Aging modifies the enzymatic activities involved in 2‐arachidonoylglycerol metabolism

Pascual, Ana Clara; Gaveglio, Virginia Lucía; Giusto, Norma M.; Pasquaré, Susana J.

doi:10.1002/biof.1055

Cited by 20 publications

(19 citation statements)

References 47 publications

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“…Therefore, specific increase in 2-AG levels observed in middle-age Ts65Dn mice could be related to the associated Alzheimer's disease-like neuropathology. Alternatively, the relative increase in older Ts65Dn mice may be secondary to age-dependent changes, since alterations in the expression and activity of endocannabinoid metabolic enzymes and particularly, in MAGL and DAGLα, have been described in aged rodents (Pascual et al, 2013;Piyanova et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome

Navarro-Romero

Vázquez-Oliver

Gomis-González

et al. 2019

Neurobiology of Disease

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Intellectual disability is the most limiting hallmark of Down syndrome, for which there is no gold-standard clinical treatment yet. The endocannabinoid system is a widespread neuromodulatory system involved in multiple functions including learning and memory processes. Alterations of this system contribute to the pathogenesis of several neurological and neurodevelopmental disorders. However, the involvement of the endocannabinoid system in the pathogenesis of Down syndrome has not been explored before. We used the best-characterized preclinical model of Down syndrome, the segmentally trisomic Ts65Dn model. In male Ts65Dn mice, cannabinoid type-1 receptor (CB1R) expression was enhanced and its function increased in hippocampal excitatory terminals. Knockdown of CB1R in the hippocampus of male Ts65Dn mice restored hippocampal-dependent memory. Concomitant with this result, pharmacological inhibition of CB1R restored memory deficits, hippocampal synaptic plasticity and adult neurogenesis in the subgranular zone of the dentate gyrus. Notably, the blockade of CB1R also normalized hippocampal-dependent memory in female Ts65Dn mice. To further investigate the mechanisms involved, we used a second transgenic mouse model overexpressing a single gene candidate for Down syndrome cognitive phenotypes, the dual specificity tyrosinephosphorylation-regulated kinase 1A (DYRK1A). CB1R pharmacological blockade similarly improved cognitive performance, synaptic plasticity and neurogenesis in transgenic male Dyrk1A mice. Our results identify CB1R as a novel druggable target potentially relevant for the improvement of cognitive deficits associated with Down syndrome.

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Section: Discussionmentioning

confidence: 99%

Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome

Navarro-Romero

Vázquez-Oliver

Gomis-González

et al. 2019

Neurobiology of Disease

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“…One possible explanation may involve aging‐related increases in endocannabinoid/CB1R tone in regions of the brain associated with appetite regulation, such as the nucleus accumbens (Maldonado‐Irizarry et al ., 1995; Winters et al ., 2012). Indeed, these changes may be brought about by increased CB1R expression, or in response to the altered activity of enzymes implicated in the synthesis and/or degradation of endocannabinoids (Pascual et al ., 2013). Consequently, such a scenario may convey the apparent augmentation of rimonabant's anorectic response in older mice.…”

Section: Discussionmentioning

confidence: 99%

“…Despite advances in our understanding of metabolic regulation by the ECS, as well as previous reports of age‐related deregulation of cannabinoid receptors and endocannabinoid hydrolysing enzymes (Pascual et al ., 2013, 2014), little is known regarding the involvement of this signalling system in aging‐associated metabolic dysfunction. Herein, we explored the effects of chronic (14 day) administration of rimonabant (SR141716), a potent and selective CB1R inverse agonist (Landsman et al ., 1997), on the energy budgets of young (4 month old) and aged (17 month old) adult male mice.…”

Section: Introductionmentioning

confidence: 99%

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

et al. 2016

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SummaryThe endocannabinoid system can modulate energy homeostasis by regulating feeding behaviour as well as peripheral energy storage and utilization. Importantly, many of its metabolic actions are mediated through the cannabinoid type 1 receptor (CB1R), whose hyperactivation is associated with obesity and impaired metabolic function. Herein, we explored the effects of administering rimonabant, a selective CB1R inverse agonist, upon key metabolic parameters in young (4 month old) and aged (17 month old) adult male C57BL/6 mice. Daily treatment with rimonabant for 14 days transiently reduced food intake in young and aged mice; however, the anorectic response was more profound in aged animals, coinciding with a substantive loss in body fat mass. Notably, reduced insulin sensitivity in aged skeletal muscle and liver concurred with increased CB1R mRNA abundance. Strikingly, rimonabant was shown to improve glucose tolerance and enhance skeletal muscle and liver insulin sensitivity in aged, but not young, adult mice. Moreover, rimonabant‐mediated insulin sensitization in aged adipose tissue coincided with amelioration of low‐grade inflammation and repressed lipogenic gene expression. Collectively, our findings indicate a key role for CB1R in aging‐related insulin resistance and metabolic dysfunction and highlight CB1R blockade as a potential strategy for combating metabolic disorders associated with aging.

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“…Thus, the activity of these enzymes in the regulation of anandamide and 2-AG contents is critical. In this regard, Pascual et al ., (2014) demonstrated that FAAH activity was decreased in the frontal cortex from patients with Alzheimer's disease [ 139 ] whereas the similar findings were reported for MAGL in Alzheimer's disease experimental murine models [ 140 - 142 ]. In line with this data, Piyanova et al ., (2015) found an elevated MAGL activity during aging [ 143 ].…”

Section: Does the Endocannabinoid System Modulate Sleep Disorders In mentioning

confidence: 77%

The Endocannabinoid System May Modulate Sleep Disorders in Aging

Murillo-Rodrı́guez

Budde

Veras

et al. 2020

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Aging is an inevitable process that involves changes across life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden. Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tool since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as an option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle. This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in the aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.

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Aging modifies the enzymatic activities involved in 2‐arachidonoylglycerol metabolism

Cited by 20 publications

References 47 publications

Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome

Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

The Endocannabinoid System May Modulate Sleep Disorders in Aging

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