Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi

4 Issues per year


CiteScore 2017: 2.48

SCImago Journal Rank (SJR) 2017: 1.021
Source Normalized Impact per Paper (SNIP) 2017: 0.830

Online
ISSN
1868-1891
See all formats and pricing
More options …
Ahead of print

Issues

Cannabinoids in health and disease: pharmacological potential in metabolic syndrome and neuroinflammation

Andrea MastinuORCID iD: http://orcid.org/0000-0002-8862-2896 / Marika Premoli
  • Department of Molecular and Translational Medicine, Section of Pharmacology, University of Brescia, Brescia, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Giulia Ferrari-Toninelli
  • Department of Molecular and Translational Medicine, Section of Pharmacology, University of Brescia, Brescia, Italy
  • Istituto Clinico Città di Brescia, Brescia, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Simone Tambaro
  • Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Huddinge, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Giuseppina Maccarinelli
  • Department of Molecular and Translational Medicine, Section of Pharmacology, University of Brescia, Brescia, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Maurizio Memo
  • Department of Molecular and Translational Medicine, Section of Pharmacology, University of Brescia, Brescia, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Sara Anna Bonini
  • Department of Molecular and Translational Medicine, Section of Pharmacology, University of Brescia, Brescia, Italy
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2018-03-30 | DOI: https://doi.org/10.1515/hmbci-2018-0013

Abstract

The use of different natural and/or synthetic preparations of Cannabis sativa is associated with therapeutic strategies for many diseases. Indeed, thanks to the widespread diffusion of the cannabinoidergic system in the brain and in the peripheral districts, its stimulation, or inhibition, regulates many pathophysiological phenomena. In particular, central activation of the cannabinoidergic system modulates the limbic and mesolimbic response which leads to food craving. Moreover, cannabinoid agonists are able to reduce inflammatory response. In this review a brief history of cannabinoids and the protagonists of the endocannabinoidergic system, i.e. synthesis and degradation enzymes and main receptors, will be described. Furthermore, the pharmacological effects of cannabinoids will be outlined. An overview of the involvement of the endocannabinoidergic system in neuroinflammatory and metabolic pathologies will be made. Finally, particular attention will also be given to the new pharmacological entities acting on the two main receptors, cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), with particular focus on the neuroinflammatory and metabolic mechanisms involved.

Keywords: Cannabis sativa; endocannabinoids; metabolic syndrome; neuroinflammation

References

  • [1]

    Zurier RB, Burstein SH. Cannabinoids, inflammation, and fibrosis. FASEB J. 2016;30:3682–9.PubMedCrossrefGoogle Scholar

  • [2]

    Andre CM, Hausman J-F, Guerriero G. Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci. 2016;7:19.PubMedGoogle Scholar

  • [3]

    Carter S, Caron A, Richard D, Picard F. Role of leptin resistance in the development of obesity in older patients. Clin Interv Aging. 2013;8:829–44.PubMedGoogle Scholar

  • [4]

    Jung UJ, Choi M-S. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15:6184–223.PubMedCrossrefGoogle Scholar

  • [5]

    Tufekci KU, Meuwissen R, Genc S, Genc K. Inflammation in Parkinson’s disease. Adv Protein Chem Struct Biol. 2012;88:69–132.PubMedCrossrefGoogle Scholar

  • [6]

    Bolós M, Perea JR, Avila J. Alzheimer’s disease as an inflammatory disease. Biomol Concepts. 2017;8:37–43.PubMedGoogle Scholar

  • [7]

    Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013;11:200.PubMedCrossrefGoogle Scholar

  • [8]

    Salim S, Chugh G, Asghar M. Inflammation in anxiety. Adv Protein Chem Struct Biol. 2012;88:1–25.CrossrefPubMedGoogle Scholar

  • [9]

    Zuardi AW. History of cannabis as a medicine: a review. Rev Bras Psiquiatr. 2006;28:153–7.PubMedCrossrefGoogle Scholar

  • [10]

    Mechoulam R. The pharmacohistory of Cannabis sativa. In: Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton, FL: CRC Press; 1986. p. 1–19.Google Scholar

  • [11]

    Mechoulam R, Shani A, Edery H, Grunfeld Y. Chemical basis of hashish activity. Science. 1970;169:611–2.CrossrefPubMedGoogle Scholar

  • [12]

    Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rational for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66:234–46.CrossrefGoogle Scholar

  • [13]

    O’Shaughnessy WB. On the preparations of the Indian hemp, or gunjah (Cannabis indica). Prov Med J Retrosp Med Sci. 1843;123(5):363–369.Google Scholar

  • [14]

    Crippa JA, Zuardi AW, Hallak JE. Therapeutical use of the cannabinoids in psychiatry. Rev Bras Psiquiatr. 2010;32:S56–66.PubMedGoogle Scholar

  • [15]

    Matias I, Di Marzo V. Endocannabinoids and the control of energy balance. Trends Endocrinol Metab. 2007;18:27–37.PubMedCrossrefGoogle Scholar

  • [16]

    Di Marzo V, De Petrocellis L. Why do cannabinoid receptors have more than one endogenous ligand? Philos Trans R Soc Lond B Biol Sci. 2012;367:3216–28.CrossrefPubMedGoogle Scholar

  • [17]

    Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, et al. Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids. Structure. 2015;23:598–604.CrossrefPubMedGoogle Scholar

  • [18]

    Sugiura T, Kobayashi Y, Oka S, Waku K. Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids. 2002;66:173–92.CrossrefPubMedGoogle Scholar

  • [19]

    Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;20:10–4.PubMedCrossrefGoogle Scholar

  • [20]

    Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “Triptan” receptors: implications in migraine. J Neurosci. 2013;33:14869–77.CrossrefPubMedGoogle Scholar

  • [21]

    Jourdan T, Djaouti L, Demizieux L, Gresti J, Vergès B, Degrace P. CB1 Antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice. Diabetes. 2010;59:926–34.PubMedCrossrefGoogle Scholar

  • [22]

    Guo J, Ikeda SR. Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons. Mol Pharmacol. 2004;65:665–74.CrossrefPubMedGoogle Scholar

  • [23]

    Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem. 2010;17:1468–86.CrossrefPubMedGoogle Scholar

  • [24]

    Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298–305.CrossrefPubMedGoogle Scholar

  • [25]

    Miller AM, Stella N. CB2 receptor-mediated migration of immune cells: it can go either way. Br J Pharmacol. 2008;153:299–308.CrossrefPubMedGoogle Scholar

  • [26]

    Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol. 2008;153:319–34.CrossrefPubMedGoogle Scholar

  • [27]

    Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010;58:1017–30.PubMedCrossrefGoogle Scholar

  • [28]

    Li Y, Kim J. Distinct roles of neuronal and microglial CB2 cannabinoid receptors in the mouse hippocampus. Neuroscience. 2017;363:11–25.PubMedCrossrefGoogle Scholar

  • [29]

    Chen DJ, Gao M, Gao FF, Su QX, Wu J. Brain cannabinoid receptor 2: expression, function and modulation. Acta Pharmacol Sin. 2017;38:312–6.CrossrefPubMedGoogle Scholar

  • [30]

    Basu S, Dittel BN. Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation in health and disease. Immunol Res. 2011;51:26–38.CrossrefPubMedGoogle Scholar

  • [31]

    Tambaro S, Casu MA, Mastinu A, Lazzari P. Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial cystitis. Eur J Pharmacol. 2014;729:67–74.CrossrefGoogle Scholar

  • [32]

    Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience. 2006;139:1405–15.PubMedCrossrefGoogle Scholar

  • [33]

    De Petrocellis L, Di Marzo V. Role of endocannabinoids and endovanilloids in Ca2+ signalling. Cell Calcium. 2009;45:611–24.CrossrefPubMedGoogle Scholar

  • [34]

    Di Marzo V, De Petrocellis L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem. 2010;17:1430–49.PubMedCrossrefGoogle Scholar

  • [35]

    Karaliota S, Siafaka-Kapadai A, Gontinou C, Psarra K, Mavri-Vavayanni M. Anandamide increases the differentiation of rat adipocytes and causes PPARgamma and CB1 receptor upregulation. Obesity. 2009;17:1830–8.CrossrefGoogle Scholar

  • [36]

    Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409–35.CrossrefPubMedGoogle Scholar

  • [37]

    Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res. 2005;51:85–94.CrossrefPubMedGoogle Scholar

  • [38]

    Huang JV, Greyson CR, Schwartz GG. PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty: thematic review series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases. J Lipid Res. 2012;53:1738–54.CrossrefGoogle Scholar

  • [39]

    Yücel M, Solowij N, Respondek C, Whittle S, Fornito A, Pantelis C, et al. Regional brain abnormalities associated with long-term heavy cannabis use. Arch Gen Psychiatry. 2008;65:694–701.PubMedCrossrefGoogle Scholar

  • [40]

    Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, et al. Effect of long-term cannabis use on axonal fibre connectivity. Brain. 2012;135:2245–55.CrossrefPubMedGoogle Scholar

  • [41]

    Paus T, Zijdenbos A, Worsley K, Collins DL, Blumenthal J, Giedd JN, et al. Structural maturation of neural pathways in children and adolescents: in vivo study. Science. 1999;283:1908–11.PubMedCrossrefGoogle Scholar

  • [42]

    Battistella G, Fornari E, Annoni JM, Chtioui H, Dao K, Fabritius M, et al. Long-term effects of cannabis on brain structure. Neuropsychopharmacology. 2014;39:2041–8.PubMedCrossrefGoogle Scholar

  • [43]

    Thompson SA, Patterson K, Hodges JR. Left/right asymmetry of atrophy in semantic dementia: behavioral-cognitive implications. Neurology. 2003;61:1196–203.CrossrefPubMedGoogle Scholar

  • [44]

    Solowij N, Battisti R. The chronic effects of cannabis on memory in humans: a review. Curr Drug Abuse Rev. 2008;1:81–98.PubMedCrossrefGoogle Scholar

  • [45]

    Lim K, See YM, Lee J. A systematic review of the effectiveness of medical cannabis for psychiatric, movement and neurodegenerative disorders. Clin Psychopharmacol Neurosci. 2017;15:301–12.CrossrefPubMedGoogle Scholar

  • [46]

    Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. J Am Med Assoc. 2015;313:2456–73.CrossrefGoogle Scholar

  • [47]

    Crippa JA, Zuardi AW, Martín-Santos R, Bhattacharyya S, Atakan Z, McGuire P, et al. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009;24:515–23.CrossrefPubMedGoogle Scholar

  • [48]

    Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66:95–105.PubMedCrossrefGoogle Scholar

  • [49]

    Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25:121–30.PubMedCrossrefGoogle Scholar

  • [50]

    Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802.CrossrefPubMedGoogle Scholar

  • [51]

    Kaur J. A comprehensive review on metabolic syndrome. Cardiol Res Pract. 2014;2014:943162.PubMedGoogle Scholar

  • [52]

    Haffner SM, Vldez RA, Hazuda HP, Mitchell BD, Morales PA, Stern MP. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabates. 1992;41:715.CrossrefGoogle Scholar

  • [53]

    Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C, National Heart, Lung, and Blood Institute, et al. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol. 2004;24:e13–8.CrossrefPubMedGoogle Scholar

  • [54]

    Grundy SM. Metabolic syndrome: a multiple cardiovascular risk factor. J Clin Endocrinol Metabol. 2007;92:396.Google Scholar

  • [55]

    Ferrannini E. Metabolic syndrome: a solution in search of problem. J Clin Endocrinol Metabol. 2007;92:396.CrossrefGoogle Scholar

  • [56]

    Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105:141–50.CrossrefPubMedGoogle Scholar

  • [57]

    Rochlani Y, Pothineni NV, Kovelamudi S, Metha JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Thera adv Cardiovasc Dis. 2017;11:215–25.CrossrefGoogle Scholar

  • [58]

    Tooke JE, Hannemann MM. Adverse endothelial function and the insulin resistance syndrome. J Intern Med. 2000;247:425–31.CrossrefPubMedGoogle Scholar

  • [59]

    Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, et al. Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes. 2003;52:2882–7.PubMedCrossrefGoogle Scholar

  • [60]

    Juhan-Vague I, Alessi MC, Mavri A, Morange PE. Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost. 2003;1:1575–9.PubMedCrossrefGoogle Scholar

  • [61]

    Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, et al. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation. 2001;104:3052–6.CrossrefPubMedGoogle Scholar

  • [62]

    Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet. 2002;360:57–8.CrossrefPubMedGoogle Scholar

  • [63]

    Vaněčková I, Maletínská L, Behuliak M, Nagelová V, Zicha J, Kuneš J. Obesity-related hypertension: possible pathophysiological mechanisms. J Endocrinol. 2014;223:R63–78.PubMedCrossrefGoogle Scholar

  • [64]

    Dai Y, Mercanti F, Dai D, Wang X, Ding Z, Pothineni NV, et al. LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells. Biochem Biophys Res Commun. 2013;437:62–6.CrossrefPubMedGoogle Scholar

  • [65]

    Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibitsbsignaling from the insulin receptor. Proc Natl Acad Sci USA. 1994;91:4854–8.CrossrefGoogle Scholar

  • [66]

    Tsigos C, Kyrou I, Chala E, Tsapogas P, Stavridis JC, Raptis SA, et al. Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity. Metabolism. 1999;48:1332–5.PubMedCrossrefGoogle Scholar

  • [67]

    Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol. 2004;15:2792–800.CrossrefPubMedGoogle Scholar

  • [68]

    Goodpaster BH, Delany JP, Otto AD, Kuller L, Vockley J, South-Paul JE, et al. Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: a randomized trial. J Am Med Assoc. 2010;304:1795–802.CrossrefGoogle Scholar

  • [69]

    Wadden TA, Butryn ML, Byrne KJ. Efficacy of lifestyle modification for long-term weight control. Obes Res. 2004;12:151S–62.PubMedCrossrefGoogle Scholar

  • [70]

    Vincent HK, Vincent KR. Considerations for initiating and progressing running programs in obese individuals. PM R. 2013;5:513–9.PubMedCrossrefGoogle Scholar

  • [71]

    Mariotti KC, Rossato LG, Fröehlich PE, Limberger RP. Amphetamine-type medicines: a review of pharmacokinetics, pharmacodynamics, and toxicological aspects. Curr Clin Pharmacol. 2013;8:350–7.PubMedCrossrefGoogle Scholar

  • [72]

    Khorassani FE, Misher A, Garris S. Past and present of antiobesity agents: focus on monoamine modulators. Am J Health Syst Pharm. 2015;72:697–706.PubMedCrossrefGoogle Scholar

  • [73]

    Filippatos TD, Derdemezis CS, Gazi IF, Nakou ES, Mikhailidis DP, Elisaf MS. Orlistat-associated adverse effects and drug interactions: a critical review. Drug Saf. 2008;31:53–65.CrossrefPubMedGoogle Scholar

  • [74]

    Derosa G, Maffioli P, Sahebkar A. Improvement of plasma adiponectin, leptin and C-reactive protein concentrations by orlistat: a systematic review and meta-analysis. Br J Clin Pharmacol. 2016;81:819–34.CrossrefPubMedGoogle Scholar

  • [75]

    Katz O, Stuible M, Golishevski N, Lifshitz L, Tremblay ML, Gassmann M, et al. Erythropoietin treatment leads to reduced blood glucose levels and body mass: insights from murine models. J Endocrinol. 2010;205:87–95.PubMedCrossrefGoogle Scholar

  • [76]

    Gianoncelli A, Bonini SA, Bertuzzi M, Guarienti M, Vezzoli S, Kumar R, et al. An integrated approach for a structural and functional evaluation of biosimilars: implications for erythropoietin. BioDrugs. 2015;29:285–300.CrossrefPubMedGoogle Scholar

  • [77]

    Bellocchio L, Cervino C, Pasquali R, Pagotto U. The endocannabinoid system and energy metabolism. J Neuroendocrinol. 2008;20:850–7.CrossrefPubMedGoogle Scholar

  • [78]

    Di Marzo V, Ligresti A, Cristino L. The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation. Int J Obes. 2009;33:S18–24.CrossrefGoogle Scholar

  • [79]

    Mahler SV, Smith KS, Berridge KC. Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances ‘liking’ of a sweet reward. Neuropsychopharmacology. 2007;32:2267–78.CrossrefGoogle Scholar

  • [80]

    Monteleone P, Maj M. Dysfunctions of leptin, ghrelin, BDNF and endocannabinoids in eating disorders: beyond the homeostatic control of food intake. Psychoneuroendocrinology. 2013;38:312–30.PubMedCrossrefGoogle Scholar

  • [81]

    Adinoff B. Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry. 2004;12:305–20.CrossrefPubMedGoogle Scholar

  • [82]

    Fattore L, Cossu G, Spano MS, Deiana S, Fadda P, Scherma M, et al. Cannabinoids and reward: interactions with the opioid system. Crit Rev Neurobiol. 2004;16:147–58.PubMedCrossrefGoogle Scholar

  • [83]

    Cristino L, Palomba L, Di Marzo V. New horizons on the role of cannabinoid CB1 receptors in palatable food intake, obesity and related dysmetabolism. Int J Obes Suppl. 2014;4:S26–30.PubMedCrossrefGoogle Scholar

  • [84]

    Skelly MJ, Guy EG, Howlett AC, Pratt WE. CB1 receptors modulate the intake of a sweetened fat diet in response to mu-opioid receptor stimulation of the nucleus accumbens. Pharmacol Biochem Behav. 2010;97:144–51.PubMedCrossrefGoogle Scholar

  • [85]

    Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrié P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord. 2004;28:640–8.CrossrefPubMedGoogle Scholar

  • [86]

    Rigamonti AE, Piscitelli F, Aveta T, Agosti F, De Col A, Bini S, et al. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults. Food Nutr Res. 2015;59:29678.PubMedCrossrefGoogle Scholar

  • [87]

    Massa F, Mancini G, Schmidt H, Steindel F, Mackie K, Angioni C, et al. Alterations in the hippocampal endocannabinoid system in diet-induced obese mice. J Neurosci. 2010;30:6273–81.PubMedCrossrefGoogle Scholar

  • [88]

    Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab. 2013;17:475–90.PubMedCrossrefGoogle Scholar

  • [89]

    Pertwee RG. Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci. 2005;76:1307–24.PubMedCrossrefGoogle Scholar

  • [90]

    Silvestri C, Di Marzo V. Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders. Expert Opin Investig Drugs. 2012;21:1309–22.CrossrefPubMedGoogle Scholar

  • [91]

    Lazzari P, Sanna A, Mastinu A, Cabasino S, Manca I, Pani L. Weight loss induced by rimonabant is associated with an altered leptin expression and hypothalamic leptin signaling in diet-induced obese mice. Behav Brain Res. 2011;217:432–8.CrossrefPubMedGoogle Scholar

  • [92]

    Richey JM, Woolcott O. Re-visiting the endocannabinoid system and its therapeutic potential in obesity and associated diseases. Curr Diab Rep. 2017;17:99.PubMedCrossrefGoogle Scholar

  • [93]

    Kintscher U. The cardiometabolic drug rimonabant: after 2 years of RIO-Europe and STRADIVARIUS. Eur Heart J. 2008;29:1709–10.PubMedCrossrefGoogle Scholar

  • [94]

    Van Gaal L, Pi-Sunyer X, Després JP, McCarthy C, Scheen A. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the rimonabant in obesity (RIO) program. Diabetes Care. 2008;31:S229–40.CrossrefPubMedGoogle Scholar

  • [95]

    Christopoulou FD, Kiortsis DN. An overview of the metabolic effects of rimonabant in randomized controlled trials: potential for other cannabinoid 1 receptor blockers in obesity. J Clin Pharm Ther. 2011;36:10–8.PubMedCrossrefGoogle Scholar

  • [96]

    Fremming BA, Boyd ST. Taranabant, a novel cannabinoid type 1 receptor inverse agonist. Curr Opin Investig Drugs. 2008;9:1116–29.PubMedGoogle Scholar

  • [97]

    Brunner M. Pharmaceutical Drug Safety. In: Müller M, editor. Clinical pharmacology: current topics and case studies. Cham: Springer; 2016.Google Scholar

  • [98]

    Cota D. CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Diabetes Metab Res Rev. 2007;23:507–17.CrossrefPubMedGoogle Scholar

  • [99]

    Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab. 2012;16:167–79.PubMedCrossrefGoogle Scholar

  • [100]

    Nogueiras R, Veyrat-Durebex C, Suchanek PM, Klein M, Tschöp J, Caldwell C, et al. Peripheral, but not central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes. 2008;57:2977–91.CrossrefPubMedGoogle Scholar

  • [101]

    Tam J, Vemuri VK, Liu J, Bátkai S, Mukhopadhyay B, Godlewski G, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 2010;120:2953–66.PubMedCrossrefGoogle Scholar

  • [102]

    Jourdan T, Demizieux L, Gresti J, Djaouti L, Gaba L, Vergès B, et al. Antagonism of peripheral hepatic cannabinoid receptor-1 improves liver lipid metabolism in mice: evidence from cultured explants. Hepatology. 2012;55:790–9.PubMedCrossrefGoogle Scholar

  • [103]

    Hsiao WC, Shia KS, Wang YT, Yeh YN, Chang CP, Lin Y, et al. A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis. Diabetes Obes Metab. 2015;17:495–504.CrossrefPubMedGoogle Scholar

  • [104]

    Chen W, Shui F, Liu C, Zhou X, Li W, Zheng Z, et al. Novel peripherally restricted cannabinoid 1 receptor selective antagonist TXX-522 with prominent weight-loss efficacy in diet induced obese mice. Front Pharmacol. 2017;8:707.PubMedCrossrefGoogle Scholar

  • [105]

    Lazzari P, Pau A, Tambaro S, Asproni B, Ruiu S, Pinna G, et al. Synthesis and pharmacological evaluation of novel 4-alkyl-5-thien-2′-yl pyrazole carboxamides. Cent Nerv Syst Agents Med Chem. 2012;12:254–76.PubMedCrossrefGoogle Scholar

  • [106]

    Manca I, Mastinu A, Olimpieri F, Falzoi M, Sani M, Ruiu S, et al. Novel pyrazole derivatives as neutral CB₁ antagonists with significant activity towards food intake. Eur J Med Chem. 2013;62:256–69.PubMedCrossrefGoogle Scholar

  • [107]

    Fulp A, Zhang Y, Bortoff K, Seltzman H, Snyder R, Wiethe R, et al. Pyrazole antagonists of the CB1 receptor with reduced brain penetration. Bioorg Med Chem. 2016;24:1063–70.CrossrefPubMedGoogle Scholar

  • [108]

    Mastinu A, Pira M, Pani L, Pinna GA, Lazzari P. NESS038C6, a novel selective CB1 antagonist agent with anti-obesity activity and improved molecular profile. Behav Brain Res. 2012;234:192–204.CrossrefPubMedGoogle Scholar

  • [109]

    Mastinu A, Pira M, Pinna GA, Pisu C, Casu MA, Reali R, et al. NESS06SM reduces body weight with an improved profile relative to SR141716A. Pharmacol Res. 2013;74:94–108.CrossrefPubMedGoogle Scholar

  • [110]

    Lazzari P, Serra V, Marcello S, Pira M, Mastinu A. Metabolic side effects induced by olanzapine treatment are neutralized by CB1 receptor antagonist compounds co-administration in female rats. Eur Neuropsychopharmacol. 2017;27:667–78.CrossrefPubMedGoogle Scholar

  • [111]

    Meye FJ, Trezza V, Vanderschuren LJ, Ramakers GM, Adan RA. Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity. Mol Psychiatry. 2013;18:1294–301.PubMedCrossrefGoogle Scholar

  • [112]

    Freeman LC, Ting JP. The pathogenic role of the inflammasome in neurodegenerative diseases. J Neurochem. 2016;136:29–38.CrossrefPubMedGoogle Scholar

  • [113]

    Radtke FA, Chapman G, Hall J, Syed YA. Modulating Neuroinflammation to treat neuropsychiatric disorders. Biomed Res Int. 2017;2017:5071786.PubMedGoogle Scholar

  • [114]

    Bjorklund G, Saad K, Chirumbolo S, Kern JK, Geier DA, Geier MR, et al. Immune dysfunction and neuroinflammation in autism spectrum disorder. Acta Neurobiol Exp. 2016;76:257–268.Google Scholar

  • [115]

    Terrone G, Salamone A, Vezzani A. Inflammation and epilepsy: preclinical findings and potential clinical translation. Curr Pharm Des. 2017;23:5569–76.PubMedGoogle Scholar

  • [116]

    Vezzani A. Fetal brain inflammation may prime hyperexcitability and behavioral dysfunction later in life. Ann Neurol. 2013;74:1–3.CrossrefPubMedGoogle Scholar

  • [117]

    Calcia MA, Bonsall DR, Bloomfield PS, Selvaraj S, Barichello T, Howes OD. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology (Berl). 2016;233:1637–50.PubMedCrossrefGoogle Scholar

  • [118]

    Schwartz M, Deczkowska A. Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol. 2016;37:668–79.CrossrefPubMedGoogle Scholar

  • [119]

    Skaper SD. Mast cell – glia dialogue in chronic pain and neuropathic pain: blood-brain barrier implications. CNS Neurol Disord Drug Targets. 2016;15:1072–78.PubMedCrossrefGoogle Scholar

  • [120]

    Frasca D, Blomberg BB, Paganelli R. Aging, obesity, and inflammatory age-related diseases. Front Immunol. 2017;8:1745.PubMedCrossrefGoogle Scholar

  • [121]

    Skaper SD. Commentary. Low-grade non-resolving neuroinflammation: age does matter. CNS Neurol Disord Drug Targets. 2015;14:432–3.CrossrefPubMedGoogle Scholar

  • [122]

    Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8.CrossrefPubMedGoogle Scholar

  • [123]

    Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014;11:98.CrossrefPubMedGoogle Scholar

  • [124]

    Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA. Neuroinflammation and synaptic loss. Neurochem Res. 2012;37:903–10.CrossrefPubMedGoogle Scholar

  • [125]

    Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3:23–35.CrossrefGoogle Scholar

  • [126]

    Hong S, Dissing-Olesen L, Stevens B. New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol. 2016;36:128–34.CrossrefPubMedGoogle Scholar

  • [127]

    Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017;23:1018–27.CrossrefPubMedGoogle Scholar

  • [128]

    Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10:698–712.CrossrefPubMedGoogle Scholar

  • [129]

    Frost GR, Li YM. The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol. 2017;7:170228.PubMedCrossrefGoogle Scholar

  • [130]

    Rom S, Persidsky Y. Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol. 2013;8:608–20.PubMedCrossrefGoogle Scholar

  • [131]

    Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1:1333–49.PubMedCrossrefGoogle Scholar

  • [132]

    McCoy KL, Gainey D, Cabral GA. delta 9-Tetrahydrocannabinol modulates antigen processing by macrophages. J Pharmacol Exp Ther. 1995;273:1216–23.PubMedGoogle Scholar

  • [133]

    Mecha M, Feliú A, Carrillo-Salinas FJ, Rueda-Zubiaurre A, Ortega-Gutiérrez S, de Sola RG, et al. Endocannabinoids drive the acquisition of an alternative phenotype in microglia. Brain Behav Immun. 2015;49:233–45.PubMedCrossrefGoogle Scholar

  • [134]

    Cabral GA, Raborn ES, Griffin L, Dennis J, Marciano-Cabral F. CB2 receptors in the brain: role in central immune function. Br J Pharmacol. 2008;153:240–51.PubMedCrossrefGoogle Scholar

  • [135]

    Sánchez AJ, García-Merino A. Neuroprotective agents: cannabinoids. Clin Immunol. 2012;142:57–67.CrossrefPubMedGoogle Scholar

  • [136]

    Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005;5:400–11.CrossrefPubMedGoogle Scholar

  • [137]

    Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873–84.CrossrefPubMedGoogle Scholar

  • [138]

    Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y, et al. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J Neuroinflammation. 2005;2:29.CrossrefPubMedGoogle Scholar

  • [139]

    Buckley NE. The peripheral cannabinoid receptor knockout mice: an update. Br J Pharmacol. 2008;153:309–18.PubMedCrossrefGoogle Scholar

  • [140]

    Gertsch J. Anti-inflammatory cannabinoids in diet: towards a better understanding of CB(2) receptor action? Commun Integr Biol. 2008;1:26–8.PubMedCrossrefGoogle Scholar

  • [141]

    Tsou K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. 1998;83:393–411.CrossrefPubMedGoogle Scholar

  • [142]

    Farquhar-Smith WP, Egertová M, Bradbury EJ, McMahon SB, Rice AS, Elphick MR. Cannabinoid CB(1) receptor expression in rat spinal cord. Mol Cell Neurosci. 2000;15:510–21.CrossrefPubMedGoogle Scholar

  • [143]

    Hohmann AG, Herkenham M. Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience. 1999;90:923–31.PubMedCrossrefGoogle Scholar

  • [144]

    Sañudo-Peña MC, Tsou K, Walker JM. Motor actions of cannabinoids in the basal ganglia output nuclei. Life Sci. 1999;65:703–13.CrossrefPubMedGoogle Scholar

  • [145]

    Panikashvili D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A, et al. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Dis. 2006;22:257–64.CrossrefPubMedGoogle Scholar

  • [146]

    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;302:84–8.PubMedCrossrefGoogle Scholar

  • [147]

    Vrechi TA, Crunfli F, Costa AP, Torrão AS. Cannabinoid receptor type 1 agonist ACEA protects neurons from death and attenuates endoplasmic reticulum stress-related apoptotic pathway signaling. Neurotox Res. 2017. [Epub ahead of print].PubMedGoogle Scholar

  • [148]

    Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011;334:809–13.CrossrefPubMedGoogle Scholar

  • [149]

    Cabral GA, Griffin-Thomas L. Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med. 2009;11:e3.PubMedCrossrefGoogle Scholar

  • [150]

    Ramírez BG, Blázquez C, Gómez del Pulgar T, Guzmán M, de Ceballos ML. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005;25:1904–13.PubMedCrossrefGoogle Scholar

  • [151]

    Velez-Pardo C, Del Rio MJ. Avoidance of Abeta[(25-35)]/(H(2)O(2)) – induced apoptosis in lymphocytes by the cannabinoid agonists CP55,940 and JWH-015 via receptor-independent and PI3K-dependent mechanisms: role of NF-kappaB and p53. Med Chem. 2006;2:471–9.PubMedCrossrefGoogle Scholar

  • [152]

    Raine CS, Wu E. Multiple sclerosis: remyelination in acute lesions. J Neuropathol Exp Neurol. 1993;52:199–204.CrossrefPubMedGoogle Scholar

  • [153]

    Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, et al. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006;6:12.CrossrefPubMedGoogle Scholar

  • [154]

    Ortega-Gutiérrez S, Molina-Holgado E, Guaza C. Effect of anandamide uptake inhibition in the production of nitric oxide and in the release of cytokines in astrocyte cultures. Glia. 2005;52:163–8.PubMedCrossrefGoogle Scholar

  • [155]

    Mestre L, Correa F, Arévalo-Martín A, Molina-Holgado E, Valenti M, Ortar G, et al. Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis. J Neurochem. 2005;92:1327–39.CrossrefGoogle Scholar

  • [156]

    Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, et al. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron. 2006;49:67–79.PubMedCrossrefGoogle Scholar

  • [157]

    Fujiwara M, Egashira N. New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application. J Pharmacol Sci. 2004;96:362–6.CrossrefPubMedGoogle Scholar

  • [158]

    Johnson DR, Stebulis JA, Rossetti RG, Burstein SH, Zurier RB. Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid. J Cell Biochem. 2007;100:184–90.CrossrefPubMedGoogle Scholar

  • [159]

    Lowin T, Apitz M, Anders S, Straub RH. Anti-inflammatory effects of N-acylethanolamines in rheumatoid arthritis synovial cells are mediated by TRPV1 and TRPA1 in a COX-2 dependent manner. Arthritis Res Ther. 2015;17:321.CrossrefGoogle Scholar

  • [160]

    Selvi E, Lorenzini S, Garcia-Gonzalez E, Maggio R, Lazzerini PE, Capecchi PL, et al. Inhibitory effect of synthetic cannabinoids on cytokine production in rheumatoid fibroblast-like synoviocytes. Clin Exp Rheumatol. 2008;26:574–81.PubMedGoogle Scholar

  • [161]

    Fukuda S, Kohsaka H, Takayasu A, Yokoyama W, Miyabe C, Miyabe Y, et al. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis. BMC Musculoskelet Disord. 2014;15:275.CrossrefPubMedGoogle Scholar

  • [162]

    Soethoudt M, Grether U, Fingerle J, Grim TW, Fezza F, de Petrocellis L, et al. Cannabinoid CB(2) receptor ligand profiling reveals biased signalling and off-target activity. Nat Commun. 2017;8:13958.CrossrefGoogle Scholar

About the article

Received: 2018-02-02

Accepted: 2018-03-02

Published Online: 2018-03-30


Author Statement

Research funding: The authors state no funding involved.

Conflict of interest: The authors declare no conflict of interest.

Informed consent: Informed consent is not applicable.

Ethical approval: The conducted research is not related to either human or animals use.


Citation Information: Hormone Molecular Biology and Clinical Investigation, 20180013, ISSN (Online) 1868-1891, DOI: https://doi.org/10.1515/hmbci-2018-0013.

Export Citation

©2018 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Jorge Manzanares, David Cabañero, Nagore Puente, María S. García-Gutiérrez, Pedro Grandes, and Rafael Maldonado
Biochemical Pharmacology, 2018
[2]
Sara Anna Bonini, Marika Premoli, Simone Tambaro, Amit Kumar, Giuseppina Maccarinelli, Maurizio Memo, and Andrea Mastinu
Journal of Ethnopharmacology, 2018

Comments (0)

Please log in or register to comment.
Log in