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.

Targeted Lipidomics Investigation of N‐acylethanolamines in a Transgenic Mouse Model of AD: A Longitudinal Study

“…Likewise, AEA was reported to promote neurogenesis after Aβ‐induced neurotoxicity and reduce gliosis and cognitive decline in several models of neurodegenerative disease . AEA content in postmortem human midfrontal cortex was found to be inversely associated with Aβ42 peptide levels and to be reduced in the hippocampus of Tg mice . The trend towards a reduction of AEA and PEA brain levels in Tg mice appears, therefore, in partial agreement with the previously reported significant decrease .…”

“…AEA content in postmortem human midfrontal cortex was found to be inversely associated with Aβ42 peptide levels and to be reduced in the hippocampus of Tg mice . The trend towards a reduction of AEA and PEA brain levels in Tg mice appears, therefore, in partial agreement with the previously reported significant decrease . While the importance of appropriate levels of ω‐3 DHA (22:6), EPA (20:5), and ω‐9 oleic acid (18:1), and balanced proportion of phospholipids (PLP) for healthy ageing is well acknowledged, the involvement of EPEA and DHEA in neurodegenerative diseases is still poorly understood.…”

Endocannabinoid system in neurodegenerative disorders

“…The levels of AEA were reduced in the hippocampus of a mouse genetic model of AD (transgenic mice overexpressing amyloid precursor protein, APP) (TgAPP‐2576) (Kofalvi et al . ). The ECs acting through transient receptor potential cation channel subfamily V member 1 (TRPV1) were suggested to play a significant role in Aβ‐induced cognitive impairment in D3 receptor KO mice (Micale et al .…”

Astrocytic transporters in Alzheimer's disease

“…For example, a recent study has reported the use of a cannabinoid receptor type 2 agonist to enhance CNS glucose uptake (131). Interventions targeting β-adrenoceptors, which induce glucose uptake and storage and breakdown of glycogen in astrocytes, also have promise to improve the supply of glucose and lactate to neurons and modify disease progression (132,133).…”