title: Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease.
abstract: Cannabinoid CB2 receptors (CB2Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of (3)H-deoxyglucose uptake in cultured cortical astrocytes and neurons and in acute hippocampal slices; 2) real-time visualization of fluorescently labeled deoxyglucose uptake in superfused hippocampal slices; and 3) in vivo PET imaging of cerebral (18)F-fluorodeoxyglucose uptake. We now show that both selective (JWH133 and GP1a) as well as non-selective (WIN55212-2) CB2R agonists, but not the CB1R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2R-selective antagonist, AM630. Glucose uptake is stimulated in astrocytes and neurons in culture, in acute hippocampal slices, in different brain areas of young adult male C57Bl/6j and CD-1 mice, as well as in middle-aged C57Bl/6j mice. Among the endocannabinoid metabolizing enzymes, the selective inhibition of COX-2, rather than that of FAAH, MAGL or α,βDH6/12, also stimulates the uptake of glucose in hippocampal slices of middle-aged mice, an effect that was again prevented by AM630. However, we found the levels of the endocannabinoid, anandamide reduced in the hippocampus of TgAPP-2576 mice (a model of β-amyloidosis), and likely as a consequence, COX-2 inhibition failed to stimulate glucose uptake in these mice. Together, these results reveal a novel general glucoregulatory role for CB2Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
authors.forename: Attila
authors.initials: A
authors.lastname: Köfalvi
authors.affiliation: CNC - Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lemos
authors.affiliation: Neurodegeneration Group, Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, CSIC, Doctor Arce, 37, 28002 Madrid, Spain; CIBERNED; Centre for Biomedical Research on Neurodegenerative Diseases, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Martín-Moreno
authors.affiliation: CNC - Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Bárbara S
authors.initials: BS
authors.lastname: Pinheiro
authors.affiliation: CAI de Cartografía Cerebral, Instituto Pluridisciplinar, UCM, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: García-García
authors.affiliation: CAI de Cartografía Cerebral, Instituto Pluridisciplinar, UCM, Madrid, Spain; PET Technology Institute, Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Pozo
authors.affiliation: CNC - Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Ângela
authors.initials: Â
authors.lastname: Valério-Fernandes
authors.affiliation: CNC - Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Rui O
authors.initials: RO
authors.lastname: Beleza
authors.affiliation: CNC - Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; FMUC, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Agostinho
authors.affiliation: CNC - Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Rodrigues
authors.affiliation: Neurodegeneration Group, Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, CSIC, Doctor Arce, 37, 28002 Madrid, Spain; Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), CONICET-Bahía Blanca and Universidad Nacional del Sur, Edificio E1, Camino La Carrindanga km 7, 8000 Bahía Blanca, Argentina.
authors.forename: Susana J
authors.initials: SJ
authors.lastname: Pasquaré
authors.affiliation: CNC - Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-504 Coimbra, Portugal; FMUC, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: Neurodegeneration Group, Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, CSIC, Doctor Arce, 37, 28002 Madrid, Spain; CIBERNED; Centre for Biomedical Research on Neurodegenerative Diseases, Spain. Electronic address: mceballos@cajal.csic.es.
authors.forename: María L
authors.initials: ML
authors.lastname: de Ceballos
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor; D000686:Amyloidosis / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006896:Hydroxyethylrutoside; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; C571431:Cnr2 protein, mouse; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D006896:Hydroxyethylrutoside; D018697:Nootropic Agents; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D005947:Glucose; C078814:anandamide
keywords: 10252734); 108223); 11507802); 2-Arachidonoylglycerol (PubChem CID; 2-Deoxy-d-glucose (PubChem CID; 25021165); 3177); 4302963); 439501); 5281969); 5282280); 5311006); 5311501); 6918505); AM630 (PubChem CID; Anandamide (AEA); Anandamide (PubChem CID; Arachidonyl-2-chloroethylamide (PubChem CID; Cannabinoid CB(2) receptor; Cerebral glucose uptake; Cyclooxygenase-2 (COX-2); DuP697 (PubChem CID; GP1a (PubChem CID; JWH133 (PubChem CID; JZL184 (PubChem CID; LY2183240 (PubChem CID; Ouabain (PubChem CID; Positron emission tomography (PET); WIN55212-2 (PubChem CID; WWL70 (PubChem CID:17759121); β-amyloid