The endocannabinoid system shows different alterations in in vitro and in vivo models of Huntington’s disease

Introduction: In this investigation we analyzed the main components of the so-called “endocannabinoid system” (ECS) in R6/2 mice, a widely used model of Huntington’s disease (HD). Methods: We measured the endogenous content of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), of their biosynthetic (NAPE-PLD and DAGL, respectively) and hydrolytic enzymes (FAAH and MAGL, respectively), and of their target receptors (CB1, CB2 and TRPV1) in the brain of wild-type and R6/2 mice of different ages. In addition, we measured FAAH activity in lymphocytes of R6/2 mice, in order to evaluate whether central ECS alterations were mirrored by peripheral cells. Results: In 12-week-old R6/2 mice we found a reduction of NAPE-PLD and DAGL activity, and of CB binding, as well as an increase in 2-AG content when compared to wild-type littermates, without any other change in ECS elements. Our analysis was extended to HD43 cells, an inducible cellular model of HD derived from rat ST14A cells. In both induced and non-induced conditions we demonstrated a fully functional ECS, and we showed that HD43 cells replicate the decrease in FAAH activity (half of that measured in ST14A cells) already observed in human brain and lymphocytes of HD patients. Conclusions: Overall, our data suggest that 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. [...]