Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6/2 mice, a transgenic model of Huntington's disease

Abstract Previous studies have shown an impairment of the endocannabinoid system in experimental models of Huntington's disease. In transgenic R6/ 2 mice, created by inserting exon 1 of the human IT15 mutant gene into the mouse, and exhibiting 150 CAG repeats as well as signs of HD, a progressive decline of CB1 receptor expression and an abnormal sensitivity to CB1 receptor stimulation have been reported. Here, by using isotope-dilution liquid chromatography-mass spectrometry, we investigated whether the levels of three endogenous neuroprotective substances, the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and palmitoylethanolamide (PEA), are altered in different brain areas of transgenic R6/2 versus wild-type (WT)mice at two different disease phases, i.e. in pre-symptomatic (4.5 weeks) or overtly symptomatic (10 weeks) R6/2 mice versus age-matched WT mice (n = 4/group). Except for a 25% decrease in 2-AG levels in the cortex, no significant changes in endocannabinoid and PEAlevelswere observed in pre-symptomaticR6/2 versusWTmice.By contrast, in symptomaticR6/2mice the levels of all three compounds were significantly (30-60%) decreased in the striatum,whereas little changeswere observed in the hippocampus, and a 28% decrease of 2-AG levels, accompanied by a 50% increase of AEA levels, was found in the cortex. These findings show that endocannabinoid levels change in a disease phase- and region-specific way in the brain of R6/2 mice and indicate that an impaired endocannabinoid system is a hallmark of symptomatic HD, thus suggesting that drugs inhibiting endocannabinoid degradation might be used to treat this disease.