Symptom-related changes of endocannabinoid and palmitoylethanolamide levels in brain areas of R6/2 mice, a transgenic model of Huntington's disease.
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 CB(1) receptor expression and an abnormal sensitivity to CB(1) 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 approximately 25% decrease in 2-AG levels in the cortex, no significant changes in endocannabinoid and PEA levels were observed in pre-symptomatic R6/2 versus WT mice. By contrast, in symptomatic R6/2 mice the levels of all three compounds were significantly (approximately 30-60%) decreased in the striatum, whereas little changes were observed in the hippocampus, and a approximately 28% decrease of 2-AG levels, accompanied by a approximately 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.
Bisogno
Tiziana
T
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Naples, Italy.
Martire
Alberto
A
Petrosino
Stefania
S
Popoli
Patrizia
P
Di Marzo
Vincenzo
V
D000577:Amides; D000818:Animals; D001921:Brain / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D004195:Disease Models, Animal; D063388:Endocannabinoids; D004983:Ethanolamines; D006816:Huntington Disease / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010169:Palmitic Acids / Q000378:metabolism*
D000577:Amides; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004983:Ethanolamines; D010169:Palmitic Acids; C005958:palmidrol