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. 2014 Jul:55:134-42.
doi: 10.1016/j.exger.2014.04.008. Epub 2014 Apr 24.

Cannabinoid receptor-dependent metabolism of 2-arachidonoylglycerol during aging

Ana C Pascual  1 , Virginia L Gaveglio  1 , Norma M Giusto  1 , Susana J Pasquaré  2
Affiliations

Cannabinoid receptor-dependent metabolism of 2-arachidonoylglycerol during aging

Ana C Pascual et al. Exp Gerontol. 2014 Jul.

Abstract

2-Arachidonoylglycerol (2-AG) is one of the principal endocannabinoids involved in the protection against neurodegenerative processes. Cannabinoids primarily interact with the seven-segment transmembrane cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), both of which are expressed in the central nervous system (CNS). The level of 2-AG is controlled through key enzymes responsible for its synthesis or degradation. We have previously observed a deregulation of 2-AG metabolism in physiological aging. The aim of this study was to analyze how 2-AG metabolism is modulated by CB1/CB2 receptors during aging. To this end, both CB1 and CB2 receptor expression and the enzymatic activities (diacylglycerol lipase (DAGL), lysophosphatidate phosphohydrolase (LPAase) and monoacylglycerol lipase (MAGL)) involved in 2-AG metabolism were analyzed in the presence of cannabinoid receptor (CBR) agonists (WIN and JWH) and/or antagonists (SR1 and SR2) in synaptosomes from adult and aged rat cerebral cortex (CC). Our results demonstrate that: (a) aging decreases the expression of both CBRs; (b) LPAase inhibition, due to the individual action of SR1 or SR2, is reverted in the presence of both antagonists together; (c) LPAase activity is regulated mainly by the CB1 receptor in adult and in aged synaptosomes while the CB2 receptor acquires importance when CB1 is blocked; (d) modulation via CBRs of DAGL and MAGL by both antagonists occurs only in aged synaptosomes, stimulating DAGL and inhibiting MAGL activities; (e) only DAGL stimulation is reverted by WIN. Taken together, the results of the present study show that CB1 and/or CB2 receptor antagonists trigger a significant modulation of 2-AG metabolism, underlining their relevance as therapeutic strategy for controlling endocannabinoid levels in physiological aging.

Keywords: 2-Arachidonoylglycerol; Aging; Cannabinoid receptors; Diacylglycerol lipase; Lysophosphatidate phosphohydrolase; Monoacylglycerol lipase.

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