Endocannabinoid system and cannabinoids in neurogenesis – new opportunities for neurological treatment? Reports from experimental studies.
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Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, Lublin Poland
Department of Physiopathology, Institute of Rural Health, Jaczewskiego 2, Lublin Poland
Department of Patophysiology, Medical University, Jaczewskiego 8, Lublin, Poland
Corresponding author
Marta Andres-Mach   

Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, Lublin Poland, Jaczewskiego 2, 20-090 Lublin, Poland
J Pre Clin Clin Res. 2017;11(1):76-80
Neurogenesis is one of the most important phenomenona affecting human life. This process consists of proliferation, migration and differentiation of neuroblasts and synaptic integrations of newborn neurons. Proliferation of new cells continues into old age, also in humans, although the most extensive process of cell formation occurs during the prenatal period. It is possible to distinguish two regions in the brain responsible for neurogenesis: the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ). Hippocampal neurogenesis is very sensitive to various physiological and pathological stimuli. The functional integration of the newly-born dentate granule cells into hippocampal circuitry, and their ability to mediate long-term potentiation in DG, has led to the hypothesis that neurogenesis in the adult brain may play a key role in learning and memory function, as well as cognitive dysfunction in some diseases. Brain disorders, such as neurodegenerative diseases or traumatic brain injuries, significantly affect migration, proliferation and differentiation of neural cells. In searching for the best neurological drugs protecting neuronal cells, stimulating neurogenesis, while also developing no side-effects, endocannabinoids proved to be a strong group of substances having many beneficial properties. Therefore, the latest data is reviewed of the various experimental studies concerning the analysis of the most commonly studied cannabinoids and their impact on neurogenesis.
Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer 2007; 7:79–94.
Haydar TF, Wang F, Schwartz ML, Rakic P. Differential modulation of proliferation in the neocortical ventricular and subventricular zones. J Neurosci 2000; 20:5764–5774.
Harkany T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K. The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 2007; 28:83–92.
Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 2008; 14:923–930.
Galve-Roperh I, Aguado T, Palazuelos J, Guzman M. Mechanisms of control of neuron survival by the endocannabinoid system. Curr Pharm Des 2008; 14:2279–2288.
Piomelli D, The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 2003; 4(11):873–84.
Watkins BA, Kim J. The endocannabinoid system: directingeating behavior and macronutrient metabolism. Front Psychol 2015; 5: 1506.
Pacher P, Steffens S. The emerging role of the endocannabinoid system in cardiovascular disease. Semin. Immunopathol. 2009 31:63–77.
Chen JK, Chen J, Imig JD, Wei S, Hachey DL, Guthi JS, Falck JR, Capdevila JH, Harris RC. Identification of novel endogenous cytochrome p450 arachidonate metabolites with high affinity for cannabinoid receptors. J Biol Chem. 2008 283:24514–24524.
Turcotte C, Chouinard F, Lefebvre JS, Flamand N. Regulation of inflammation by cannabinoids, the endocannabinoids 2-arachidonoyl-glycerol and arachidonoyl-ethanolamide, and their metabolites. J Leukoc Biol. 2015 Jun;97(6):1049–70.
Di Marzo V, Bifulco M, De Petrocellis L: The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004; 3:771–784.
Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 1994; 372(6507):686–91.
Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol. 2003;163(3):463–8.
Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996;384(6604):83–7.
Petrosino S, Di Marzo V: FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels. Curr Opin Investig Drugs 2010; 11:51–62.
Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389–462.
Schurman LD, Lichtman AH. Endocannabinoids: A Promising Impact for Traumatic Brain Injury. Front Pharmacol. 2017; Feb 17;8:69.
Arévalo-Martín A, García-Ovejero D, Rubio-Araiz A, Gómez O, Molina-Holgado F, Molina-Holgado E. Cannabinoids modulate Olig2 and polysialylated neural cell adhesion molecule expression in the subventricular zone of post-natal rats through cannabinoid receptor 1 and cannabinoid receptor 2. Eur J Neurosci. 2007;26(6):1548–59.
Mackie K, Devane WA, Hille B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol Pharmacol. 1993;44(3):498–503.
Hampson RE, Mu J, Deadwyler SA. Cannabinoid and kappa opioid receptors reduce potassium K current via activation of G(s) proteins in cultured hippocampal neurons. J Neurophysiol. 2000;84(5):2356–64.
Howlett, A.C., Barth, F., Bonner, T.I. Et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002, 54(2): 161–202.
Mechoulam R, Spatz M, Shohami E. Endocannabinoids and neuroprotection. Sci STKE. 2002; 23;2002(129):re5.
Guzmán M. Cannabinoids: potential anticancer agents. Nat Rev Cancer. 2003 Oct;3(10):745–55.
Friedman D, Devinsky O. Cannabinoids in the Treatment of Epilepsy. N Engl J Med. 2015 Sep 10;373(11):1048–58.
Matsuda LA, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–564.
Baker D, Pryce G, Davies WL, Hiley CR. In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci 2006;27(1):1–4.
Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993 Sep 2;365(6441):61–5.
Onaivi, E.S. Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB2 receptors in the brain. Neuropsychobiology, 2006; 54(4), 231–246.
Moreira, F.A.; Aguiar, D.C.; Guimarães, F.S. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2006; 30(8), 1466–71.
Bergamaschi, M.M.; Queiroz, R.H.; Chagas, M.H.;de Oliveira D.C.; De Martinis, B.S.; Kapczinski, F.; et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology, 2011;36, 1219–26.
Zoppi S, Pérez Nievas BG, Madrigal JL, Anzanares J, Eza JC, García- Bueno B. Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation. Neuropsychopharmacology. 2011;36(4):805–18.
Szabo, B, Schlicker, E. Effects of cannabinoids on neurotransmission. Handb. Exp. Pharmacol., 2005; 168, 327–165.
Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science. 2003;302(5642):84–8.
Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci. 2005;28:223–50.
Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965 Jun;124(3):319–35.
Altman J, Das GD. Postnatal neurogenesis in the guinea-pig. Nature 1967 Jun 10;214(5093):1098–101.
Christie B. R., Cameron H. A. Neurogenesis in the adult hippocampus. Hippocampus 2006 16, 199–207.
Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011 May 26;70(4):687–702.
Altman J. Are new neurons formed in the brains of adult mammals? Science. 1962 Mar 30;135(3509):1127–8.
Bernier P. J., Bedard A., Vinet J., Levesque M., Parent A. Newly generated neurons in the amygdala and adjoining cortex of adult primates. Proc. Natl. Acad. Sci. U.S.A 2002. 99, 11464–11469.
Cameron HA, Dayer AG. New interneurons in the adult neocortex: small, sparse, but significant? Biol Psychiatry. 2008 Apr 1;63(7):650–5.
Bédard A, Lévesque M, Bernier PJ, Parent A. The rostral migratory stream in adult squirrel monkeys: contribution of new neurons to the olfactory tubercle and involvement of the antiapoptotic protein Bcl-2. Eur J Neurosci. 2002; (10):1917–24.
Wolf SA, Bick-Sander A, Fabel K, Leal-Galicia P, Tauber S, Ramirez- Rodriguez G, et al. Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis. Cell Commun Signal. 2010 17;8:12.
Molina-Holgado E., Molina-Holgado F. Mending the broken brain: neuroimmune interactions in neurogenesis. J Neurochem. 2010114:1277–1290.
Campos AC, Ortega Z, Palazuelos J, Fogaça MV, Aguiar DC, Díaz- Alonso J, et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol. 2013 Jul;16(6):1407–19.
Abboussi O. Chronic exposure to WIN55,212–2 affects more potently spatial learning and memory in adolescents than in adult rats via a negative action on dorsal hippocampal neurogenesis. Pharmacol Biochem Behav. 2014 120:95–102.
Compagnucci C, Di Siena S, Bustamante MB, Di Giacomo D, Di Tommaso M, Maccarrone M, et al. Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells. PLoS One. 2013;8(1):e54271.
Avraham HK, Jiang S, Fu Y, Rockenstein E, Makriyannis A, Zvonok A, et al. The cannabinoid CB2 receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis. Br J Pharmacol. 2014; 171(2):468–79.
Kim HY, Moon HS, Cao D, Lee J, Kevala K, Jun SB, et al. N-Docosahexaenoylethanolamide promotes development of hippocampal neurons. Biochem J. 2011 15;435(2):327–36.
Jin K, Xie L, Kim SH, Parmentier-Batteur S, Sun Y, Mao XO, Childs J, Greenberg DA. Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice. Mol Pharmacol. 2004 66(2):204–8.
Rashid MA, Katakura M, Kharebava G, Kevala K, Kim HY. N-Docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation. J Neurochem. 2013 Jun;125(6):869–84.
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 6;287(2):1198–209.
Steel RW, Miller JH, Sim DA, Day DJ. Delta-9-tetrahydrocannabinol disrupts hippocampal neuroplasticity and neurogenesis in trained, but not untrained adolescent Sprague-Dawley rats. Brain Res. 2014 Feb 22;1548:12–9.
Hutch CR, Hegg CC. Cannabinoid receptor signaling induces proliferation but not neurogenesis in the mouse olfactory epithelium. Neurogenesis (Austin). 2016 Jan 13;3(1).
Marchalant, Y; Brothers, HM; Wenk, GL. Cannabinoid agonist WIN- 55, 212–2 partially restores neurogenesis in the aged rat brain. Mol. Psychiatry, 2009, 14(12), 1068–9.
Andres-Mach M, Haratym-Maj A, Zagaja M, Rola R, Maj M, Chrościńska-Krawczyk M, et al. ACEA (a highly selective cannabinoid CB1 receptor agonist) stimulates hippocampal neurogenesis in mice treated with antiepileptic drugs. Brain Res. 2015 Oct 22;1624:86–94.
Andres-Mach M, Zagaja M, Haratym-Maj A, Rola R, Maj M, Haratym J, et al. A Long-Term Treatment with Arachidonyl-2’-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy. Int J Mol Sci. 2017; 25;18(5).
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