title: In vitro and in vivo models of Huntington's disease show alterations in the endocannabinoid system.
abstract: In this study, we analyzed the components of the endocannabinoid system (ECS) in R6/2 mice, a widely used model of Huntington's disease (HD). We measured the endogenous content of N-arachidonoylethanolamine and 2-arachidonoylglycerol and the activity of their biosynthetic enzymes (N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and diacylglycerol lipase, respectively) and hydrolytic enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively] and of their target receptors (type 1 cannabinoid receptor, type 2 cannabinoid receptor, and transient receptor potential vanilloid-1) in the brains of wild-type and R6/2 mice of different ages, as well as in the striatum and cortex of 12-week-old animals. In addition, we measured FAAH activity in lymphocytes of R6/2 mice. In the whole brains of 12-week-old R6/2 mice, we found reductions in N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D activity, diacylglycerol lipase activity and cannabinoid receptor binding, mostly associated with changes in the striatum but not in the cortex, as well as an increase in 2-arachidonoylglycerol content as compared with wild-type littermates, without any other change in ECS elements. Then, our analysis was extended to HD43 cells, an inducible cellular model of HD derived from rat ST14A cells. In both induced and noninduced conditions, we demonstrated a fully functional ECS. Overall, our data suggest that the ECS is differently affected in mouse and human HD, and that HD43 cells are suitable for high-throughput screening of FAAH-oriented drugs affecting HD progression.
authors: Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy.
authors: Monica
authors: M
authors: Bari
authors: Natalia
authors: N
authors: Battista
authors: Marta
authors: M
authors: Valenza
authors: Nicolina
authors: N
authors: Mastrangelo
authors: Marinella
authors: M
authors: Malaponti
authors: Giuseppina
authors: G
authors: Catanzaro
authors: Diego
authors: D
authors: Centonze
authors: Alessandro
authors: A
authors: Finazzi-Agrò
authors: Elena
authors: E
authors: Cattaneo
authors: Mauro
authors: M
authors: Maccarrone
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism / Q000502:physiology*; D005989:Glycerides / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D007700:Kinetics; D008214:Lymphocytes / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D017072:Neostriatum / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D051381:Rats; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C094503:glyceryl 2-arachidonate; C078814:anandamide
keywords: Huntington's disease; R6/2 mice; endocannabinoid; fatty acid amide hydrolase (FAAH); lymphocyte