Robert B Laprairie a , b , Amina M Bagher c , b , Jillian L Rourke b , d , Adel Zrein b , Elizabeth A Cairns b , Melanie E M Kelly b , e , Christopher J Sinal b , Pushkar M Kulkarni f , Ganesh A Thakur f , Eileen M Denovan-Wright b , *
30 March 2019
Huntington’s disease (HD) is an inherited progressive neurodegenerative disease characterized by motor, cognitive, and behavioural changes. One of the earliest changes to occur in HD is a reduction in cannabinoid 1 receptor (CB 1) levels in the striatum, which is strongly correlated with HD pathogenesis. CB 1 positive allosteric modulators (PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands, including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of this study was to determine whether the recently characterized CB 1 allosteric modulators GAT211 (racemic), GAT228 ( R-enantiomer), and GAT229 ( S-enantiomer), affected the signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice, 10 mg/kg/d, 21 d, i.p.). GAT229 was a CB 1 PAM that improved cell viability in HD cells and improved motor coordination, delayed symptom onset, and normalized gene expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed intermediate effects between its enantiomers. The compounds used here are not drugs, but probe compounds used to determine the potential utility of CB 1 PAMs in HD. Changes in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis is associated with dysregulation of mRNA levels. The data presented here provide the first proof of principle for the use of CB 1 PAMs to treat the signs and symptoms of HD.