Author: Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM.
Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB1) decrease in the basal ganglia. Decreasing CB1 levels are strongly correlated with chorea and cognitive deficit. CB1 agonists are functionally selective (biased) for divergent signalling pathways. In this study, sixcannabinoids were tested for signalling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdhQ7/Q7) or mutant huntingtin protein (STHdhQ111/Q111). Signalling bias was assessed using the Black and Leff operational model. Relative activity [ΔlogR (τ;/KA)] and system bias (ΔΔlogR) were calculated relative to the reference compound WIN55,212-2 for Gα;i/o, Gαs, Gαq, Gβγ, and β-arrestin1 signalling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC+CBD (1:1) and compared between wild-type and HD cells. The Emax of Gαi/o-dependent ERK signalling was 50% lower in HD cells compared to wild-type cells. 2-AG and AEA displayed Gαi/o/Gβγ bias and normalized CB1 protein levels and improved cell viability, whereas CP55,940 and THC displayed β-arrestin1 bias and reduced CB1 protein levels and cell viability, in HD cells. CBD was not a CB1 agonist, but inhibited THC-dependent signalling (THC+CBD). Therefore, enhancing Gαi/o-biased endocannabinoid signalling may be therapeutically beneficial in HD. In contrast, cannabinoids that are β-arrestin-biased – such as THC found at high levels in modern varieties of marijuana – may be detrimental to CB1 signalling, particularly in HD where CB1 levels are already reduced.
The American Society for Pharmacology and Experimental Therapeutics.