Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease

NEUROPHARMACOLOGY

卷:110

Article

Kofalvi, Attila^1,2  Lemos, Cristina^1,11  Martin-Moreno, Ana M.^3,4,10  Pinheiro, Barbara S.^1,11  Garcia-Garcia, Luis⁵  Pozo, Miguel A.^5,6  Valerio-Fernandes, Angela¹  Beleza, Rui O.¹  Agostinho, Paula^1,7  Rodrigues, Ricardo J.^1,2  Pasquare, Susana J.^3,8,9  Cunha, Rodrigo A.^1,7  de Ceballos, Maria L.^3,4 

[1] Univ Coimbra, CNC Ctr Neurosci & Cell Biol Coimbra, P-3004504 Coimbra, Portugal

[2] Univ Coimbra, Inst Interdisciplinary Res, Coimbra, Portugal

[3] CSIC, Inst Cajal, Dept Cellular Mol & Dev Neurobiol, Neurodegenerat Grp, Doctor Arce,37, E-28002 Madrid, Spain

[4] CIBERNED Ctr Biomed Res Neurodegenerat Dis, Madrid, Spain

[5] UCM, Inst Pluridisciplinar, CAI Cartograffa Cerebral, Madrid, Spain

[6] PET Technol Inst, Madrid, Spain

[7] Univ Coimbra, Fac Med, FMUC, Coimbra, Portugal

[8] CONICET Bahia Blanca, Inst Invest Bioquim Bahia Blanca INIBIBB, Edificio E1,Camino La Carrindanga Km 7, RA-8000 Bahia Blanca, Argentina

[9] Univ Nacl Sur, Edificio E1,Camino La Carrindanga Km 7, RA-8000 Bahia Blanca, Argentina

[10] MD Anderson Canc Ctr, Arturo Soria 270, Madrid 28033, Spain

[11] Med Univ Innsbruck, Ctr Psychiat & Psychotherapy, Expt Psychiat Unit, A-6020 Innsbruck, Austria

关键词: Anandamide (AEA);    beta-amyloid;    Cerebral glucose uptake;    Cannabinoid CB2 receptor;    Cyclooxygenase-2 (COX-2);    Positron emission tomography (PET);   

DOI  :  10.1016/j.neuropharm.2016.03.015

来源: Elsevier

【 摘 要 】

Cannabinoid CB2 receptors (CB(2)Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB(2)Rs in the regulation of glucose uptake in the mouse brain. To that aim, we have undertaken 1) measurement of H-3-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 F-18-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 alpha,beta DH6/12, 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 beta-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 CB(2)Rs in the brain, raising therapeutic interest in CB2R agonists as nootropic agents. (C) 2016 The Authors. Published by Elsevier Ltd.

【 授权许可】

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