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

Attila Köfalvi, Cristina Lemos, Ana M. Martín-Moreno, Bárbara S. Pinheiro, Luis García-García, Miguel A. Pozo, Ângela Valério-Fernandes, Rui O. Beleza, Paula Agostinho, Ricardo J. Rodrigues, Susana J. Pasquaré, Rodrigo A. Cunha, María L. de Ceballos
Neuropharmacology. 2016-11-01; 110: 519-529
DOI: 10.1016/j.neuropharm.2016.03.015

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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.


Auteurs Bordeaux Neurocampus