Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease. (November 2016)

• Record Type: Journal Article
• Authors: Köfalvi, Attila; Lemos, Cristina; Martín-Moreno, Ana M.; Pinheiro, Bárbara S.; García-García, Luis; Pozo, Miguel A.; Valério-Fernandes, Ângela; Beleza, Rui O.; Agostinho, Paula; Rodrigues, Ricardo J.; Pasquaré, Susana J.; Cunha, Rodrigo A.; de Ceballos, María L.
• Is Part Of: Neuropharmacology. Volume 110(2016) Part A
• Page Start: 519
• Page End: 529
• Publication Date: 2016-11
• Subjects: Anandamide (AEA) -- β-amyloid -- Cerebral glucose uptake -- Cannabinoid CB2 receptor -- Cyclooxygenase-2 (COX-2) -- Positron emission tomography (PET); 2-AG 2-arachidonoylglycerol -- 3Rs replacement, refinement and reduction of animals in research -- ABDH6/12 α/β-hydrolase domain 6/12 -- ACEA arachidonyl-2′-chloroethylamide -- AEA anandamide (N-arachidonoylethanolamine) -- CB1Rs and CB2Rs cannabinoid CB1 and CB2 receptors -- COX-2 cycloxygenase-2 -- DMEM Dulbecco's modified eagle medium -- 3HDG 3H-2-deoxyglucose -- DMSO dimethyl-sulfoxide -- FAAH fatty acid amide hydrolase -- 18FDG 18F-fluoro-deoxyglucose -- HEPES N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) -- MAGL monoacylglycerol lipase -- 2-NBDG 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-2-deoxyglucose -- TgAPP transgenic amyloid precursor protein -- WT wild-type; AM630 (PubChem CID -- 4302963) -- Anandamide (PubChem CID -- 5281969) -- Arachidonyl-2-chloroethylamide (PubChem CID -- 5311006) -- 2-Arachidonoylglycerol (PubChem CID -- 5282280) -- 2-Deoxy-d-glucose (PubChem CID -- 108223) -- DuP697 (PubChem CID -- 3177) -- GP1a (PubChem CID -- 10252734) -- JWH133 (PubChem CID -- 6918505) -- JZL184 (PubChem CID -- 25021165) -- LY2183240 (PubChem CID -- 11507802) -- Ouabain (PubChem CID -- 439501) -- WIN55212-2 (PubChem CID -- 5311501) -- WWL70 (PubChem CID:17759121); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.03.015
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Cannabinoid CB2 receptors (CB2 Rs) are emerging as important therapeutic targets in brain disorders that typically involve neurometabolic alterations. We here addressed the possible role of CB2 Rs 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) CB2 R agonists, but not the CB1 R-selective agonist, ACEA, stimulate glucose uptake, in a manner that is sensitive to the CB2 R-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 CB2 Rs in the brain, raising therapeutic interest in CB2 R agonists as nootropic agents. Graphical abstract: Highlights: CB2 R activation stimulates glucose uptake in the mouse brain in vivo . CB2 R activation rapidly stimulates glucose uptake in brain slices and cell cultures. COX-2 inhibition also stimulates hippocampal glucose uptake via CB2 R activation. β-amyloidosis decreases anandamide levels, preventing the effect of COX-2 blockade.