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Current Neuropharmacology


ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Review Article

Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer’s Disease

Author(s): Giuseppina Talarico*, Alessandro Trebbastoni, Giuseppe Bruno and Carlo de Lena

Volume 17, Issue 2, 2019

Page: [176 - 183] Pages: 8

DOI: 10.2174/1570159X16666180702144644

Price: $65


The pathogenesis of Alzheimer’s disease (AD) is somewhat complex and has yet to be fully understood. As the effectiveness of the therapy currently available for AD has proved to be limited, the need for new drugs has become increasingly urgent. The modulation of the endogenous cannabinoid system (ECBS) is one of the potential therapeutic approaches that is attracting a growing amount of interest. The ECBS consists of endogenous compounds and receptors. The receptors CB1 and CB2 have already been well characterized: CB1 receptors, which are abundant in the brain, particularly in the hippocampus, basal ganglia and cerebellum, regulate memory function and cognition. It has been suggested that the activation of CB1 receptors reduces intracellular Ca concentrations, inhibits glutamate release and enhances neurotrophin expression and neurogenesis. CB2 receptors are expressed, though to a lesser extent, in the central nervous system, particularly in the microglia and immune system cells involved in the release of cytokines. CB2 receptors have been shown to be upregulated in neuritic plaque-associated microglia in the hippocampus and entorhinal cortex of patients, which suggests that these receptors play a role in the inflammatory pathology of AD. The role of the ECBS in AD is supported by cellular and animal models. By contrast, few clinical studies designed to investigate therapies aimed at reducing behaviour disturbances, especially night-time agitation, eating behaviour and aggressiveness, have yielded positive results. In this review, we will describe how the manipulation of the ECBS offers a potential approach to the treatment of AD.

Keywords: Alzheimer's disease, endocannabinoid system, dementia, CB1 receptors, CB2 receptors, new therapeutic approach.

Graphical Abstract
Hebert, L.E.; Weuve, J.; Scherr, P.A.; Evans, D.A. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology, 2013, 80(19), 1778-1783.
[ 1212/WNL.0b013e31828726f5] [PMID: 23390181]
Querfurth, H.W.; LaFerla, F.M. Alzheimer’s disease. N. Engl. J. Med., 2010, 362(4), 329-344.
[ 0909142] [PMID: 20107219]
Speriling, R.A.; Aisen, P.S.; Beckett, L.A.; Bennet, D.A.; Craft, S.; Fagan, A.M.; Iwatsubo, T.; Jack, C.R.; Kaye, J.; Montine, T.J.; Park, D.C.; Reiman, E.M.; Rowe, C.C.; Siemers, E.; Stern, Y.; Yaffe, K.; Carrillo, M.C.; Thies, B.; Morrison-Bogorad, M.; Wagster, M.V.; Phelps, C.H. Alzheimers Dement., 2011, 7, 280-292.
[] [PMID: 21514248]
Perry, E.; Walker, M.; Grace, J.; Perry, R. Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci., 1999, 22(6), 273-280.
[ 01361-7] [PMID: 10354606]
Cacabelos, R.; Takeda, M.; Winblad, B. The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer’s disease. Int. J. Geriatr. Psychiatry, 1999, 14(1), 3-47.
[<3:AID-GPS897>3.0.CO;2-7] [PMID: 10029935]
Aso, E.; Ferrer, I. Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Front. Pharmacol., 2014, 5, 37.
[] [PMID: 24634659]
Lu, H.C.; Mackie, K. An introduction to the endogenous cannabinoid system. Biol. Psychiatry, 2016, 79(7), 516-525.
[] [PMID: 26698193]
Pertwee, R.G. Endocannabinoids and their pharmacological actions. Handb. Exp. Pharmacol., 2015, 231, 1-37.
[ 10.1007/978-3-319-20825-1_1] [PMID: 26408156]
Lu, Y.; Anderson, H.D. Cannabinoid signaling in health and disease. Can. J. Physiol. Pharmacol., 2017, 95(4), 311-327.
[] [PMID: 28263083]
Piomelli, D. The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci., 2003, 4(11), 873-884.
[ 1038/nrn1247] [PMID: 14595399]
Wilson, R.I.; Nicoll, R.A. Endocannabinoid signaling in the brain. Science, 2002, 296(5568), 678-682.
[] [PMID: 11976437]
Freund, T.F.; Katona, I.; Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev., 2003, 83(3), 1017-1066.
[] [PMID: 12843414]
Maccarrone, M.; Bari, M.; Battista, N.; Di Rienzo, M.; Finazzi-Agrò, A. Endogenous cannabinoids in neuronal and immune cells: toxic effects, levels and degradation. Funct. Neurol., 2001, 16(4), 53-60.
[PMID: 11996531]
Cabral, G.A.; Griffin-Thomas, L. Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev. Mol. Med., 2009, 11, e3.
[] [PMID: 19152719]
Viscomi, M.T.; Oddi, S.; Latini, L.; Pasquariello, N.; Florenzano, F.; Bernardi, G.; Molinari, M.; Maccarrone, M. Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J. Neurosci., 2009, 29(14), 4564-4570.
[ 0786-09.2009] [PMID: 19357281]
Palazuelos, J.; Ortega, Z.; Díaz-Alonso, J.; Guzmán, M.; Galve-Roperh, I. CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J. Biol. Chem., 2012, 287(2), 1198-1209.
[] [PMID: 22102284]
Li, Y.; Kim, J. Deletion of CB2 cannabinoid receptors reduces synaptic transmission and long-term potentiation in the mouse hippocampus. Hippocampus, 2016, 26(3), 275-281.
[ 10.1002/hipo.22558] [PMID: 26663094]
Stella, N. Endocannabinoid signaling in microglial cells. Neuropharmacology, 2009, 56(Suppl. 1), 244-253.
[ 10.1016/j.neuropharm.2008.07.037] [PMID: 18722389]
Liu, Q.R.; Pan, C.H.; Hishimoto, A.; Li, C.Y.; Xi, Z.X.; Llorente-Berzal, A.; Viveros, M.P.; Ishiguro, H.; Arinami, T.; Onaivi, E.S.; Uhl, G.R. Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav., 2009, 8(5), 519-530.
[] [PMID: 19496827]
Ramírez, B.G.; Blázquez, C.; Gómez del Pulgar, T.; Guzmán, M.; de Ceballos, M.L. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci., 2005, 25(8), 1904-1913.
[ 10.1523/JNEUROSCI.4540-04.2005] [PMID: 15728830]
Solas, M.; Francis, P.T.; Franco, R.; Ramirez, M.J. CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol. Aging, 2013, 34(3), 805-808.
[] [PMID: 22763024]
Benito, C.; Núñez, E.; Tolón, R.M.; Carrier, E.J.; Rábano, A.; Hillard, C.J.; Romero, J. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J. Neurosci., 2003, 23(35), 11136-11141.
[] [PMID: 14657172]
Lee, J.H.; Agacinski, G.; Williams, J.H.; Wilcock, G.K.; Esiri, M.M.; Francis, P.T.; Wong, P.T.; Chen, C.P.; Lai, M.K. Intact cannabinoid CB1 receptors in the Alzheimer’s disease cortex. Neurochem. Int., 2010, 57(8), 985-989.
[ neuint.2010.10.010] [PMID: 21034788]
Mulder, J.; Zilberter, M.; Pasquaré, S.J.; Alpár, A.; Schulte, G.; Ferreira, S.G.; Köfalvi, A.; Martín-Moreno, A.M.; Keimpema, E.; Tanila, H.; Watanabe, M.; Mackie, K.; Hortobágyi, T.; de Ceballos, M.L.; Harkany, T. Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease. Brain, 2011, 134(Pt 4), 1041-1060.
[] [PMID: 21459826]
Ahmad, R.; Goffin, K.; Van den Stock, J.; De Winter, F.L.; Cleeren, E.; Bormans, G.; Tournoy, J.; Persoons, P.; Van Laere, K.; Vandenbulcke, M. In vivo type 1 cannabinoid receptor availability in Alzheimer’s disease. Eur. Neuropsychopharmacol., 2014, 24(2), 242-250.
[] [PMID: 24189376]
Westlake, T.M.; Howlett, A.C.; Bonner, T.I.; Matsuda, L.A.; Herkenham, M. 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, 1994, 63(3), 637-652.
[] [PMID: 7898667]
Christensen, R.; Kristensen, P.K.; Bartels, E.M.; Bliddal, H.; Astrup, A.V. A meta-analysis of the efficacy and safety of the anti-obesity agent Rimonabant. Ugeskr. Laeger, 2007, 169(50), 4360-4363.
[PMID: 18211795]
Tolón, R.M.; Núñez, E.; Pazos, M.R.; Benito, C.; Castillo, A.I.; Martínez-Orgado, J.A.; Romero, J. The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages. Brain Res., 2009, 1283, 148-154.
[] [PMID: 19505450]
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.
[] [PMID: 23808969]
Di Marzo, V.; Stella, N.; Zimmer, A. Endocannabinoid signalling and the deteriorating brain. Nat. Rev. Neurosci., 2015, 16(1), 30-42.
[] [PMID: 25524120]
Wu, J.; Bie, B.; Yang, H.; Xu, J.J.; Brown, D.L.; Naguib, M. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol. Aging, 2013, 34(3), 791-804.
[] [PMID: 22795792]
Martín-Moreno, A.M.; Brera, B.; Spuch, C.; Carro, E.; García-García, L.; Delgado, M.; Pozzo, M.A.; Innamorato, N.G.; Cuadrado, A.; de Ceballos, M.L. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance inTg APP 2576 mice. J. Neuroinflammation, 2012, 9, 8.
[PMID: 22248049]
Shibata, M.; Yamada, S.; Kumar, S.R.; Calero, M.; Bading, J.; Frangione, B.; Holtzman, D.M.; Miller, C.A.; Strickland, D.K.; Ghiso, J.; Zlokovic, B.V. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J. Clin. Invest., 2000, 106(12), 1489-1499.
[] [PMID: 11120756]
Chen, R.; Zhang, J.; Fan, N.; Teng, Z.Q.; Wu, Y.; Yang, H.; Tang, Y.P.; Sun, H.; Song, Y.; Chen, C.Δ. 9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell, 2013, 155(5), 1154-1165.
[ 10.042] [PMID: 24267894]
Bachmeier, C.; Beaulieu-Abdelahad, D.; Mullan, M.; Paris, D. Role of the cannabinoid system in the transit of beta-amyloid across the blood-brain barrier. Mol. Cell. Neurosci., 2013, 56, 255-262.
[] [PMID: 23831388]
Ferrer, I.; Gómez-Isla, T.; Puig, B.; Freixes, M.; Ribé, E.; Dalfó, E.; Avila, J. Current advances on different kinases involved in tau phosphorylation, and implications in Alzheimer’s disease and tauopathies. Curr. Alzheimer Res., 2005, 2(1), 3-18.
[] [PMID: 15977985]
Aso, E.; Juvés, S.; Maldonado, R.; Ferrer, I. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AβPP/PS1 mice. J. Alzheimers Dis., 2013, 35(4), 847-858.
[] [PMID: 23515018]
Esposito, G.; De Filippis, D.; Steardo, L.; Scuderi, C.; Savani, C.; Cuomo, V.; Iuvone, T. CB1 receptor selective activation inhibits beta-amyloid-induced iNOS protein expression in C6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons. Neurosci. Lett., 2006, 404(3), 342-346.
[ 10.1016/j.neulet.2006.06.012] [PMID: 16837132]
Casarejos, M.J.; Perucho, J.; Gomez, A.; Muñoz, M.P.; Fernandez-Estevez, M.; Sagredo, O.; Fernandez Ruiz, J.; Guzman, M.; de Yebenes, J.G.; Mena, M.A. Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J. Alzheimers Dis., 2013, 35(3), 525-539.
[] [PMID: 23478312]
Eubanks, L.M.; Rogers, C.J.; Beuscher, A.E., IV; Koob, G.F.; Olson, A.J.; Dickerson, T.J.; Janda, K.D. A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol. Pharm., 2006, 3(6), 773-777.
[] [PMID: 17140265]
Feigenbaum, J.J.; Bergmann, F.; Richmond, S.A.; Mechoulam, R.; Nadler, V.; Kloog, Y.; Sokolovsky, M. Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker. Proc. Natl. Acad. Sci. USA, 1989, 86(23), 9584-9587.
[] [PMID: 2556719]
Eshhar, N.; Striem, S.; Biegon, A. HU-211, a non-psychotropic cannabinoid, rescues cortical neurones from excitatory amino acid toxicity in culture. Neuroreport, 1993, 5(3), 237-240.
[] [PMID: 8298080]
Nadler, V.; Mechoulam, R.; Sokolovsky, M. The non-psychotropic cannabinoid (+)-(3S,4S)-7-hydroxy-delta 6- tetrahydrocannabinol 1,1-dimethylheptyl (HU-211) attenuates N-methyl-D-aspartate receptor-mediated neurotoxicity in primary cultures of rat forebrain. Neurosci. Lett., 1993, 162(1-2), 43-45.
[] [PMID: 8121633]
Marsicano, G.; Goodenough, S.; Monory, K.; Hermann, H.; Eder, M.; Cannich, A.; Azad, S.C.; Cascio, M.G.; Gutierrez, S.O.; van der Stelt, M. Lopez-Rodriguez; M.L.; Casanova, E.; Schutz, G.; Zieglgansberger, W.; Di Marzo; V.; Behl, C.; Lutz B. CB1 receptors and on-demand defense against excitotoxicity. Science, 2003, 302, 84-88.
[] [PMID: 14526074]
Mackie, K.; Hille, B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc. Natl. Acad. Sci. USA, 1992, 89(9), 3825-3829.
[] [PMID: 1315042]
Twitchell, W.; Brown, S.; Mackie, K. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol., 1997, 78(1), 43-50.
[ 1997.78.1.43] [PMID: 9242259]
Zhuang, S.Y.; Bridges, D.; Grigorenko, E.; McCloud, S.; Boon, A.; Hampson, R.E.; Deadwyler, S.A. Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodine-sensitive stores. Neuropharmacology, 2005, 48(8), 1086-1096.
[] [PMID: 15910885]
Esposito, G.; Scuderi, C.; Valenza, M.; Togna, G.I.; Latina, V.; De Filippis, D.; Cipriano, M.; Iuovone, T.; Steardo, L. Cannabidiol reduces Abeta-induced neuroinflammation and promotes hippocampal neurogenesis through PPAR gamma involvement. PloS One,, 2011. 6, 12 e28668.
Iuvone, T.; Esposito, G.; Esposito, R.; Santamaria, R.; Di Rosa, M.; Izzo, A.A. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J. Neurochem., 2004, 89(1), 134-141.
[] [PMID: 15030397]
Mecha, M.; Feliú, A.; Carrillo-Salinas, F.J.; Rueda-Zubiaurre, A.; Ortega-Gutiérrez, S.; de Sola, R.G.; Guaza, C. Endocannabinoids drive the acquisition of an alternative phenotype in microglia. Brain Behav. Immun., 2015, 49, 233-245.
[ 10.1016/j.bbi.2015.06.002] [PMID: 26086345]
Benito, C.; Tolón, R.M.; Pazos, M.R.; Núñez, E.; Castillo, A.I.; Romero, J. Cannabinoid CB2 receptors in human brain inflammation. Br. J. Pharmacol., 2008, 153(2), 277-285.
[ 10.1038/sj.bjp.0707505] [PMID: 17934510]
Bénard, G.; Massa, F.; Puente, N.; Lourenço, J.; Bellocchio, L.; Soria-Gómez, E.; Matias, I.; Delamarre, A.; Metna-Laurent, M.; Cannich, A.; Hebert-Chatelain, E.; Mulle, C.; Ortega-Gutiérrez, S.; Martín-Fontecha, M.; Klugmann, M.; Guggenhuber, S.; Lutz, B.; Gertsch, J.; Chaouloff, F.; López-Rodríguez, M.L.; Grandes, P.; Rossignol, R.; Marsicano, G. Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat. Neurosci., 2012, 15(4), 558-564.
[] [PMID: 22388959]
Ferrer, I. Altered mitochondria, energy metabolism, voltage-dependent anion channel, and lipid rafts converge to exhaust neurons in Alzheimer’s disease. J. Bioenerg. Biomembr., 2009, 41(5), 425-431.
[] [PMID: 19798558]
Burchell, V.S.; Gandhi, S.; Deas, E.; Wood, N.W.; Abramov, A.Y.; Plun-Favreau, H. Targeting mitochondrial dysfunction in neurodegenerative disease: Part I. Expert Opin. Ther. Targets, 2010, 14(4), 369-385.
[] [PMID: 20184395]
Esposito, G.; De Filippis, D.; Maiuri, M.C.; De Stefano, D.; Carnuccio, R.; Iuvone, T. Cannabidiol inhibits inducible NOS expression and NO production in b-amyloid-stimulated PC12 neurons through p38 MAP kinase and NFkB involvement. Neurosci. Lett., 2006, 399, 91-95.
[] [PMID: 16490313]
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 relevance to Alzheimer’s disease. Mol. Pharmacol., 2011, 79(6), 964-973.
[] [PMID: 21350020]
Athanasiou, A.; Clarke, A.B.; Turner, A.E.; Kumaran, N.M.; Vakilpour, S.; Smith, P.A.; Bagiokou, D.; Bradshaw, T.D.; Westwell, A.D.; Fang, L.; Lobo, D.N.; Constantinescu, C.S.; Calabrese, V.; Loesch, A.; Alexander, S.P.H.; Clothier, R.H.; Kendall, D.A.; Bates, T.E. Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death. Biochem. Biophys. Res. Commun., 2007, 364(1), 131-137.
[ 107] [PMID: 17931597]
Walther, S. Mahlberg. R.; Eichmann. U.; Kunz, D. D9-Tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology (Berl.), 2006, 185, 524-528.
[] [PMID: 16521031]
Volicer, L.; Stelly, M.; Morris, J.; McLaughlin, J.; Volicer, B.J. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry, 1997, 12(9), 913-919.
[ (199709)12:9<913:AID-GPS663>3.0.CO;2-D] [PMID: 9309469]
Koppel, J.; Bradshaw, H.; Goldberg, T.E.; Khalili, H.; Marambaud, P.; Walker, M.J.; Pazos, M.; Gordon, M.L.; Christen, E.; Davies, P. Endocannabinoids in Alzheimer’s disease and their impact on normative cognitive performance: a case-control and cohort study. Lipids Health Dis., 2009, 8, 2.
[] [PMID: 19144193]
Krishnan, S.; Cairns, R.; Howard, R. Cannabinoids for the treatment of dementia. Cochrane Database Syst. Rev., 2009, (2), CD007204.
[] [PMID: 19370677]
van den Elsen, G.A.H.; Ahmed, A.I.A.; Lammers, M.; Kramers, C.; Verkes, R.J.; van der Marck, M.A.; Rikkert, M.G. Efficacy and safety of medical cannabinoids in older subjects: a systematic review. Ageing Res. Rev., 2014, 14, 56-64.
[ 1016/j.arr.2014.01.007] [PMID: 24509411]
Woodward, M.R.; Harper, D.G.; Stolyar, A.; Forester, B.P.; Ellison, J.M. Dronabinol for the treatment of agitation and aggressive behavior in acutely hospitalized severely demented patients with noncognitive behavioral symptoms. Am. J. Geriatr. Psychiatry, 2014, 22(4), 415-419.
[] [PMID: 23597932]
Shelef, A.; Barak, Y.; Berger, U.; Paleacu, D.; Tadger, S.; Plopsky, I.; Baruch, Y. Safety and efficacy of medical cannabis oil for bBehavioral and psychological symptoms of dementia: An-open label, add-On, pilot study. J. Alzheimers Dis., 2016, 51(1), 15-19.
[] [PMID: 26757043]
van den Elsen, G.A.H.; Ahmed, A.I.A.; Verkes, R-J.; Kramers, C.; Feuth, T.; Rosenberg, P.B.; van der Marck, M.A.; Olde Rikkert, M.G. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial. Neurology, 2015, 84(23), 2338-2346.
[] [PMID: 25972490]

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