.; Westenbroek, R.; Mitchell, R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J. Neurosci., 1995, 15(10), 6552-6561.
[27]
Maresz, K.; Pryce, G.; Ponomarev, E.D.; Marsicano, G.; Croxford, J.L.; Shriver, L.P.; Ledent, C.; Cheng, X.; Carrier, E.J.; Mann, M.K.; Giovannoni, G.; Pertwee, R.G.; Yamamura, T.; Buckley, N.E.; Hillard, C.J.; Lutz, B.; Baker, D.; Dittel, B.N. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat. Med., 2007, 13(4), 492-497.
[28]
Stella, N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia, 2010, 58(9), 1017-1030.
[29]
Navarrete, M.; Díez, A.; Araque, A. Astrocytes in Endocannabinoid Signalling. Philos. Trans. R. Soc. B Biol. Sci., 2014, 369, 20130599.
[30]
Navarrete, M.; Araque, A. Endocannabinoids mediate neuron-astrocyte communication. Neuron, 2008, 57(6), 883-893.
[31]
Coiret, G.; Ster, J.; Grewe, B.; Wendling, F.; Helmchen, F.; Gerber, U.; Benquet, P. Neuron to astrocyte communication via cannabinoid receptors is necessary for sustained epileptiform activity in rat hippocampus. PLoS One, 2012, 7(5), e37320.
[32]
Fernández-Trapero, M.; Espejo-Porras, F.; Rodríguez-Cueto, C.; Coates, J.R.; Pérez-Díaz, C.; de Lago, E.; Fernández-Ruiz, J. Upregulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis. Dis. Model. Mech., 2017, 10(5), 551-558.
[33]
Fernández-Ruiz, J.; Romero, J.; Velasco, G.; Tolón, R.M.; Ramos, J.A.; Guzmán, M. Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol. Sci., 2007, 28(1), 39-45.
[34]
Gong, J-P.; Onaivi, E.S.; Ishiguro, H.; Liu, Q-R.; Tagliaferro, P.A.; Brusco, A.; Uhl, G.R. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res., 2006, 1071(1), 10-23.
[35]
Onaivi, E.S.; Ishiguro, H.; Gong, J-P.; Patel, S.; Perchuk, A.; Meozzi, P.A.; Myers, L.; Mora, Z.; Tagliaferro, P.; Gardner, E.; Brusco, A.; Akinshola, B.E.; Liu, Q-R.; Hope, B.; Iwasaki, S.; Arinami, T.; Teasenfitz, L.; Uhl, G.R. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann. N. Y. Acad. Sci., 2006, 1074, 514-536.
[36]
Cassano, T.; Calcagnini, S.; Pace, L.; De Marco, F.; Romano, A.; Gaetani, S. Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target. Front. Neurosci., 2017, 11, 30.
[37]
Luongo, L.; Maione, S.; Di Marzo, V. Endocannabinoids and neuropathic pain: focus on neuron-glia and endocannabinoid-neurotrophin interactions. Eur. J. Neurosci., 2014, 39(3), 401-408.
[38]
Di Marzo, V.; Stella, N.; Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat. Rev. Neurosci., 2015, 16(1), 30-42.
[39]
Rodríguez-Cueto, C.; Benito, C.; Fernández-Ruiz, J.; Romero, J.; Hernández-Gálvez, M.; Gómez-Ruiz, M. Changes in CB(1) and CB(2) receptors in the post-mortem cerebellum of humans affected by spinocerebellar ataxias. Br. J. Pharmacol., 2014, 171(6), 1472-1489.
[40]
Beltramo, M.; Bernardini, N.; Bertorelli, R.; Campanella, M.; Nicolussi, E.; Fredduzzi, S.; Reggiani, A. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur. J. Neurosci., 2006, 23(6), 1530-1538.
[41]
Racz, I.; Nadal, X.; Alferink, J.; Baños, J.E.; Rehnelt, J.; Martín, M.; Pintado, B.; Gutierrez-Adan, A.; Sanguino, E.; Manzanares, J.; Zimmer, A.; Maldonado, R. Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain. J. Neurosci., 2008, 28(46), 12125-12135.
[42]
Luongo, L.; Palazzo, E.; Tambaro, S.; Giordano, C.; Gatta, L.; Scafuro, M.A.; Rossi, F.S.; Lazzari, P.; Pani, L.; de Novellis, V.; Malcangio, M.; Maione, S. 1-(2′,4′-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice. Neurobiol. Dis., 2010, 37(1), 177-185.
[43]
Kauppinen, A.; Nevalainen, T.; Hytti, M.; Salminen, A.; Kaarniranta, K.; Parkkari, T. CB2 Receptor as a Potential Target in Age-Related Diseases. J. Biochem. Pharmacol. Res., 2014, 2, 33-43.
[44]
Alvarez-Buylla, A.; Garcia-Verdugo, J.M. Neurogenesis in adult subventricular zone. J. Neurosci., 2002, 22(3), 629-634.
[45]
Compagnucci, C.; Di Siena, S.; Bustamante, M.B.; Di Giacomo, D.; Di Tommaso, M.; Maccarrone, M.; Grimaldi, P.; Sette, C. Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells. PLoS One, 2013, 8(1), e54271.
[46]
Planells-Cases, R.; Garcìa-Sanz, N.; Morenilla-Palao, C.; Ferrer-Montiel, A. Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia. Pflugers Arch., 2005, 451(1), 151-159.
[47]
Mahmud, A.; Santha, P.; Paule, C.C.; Nagy, I. Cannabinoid 1 receptor activation inhibits transient receptor potential vanilloid type 1 receptor-mediated cationic influx into rat cultured primary sensory neurons. Neuroscience, 2009, 162(4), 1202-1211.
[48]
Akopian, A.N.; Ruparel, N.B.; Patwardhan, A.; Hargreaves, K.M. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J. Neurosci., 2008, 28(5), 1064-1075.
[49]
Bouaboula, M.; Hilairet, S.; Marchand, J.; Fajas, L.; Le Fur, G.; Casellas, P. Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur. J. Pharmacol., 2005, 517(3), 174-181.
[50]
Guida, F.; Luongo, L.; Boccella, S.; Giordano, M.E.; Romano, R.; Bellini, G.; Manzo, I.; Furiano, A.; Rizzo, A.; Imperatore, R.; Iannotti, F.A.; D’Aniello, E.; Piscitelli, F.; Sca Rossi, F.; Cristino, L.; Di Marzo, V.; de Novellis, V.; Maione, S. Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor. Sci. Rep., 2017, 7(1), 375.
[51]
Gaoni, Y.; Mechoulam, R. The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish. J. Am. Chem. Soc., 1971, 93(1), 217-224.
[52]
Russo, E.B. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br. J. Pharmacol., 2011, 163(7), 1344-1364.
[53]
Turner, S.E.; Williams, C.M.; Iversen, L.; Whalley, B.J. Molecular Pharmacology of Phytocannabinoids. Prog. Chem. Org. Nat. Prod., 2017, 103, 61-101.
[54]
Pertwee, R.G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol., 2008, 153(2), 199-215.
[55]
Cabral, G.A.; Rogers, T.J.; Lichtman, A.H. Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function. J. Neuroimmune Pharmacol., 2015, 10(2), 193-203.
[56]
Rieder, S.A.; Chauhan, A.; Singh, U.; Nagarkatti, M.; Nagarkatti, P. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology, 2010, 215(8), 598-605.
[57]
Klein, T.W.; Cabral, G.A. Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. J. Neuroimmune Pharmacol., 2006, 1(1), 50-64.
[58]
Burstein, S.H.; Zurier, R.B. Cannabinoids, endocannabinoids, and related analogs in inflammation. AAPS J., 2009, 11(1), 109-119.
[59]
Jeon, Y.J.; Yang, K.H.; Pulaski, J.T.; Kaminski, N.E. Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor- kappa B/Rel activation. Mol. Pharmacol., 1996, 50(2), 334-341.
[60]
Puffenbarger, R.A.; Boothe, A.C.; Cabral, G.A. Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia, 2000, 29(1), 58-69.
[61]
Fishbein-Kaminietsky, M.; Gafni, M.; Sarne, Y. Ultralow doses of cannabinoid drugs protect the mouse brain from inflammation-induced cognitive damage. J. Neurosci. Res., 2014, 92(12), 1669-1677.
[62]
Yin, J.C.; Tully, T. CREB and the formation of long-term memory. Curr. Opin. Neurobiol., 1996, 6(2), 264-268.
[63]
Samuels, I.S.; Saitta, S.C.; Landreth, G.E. MAP’ing CNS development and cognition: an ERKsome process. Neuron, 2009, 61(2), 160-167.
[64]
Lipsky, R.H.; Marini, A.M. Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann. N. Y. Acad. Sci., 2007, 1122, 130-143.
[65]
Landreth, G.; Jiang, Q.; Mandrekar, S.; Heneka, M. PPARgamma agonists as therapeutics for the treatment of Alzheimer’s disease. Neurotherapeutics, 2008, 5(3), 481-489.
[66]
Marchalant, Y.; Cerbai, F.; Brothers, H.M.; Wenk, G.L. Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. Neurobiol. Aging, 2008, 29(12), 1894-1901.
[67]
Gaston, T.E.; Friedman, D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav., 2017, 70(Pt B), 313-318.
[68]
Chesher, G.B.; Jackson, D.M. The effect of withdrawal from cannabis on pentylenetetrazol convulsive threshold in mice. Psychopharmacology (Berl.), 1974, 40(2), 129-135.
[69]
Chesher, G.B.; Jackson, D.M.; Malor, R.M. Interaction of delta9-tetrahydrocannabinol and cannabidiol with phenobarbitone in protecting mice from electrically induced convulsions. J. Pharm. Pharmacol., 1975, 27(8), 608-609.
[70]
Ten Ham, M.; Loskota, W.J.; Lomax, P. Acute and chronic effects of beta9-tetrahydrocannabinol on seizures in the gerbil. Eur. J. Pharmacol., 1975, 31(1), 148-152.
[71]
Oviedo, A.; Glowa, J.; Herkenham, M. Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study. Brain Res., 1993, 616(1-2), 293-302.
[72]
Rosenberg, E.C.; Tsien, R.W.; Whalley, B.J.; Devinsky, O. Cannabinoids and Epilepsy. Neurotherapeutics, 2015, 12(4), 747-768.
[73]
Valdeolivas, S.; Satta, V.; Pertwee, R.G.; Fernández-Ruiz, J.; Sagredo, O. Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: role of CB1 and CB2 receptors. ACS Chem. Neurosci., 2012, 3(5), 400-406.
[74]
Janefjord, E.; Mååg, J.L.; Harvey, B.S.; Smid, S.D. Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell. Mol. Neurobiol., 2014, 34(1), 31-42.
[75]
McHugh, D.; Roskowski, D.; Xie, S.; Bradshaw, H.B.Δ. (9)-THC and N-arachidonoyl glycine regulate BV-2 microglial morphology and cytokine release plasticity: implications for signaling at GPR18. Front. Pharmacol., 2014, 4, 162.
[76]
Parrott, A.C.; Milani, R.M.; Gouzoulis-Mayfrank, E.; Daumann, J. Cannabis and Ecstasy/MDMA (3,4-methylenedioxymethamphetamine): an analysis of their neuropsychobiological interactions in recreational users. J. Neural Transm. (Vienna), 2007, 114(8), 959-968.
[77]
Touriño, C.; Zimmer, A.; Valverde, O. THC Prevents MDMA Neurotoxicity in Mice. PLoS One, 2010, 5(2), e9143.
[78]
Soneji, N.D.; Paule, C.C.; Mlynarczyk, M.; Nagy, I. Effects of cannabinoids on capsaicin receptor activity following exposure of primary sensory neurons to inflammatory mediators. Life Sci., 2010, 87(5-6), 162-168.
[79]
Lastres-Becker, I.; Molina-Holgado, F.; Ramos, J.A.; Mechoulam, R.; Fernández-Ruiz, J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol. Dis., 2005, 19(1-2), 96-107.
[80]
Suliman, N.A.; Taib, C.N.M.; Moklas, M.A.M.; Basir, R. Delta-9-Tetrahydrocannabinol (∆ 9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats E1 E2. Neurotox. Res., 2018, 33(2), 402-411.
[81]
Nagarkatti, P.; Pandey, R.; Rieder, S.A.; Hegde, V.L.; Nagarkatti, M. Cannabinoids as novel anti-inflammatory drugs. Future Med. Chem., 2009, 1(7), 1333-1349.
[82]
Bindukumar, B.; Mahajan, S.D.; Reynolds, J.L.; Hu, Z.; Sykes, D.E.; Aalinkeel, R.; Schwartz, S.A. Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res., 2008, 1191, 1-11.
[83]
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., 2010, 285(3), 1616-1626.
[84]
Kaplan, B.L.F.; Springs, A.E.B.; Kaminski, N.E. The profile of immune modulation by cannabidiol (CBD) involves deregulation of nuclear factor of activated T cells (NFAT). Biochem. Pharmacol., 2008, 76(6), 726-737.
[85]
Lee, C.Y.; Wey, S.P.; Liao, M.H.; Hsu, W.L.; Wu, H.Y.; Jan, T.R. A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells. Int. Immunopharmacol., 2008, 8(5), 732-740.
[86]
Liu, D.Z.; Hu, C.M.; Huang, C.H.; Wey, S.P.; Jan, T.R. Cannabidiol attenuates delayed-type hypersensitivity reactions via suppressing T-cell and macrophage reactivity. Acta Pharmacol. Sin., 2010, 31(12), 1611-1617.
[87]
Hunter, S.A.; Burstein, S.H. Receptor mediation in cannabinoid stimulated arachidonic acid mobilization and anandamide synthesis. Life Sci., 1997, 60(18), 1563-1573.
[88]
Solinas, M.; Massi, P.; Cinquina, V.; Valenti, M.; Bolognini, D.; Gariboldi, M.; Monti, E.; Rubino, T.; Parolaro, D. Cannabidiol, a non-psychoactive cannabinoid compound, inhibits proliferation and invasion in U87-MG and T98G glioma cells through a multitarget effect. PLoS One, 2013, 8(10), e76918.
[89]
Mecha, M.; Feliú, A.; Iñigo, 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., 2013, 59, 141-150.
[90]
Martín-Moreno, A.M.; Reigada, D.; Ramírez, B.G.; Mechoulam, R.; Innamorato, N.; Cuadrado, A.; de Ceballos, M.L. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease. Mol. Pharmacol., 2011, 79(6), 964-973.
[91]
Hassan, S.; Eldeeb, K.; Millns, P.J.; Bennett, A.J.; Alexander, S.P.H.; Kendall, D.A. Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation. Br. J. Pharmacol., 2014, 171(9), 2426-2439.
[92]
Kozela, E.; Juknat, A.; Vogel, Z. Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid. Int. J. Mol. Sci., 2017, 18(8), E1669.
[93]
Fernández-Ruiz, J.; Sagredo, O.; Pazos, M.R.; García, C.; Pertwee, R.; Mechoulam, R.; Martínez-Orgado, J. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br. J. Clin. Pharmacol., 2013, 75(2), 323-333.
[94]
Mori, M.A.; Meyer, E.; Soares, L.M.; Milani, H.; Guimarães, F.S.; de Oliveira, R.M.W. Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2017, 75, 94-105.
[95]
Esposito, G.; Scuderi, C.; Valenza, M.; Togna, G.I.; Latina, V.; De Filippis, D.; Cipriano, M.; Carratù, M.R.; Iuvone, T.; Steardo, L. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One, 2011, 6(12), e28668.
[96]
Esposito, G.; De Filippis, D.; Maiuri, M.C.; De Stefano, D.; Carnuccio, R.; Iuvone, T. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement. Neurosci. Lett., 2006, 399(1-2), 91-95.
[97]
Janefjord, E.; Mååg, J.L.V.; Harvey, B.S.; Smid, S.D. Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cell. Mol. Neurobiol., 2014, 34(1), 31-42.
[98]
Dirikoc, S.; Priola, S.A.; Marella, M.; Zsürger, N.; Chabry, J. Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity. J. Neurosci., 2007, 27(36), 9537-9544.
[99]
Shinjyo, N.; Di Marzo, V. The effect of cannabichromene on adult neural stem/progenitor cells. Neurochem. Int., 2013, 63(5), 432-437.
[100]
Romano, B.; Borrelli, F.; Fasolino, I.; Capasso, R.; Piscitelli, F.; Cascio, M.; Pertwee, R.; Coppola, D.; Vassallo, L.; Orlando, P.; Di Marzo, V.; Izzo, A. The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis. Br. J. Pharmacol., 2013, 169(1), 213-229.
[101]
Borrelli, F.; Fasolino, I.; Romano, B.; Capasso, R.; Maiello, F.; Coppola, D.; Orlando, P.; Battista, G.; Pagano, E.; Di Marzo, V.; Izzo, A.A. Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochem. Pharmacol., 2013, 85(9), 1306-1316.
[102]
Granja, A.G.; Carrillo-Salinas, F.; Pagani, A.; Gómez-Cañas, 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.; Muñoz, E. A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis. J. Neuroimmune Pharmacol., 2012, 7(4), 1002-1016.
[103]
Carrillo-Salinas, F.J.; Navarrete, C.; Mecha, M.; Feliú, A.; Collado, J.A.; Cantarero, I.; Bellido, M.L.; Muñoz, E.; Guaza, C. A cannabigerol derivative suppresses immune responses and protects mice from experimental autoimmune encephalomyelitis. PLoS One, 2014, 9(4), e94733.
[104]
De Petrocellis, L.; Vellani, V.; Schiano-Moriello, A.; Marini, P.; Magherini, P.C.; Orlando, P.; Di Marzo, V. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J. Pharmacol. Exp. Ther., 2008, 325(3), 1007-1015.
[105]
Evans, F.J. Cannabinoids: The Separation of Central from Peripheral Effects on a Structural Basis. Planta Med., 1991, 57, S60-S67.
[106]
Brenneisen, R. Chemistry and Analysis of Phytocannabinoids and Other Cannabis Constituents.Marijuana and the Cannabinoid; Springer Science Business Media, 2007, pp. 17-49.
[107]
Fischedick, J.T.; Hazekamp, A.; Erkelens, T.; Choi, Y.H.; Verpoorte, R. Metabolic fingerprinting of Cannabis sativa L., cannabinoids and terpenoids for chemotaxonomic and drug standardization purposes. Phytochemistry, 2010, 71(17-18), 2058-2073.
[108]
Rı, C.; Gutie, A. Chemical Characterization of Pitch Deposits Produced in the Manufacturing of High-Quality Paper Pulps from Hemp Fibers., 2005, 96, 1445-1450.
[109]
Souza, M.T.; Almeida, J.R.; Araujo, A.A.; Duarte, M.C.; Gelain, D.P.; Moreira, J.C.; dos Santos, M.R.; Quintans-Júnior, L.J. Structure-activity relationship of terpenes with anti-inflammatory profile - a systematic review. Basic Clin. Pharmacol. Toxicol., 2014, 115(3), 244-256.
[110]
Leyva-López, N.; Nair, V.; Bang, W.Y.; Cisneros-Zevallos, L.; Heredia, J.B. Protective role of terpenes and polyphenols from three species of Oregano (Lippia graveolens, Lippia palmeri and Hedeoma patens) on the suppression of lipopolysaccharide-induced inflammation in RAW 264.7 macrophage cells. J. Ethnopharmacol., 2016, 187, 302-312.
[111]
Zeng, K.W.; Wang, S.; Dong, X.; Jiang, Y.; Tu, P.F. Sesquiterpene dimer (DSF-52) from Artemisia argyi inhibits microglia-mediated neuroinflammation via suppression of NF-κB, JNK/p38 MAPKs and Jak2/Stat3 signaling pathways. Phytomedicine, 2014, 21(3), 298-306.
[112]
Moon, D.O.; Choi, Y.H.; Kim, N.D.; Park, Y.M.; Kim, G.Y. Anti-inflammatory effects of β-lapachone in lipopolysaccharide-stimulated BV2 microglia. Int. Immunopharmacol., 2007, 7(4), 506-514.
[113]
Yoon, W.J.; Lee, N.H.; Hyun, C.G. Limonene suppresses lipopolysaccharide-induced production of nitric oxide, prostaglandin E2, and pro-inflammatory cytokines in RAW 264.7 macrophages. J. Oleo Sci., 2010, 59(8), 415-421.
[114]
Peana, A.T.; D’Aquila, P.S.; Panin, F.; Serra, G.; Pippia, P.; Moretti, M.D. Anti-inflammatory activity of linalool and linalyl acetate constituents of essential oils. Phytomedicine, 2002, 9(8), 721-726.
[115]
Choi, I.Y.; Lim, J.H.; Hwang, S.; Lee, J.C.; Cho, G.S.; Kim, W.K. Anti-ischemic and anti-inflammatory activity of (S)-cis-verbenol. Free Radic. Res., 2010, 44(5), 541-551.
[116]
Gertsch, J.; Leonti, M.; Raduner, S.; Racz, I.; Chen, J-Z.; Xie, X-Q.; Altmann, K-H.; Karsak, M.; Zimmer, A. Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. USA, 2008, 105(26), 9099-9104.
[117]
Guo, K.; Mou, X.; Huang, J.; Xiong, N.; Li, H. Trans-caryophyllene suppresses hypoxia-induced neuroinflammatory responses by inhibiting NF-κB activation in microglia. J. Mol. Neurosci., 2014, 54(1), 41-48.
[118]
Ojha, S.; Javed, H.; Azimullah, S.; Haque, M.E. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Mol. Cell. Biochem., 2016, 418(1-2), 59-70.
[119]
Fidyt, K.; Fiedorowicz, A.; Strządała, L.; Szumny, A. β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties. Cancer Med., 2016, 5(10), 3007-3017.
[120]
Flores-Sanchez, I.J.; Verpoorte, R. Secondary Metabolism in Cannabis. Phytochem. Rev., 2008, 7, 615-639.
[121]
George, V.C.; Vijesh, V.V.; Amararathna, D.I.M.; Lakshmi, C.A.; Anbarasu, K.; Kumar, D.R.N.; Ethiraj, K.R.; Kumar, R.A.; Rupasinghe, H.P.V. Mechanism of Action of Flavonoids in Prevention of Inflammation- Associated Skin Cancer. Curr. Med. Chem., 2016, 23(32), 3697-3716.
[122]
Spencer, J.P.E. Beyond antioxidants: the cellular and molecular interactions of flavonoids and how these underpin their actions on the brain. Proc. Nutr. Soc., 2010, 69(2), 244-260.
[123]
Yuan, L.; Wu, Y.; Ren, X.; Liu, Q.; Wang, J.; Liu, X. Isoorientin attenuates lipopolysaccharide-induced pro-inflammatory responses through down-regulation of ROS-related MAPK/NF-κB signaling pathway in BV-2 microglia. Mol. Cell. Biochem., 2014, 386(1-2), 153-165.
[124]
Leonardo, C.C.; Doré, S. Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins. Nutr. Neurosci., 2011, 14(5), 226-236.
[125]
Sun, G.Y.; Chen, Z.; Jasmer, K.J.; Chuang, D.Y.; Gu, Z.; Hannink, M.; Simonyi, A. Quercetin Attenuates Inflammatory Responses in BV-2 Microglial Cells: Role of MAPKs on the Nrf2 Pathway and Induction of Heme Oxygenase-1. PLoS One, 2015, 10(10), e0141509.
[126]
Zhou, L.T.; Wang, K.J.; Li, L.; Li, H.; Geng, M. Pinocembrin inhibits lipopolysaccharide-induced inflammatory mediators production in BV2 microglial cells through suppression of PI3K/Akt/NF-κB pathway. Eur. J. Pharmacol., 2015, 761, 211-216.
[127]
Thilakarathna, S.H.; Rupasinghe, H.P.V. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients, 2013, 5(9), 3367-3387.
[128]
Liao, Y.; Shen, W.; Kong, G.; Lv, H.; Tao, W.; Bo, P. Apigenin induces the apoptosis and regulates MAPK signaling pathways in mouse macrophage ANA-1 cells. PLoS One, 2014, 9(3), e92007.
[129]
Kwon, Y. Luteolin as a potential preventive and therapeutic candidate for Alzheimer’s disease. Exp. Gerontol., 2017, 95, 39-43.
[130]
Jang, S.; Kelley, K.W.; Johnson, R.W. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc. Natl. Acad. Sci. USA, 2008, 105(21), 7534-7539.
[131]
Zhu, L.; Bi, W.; Lu, D.; Zhang, C.; Shu, X.; Lu, D. Luteolin inhibits SH-SY5Y cell apoptosis through suppression of the nuclear transcription factor-κB, mitogen-activated protein kinase and protein kinase B pathways in lipopolysaccharide-stimulated cocultured BV2 cells. Exp. Ther. Med., 2014, 7(5), 1065-1070.
[132]
Patil, S.P.; Jain, P.D.; Sancheti, J.S.; Ghumatkar, P.J.; Tambe, R.; Sathaye, S. Neuroprotective and neurotrophic effects of Apigenin and Luteolin in MPTP induced parkinsonism in mice. Neuropharmacology, 2014, 86, 192-202.
[133]
Hougee, S.; Sanders, A.; Faber, J.; Graus, Y.M.F.; van den Berg, W.B.; Garssen, J.; Smit, H.F.; Hoijer, M.A. Decreased pro-inflammatory cytokine production by LPS-stimulated PBMC upon in vitro incubation with the flavonoids apigenin, luteolin or chrysin, due to selective elimination of monocytes/macrophages. Biochem. Pharmacol., 2005, 69(2), 241-248.
[134]
Costa, S.L.; Silva, V.D.; Dos Santos Souza, C.; Santos, C.C.; Paris, I.; Muñoz, P.; Segura-Aguilar, J. Impact of Plant-Derived Flavonoids on Neurodegenerative Diseases. Neurotox. Res., 2016, 30(1), 41-52.
[135]
García-Mediavilla, V.; Crespo, I.; Collado, P.S.; Esteller, A.; Sánchez-Campos, S.; Tuñón, M.J.; González-Gallego, J. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur. J. Pharmacol., 2007, 557(2-3), 221-229.
[136]
Olszanecki, R.; Gêbska, A.; Kozlovski, V.I.; Gryglewski, R.J. Flavonoids and nitric oxide synthase. J. Physiol. Pharmacol., 2002, 53(4 Pt 1), 571-584.
[137]
Park, S.E.; Sapkota, K.; Kim, S.; Kim, H.; Kim, S.J. Kaempferol acts through mitogen-activated protein kinases and protein kinase B/AKT to elicit protection in a model of neuroinflammation in BV2 microglial cells. Br. J. Pharmacol., 2011, 164(3), 1008-1025.
[138]
Barrett, M.L.; Gordon, D.; Evans, F.J. Isolation from Cannabis sativa L. of cannflavin--a novel inhibitor of prostaglandin production. Biochem. Pharmacol., 1985, 34(11), 2019-2024.
[139]
Werz, O.; Seegers, J.; Schaible, A.M.; Weinigel, C.; Barz, D.; Koeberle, A.; Allegrone, G.; Pollastro, F.; Zampieri, L.; Grassi, G.; Appendino, G. Cannflavins from Hemp Sprouts, a Novel Cannabinoid-Free Hemp Food Product, Target Microsomal Prostaglandin E2 Synthase-1 and 5-Lipoxygenase. PharmaNutrition, 2014, 2, 53-60.

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