rutin and Alzheimer-Disease

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.

Topics: Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Arachidonic Acids; Astrocytes; Brain; Cannabinoid Receptor Modulators; Cells, Cultured; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Endocannabinoids; Glucose; Hydroxyethylrutoside; Male; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Nootropic Agents; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB2; Tissue Culture Techniques

Alzheimer׳s disease (AD) is a neurodegenerative disorder with a progressive cognitive decline and memory loss. Multiple pathogenetic factors including aggregated β-amyloid (Aβ), neurofibrillary tangles (NFTs), cholinergic dysfunction and oxidative stress are involved in AD. Aβ, a major constituent of the senile plaques, is a potent neurotoxic peptide and has a pivotal role in cognitive deficit and reduced synaptic plasticity in AD. In the present study we examined the protective effect of troxerutin, as a multipotent bioflavonoid, on Aβ (1-42)-induced impairment of evoked field potential in hippocampal DG neurons. Male Wistar rats were divided into four groups including Aβ (42-1), Aβ (1-42), Aβ (1-42) plus troxerutin and Aβ (42-1) plus troxerutin groups. Aβ was injected intracerebroventricularly (i.c.v.) into right lateral ventricle and after two weeks the evoked field potential recorded from perforant path-DG synapses to assess paired pulse paradigm and long term potentiation (LTP). Administration of Aβ (1-42) drastically attenuated the LTP of DG neurons, while there was no significant difference in evoked field potentials between Aβ (1-42) plus troxerutin group with respect to Aβ (42-1) group. This study revealed that troxerutin improves the synaptic failure induced by Aβ peptide and can be introduced as a promising multi-potent pharmacological agent in prevention or treatment of AD in the future.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Dentate Gyrus; Electrophysiological Phenomena; Hydroxyethylrutoside; Long-Term Potentiation; Male; Maze Learning; Memory Disorders; Neuronal Plasticity; Neuroprotective Agents; Rats; Rats, Wistar; Synapses