Cannabinoid receptor-dependent metabolism of 2-arachidonoylglycerol during aging.
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.
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Edificio E1. Camino La Carrindanga Km 7, 8000 Bahía Blanca, Argentina.
Ana C
AC
Pascual
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Edificio E1. Camino La Carrindanga Km 7, 8000 Bahía Blanca, Argentina.
Virginia L
VL
Gaveglio
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Edificio E1. Camino La Carrindanga Km 7, 8000 Bahía Blanca, Argentina.
Norma M
NM
Giusto
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Edificio E1. Camino La Carrindanga Km 7, 8000 Bahía Blanca, Argentina. Electronic address: pasquare@criba.edu.ar.
Susana J
SJ
Pasquaré
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000378:metabolism; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism
D001095:Arachidonic Acids; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D008071:Lipoprotein Lipase; D010711:Phosphatidate Phosphatase
2-Arachidonoylglycerol; Aging; Cannabinoid receptors; Diacylglycerol lipase; Lysophosphatidate phosphohydrolase; Monoacylglycerol lipase