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

• Published in: Neuropharmacology Vol. 110; no. Pt A; pp. 519 - 529
• Main 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.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2016
• Subjects: Aging - drug effects; Aging - metabolism; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Amyloid beta-Protein Precursor; Amyloidosis - diagnostic imaging; Amyloidosis - drug therapy; Amyloidosis - metabolism; Anandamide (AEA); Animals; Arachidonic Acids - metabolism; Astrocytes - drug effects; Astrocytes - metabolism; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Cannabinoid CB2 receptor; Cannabinoid Receptor Modulators - pharmacology; Cells, Cultured; Cerebral glucose uptake; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2 (COX-2); Endocannabinoids - metabolism; Glucose - metabolism; Hydroxyethylrutoside; Male; Mice, Inbred C57BL; Mice, Transgenic; Neurons - drug effects; Neurons - metabolism; Nootropic Agents - pharmacology; Polyunsaturated Alkamides - metabolism; Positron emission tomography (PET); Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Receptor, Cannabinoid, CB2 - metabolism; Tissue Culture Techniques; β-amyloid; TgAPP; 25021165; FAAH; 2-NBDG; 5311006; JWH133 (PubChem CID; 5311501; JZL184 (PubChem CID; COX-2; 11507802; DMSO; 108223; Arachidonyl-2-chloroethylamide (PubChem CID; AM630 (PubChem CID; Anandamide (AEA); Ouabain (PubChem CID; 5281969; Cannabinoid CB2 receptor; 18FDG; DMEM; Anandamide (PubChem CID; 10252734; 4302963; 3Rs; 2-Deoxy-d-glucose (PubChem CID; MAGL; 5282280; WIN55212-2 (PubChem CID; Cerebral glucose uptake; AEA; WT; ABDH6/12; β-amyloid; GP1a (PubChem CID; ACEA; 3HDG; WWL70 (PubChem CID:17759121); Positron emission tomography (PET); LY2183240 (PubChem CID; 3177; DuP697 (PubChem CID; 2-Arachidonoylglycerol (PubChem CID; Cyclooxygenase-2 (COX-2); 6918505; 2-AG; CB1Rs and CB2Rs; HEPES; 439501; Cannabinoid CB receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.03.015

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 3H-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 18F-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. [Display omitted] •CB2R activation stimulates glucose uptake in the mouse brain in vivo.•CB2R activation rapidly stimulates glucose uptake in brain slices and cell cultures.•COX-2 inhibition also stimulates hippocampal glucose uptake via CB2R activation.•β-amyloidosis decreases anandamide levels, preventing the effect of COX-2 blockade.