Cannabinoid signaling modulation through JZL184 restores key phenotypes of a mouse model for Williams–Beuren syndrome

Abstract

Williams–Beuren syndrome (WBS) is a rare genetic multisystemic disorder characterized by mild-to-moderate intellectual disability and hypersocial phenotype, while the most life-threatening features are cardiovascular abnormalities. Nowadays, there are no pharmacological treatments to directly ameliorate the main traits of WBS. The endocannabinoid system (ECS), given its relevance for both cognitive and cardiovascular function, could be a potential druggable target in this syndrome. We analyzed the components of the ECS in the complete deletion (CD) mouse model of WBS and assessed the impact of its pharmacological modulation in key phenotypes relevant for WBS. CD mice showed the characteristic hypersociable phenotype with no preference for social novelty and poor short-term object-recognition performance. Brain cannabinoid type-1 receptor (CB1R) in CD male mice showed alterations in density and coupling with no detectable change in main endocannabinoids. Endocannabinoid signaling modulation with subchronic (10 days) JZL184, a selective inhibitor of monoacylglycerol lipase, specifically normalized the social and cognitive phenotype of CD mice. Notably, JZL184 treatment improved cardiovascular function and restored gene expression patterns in cardiac tissue. These results reveal the modulation of the ECS as a promising novel therapeutic approach to improve key phenotypic alterations in WBS.

Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis

“…In the only publication describing the effects of chronic administration of a MAGL inhibitor, JZL184 (8 mg/kg; i.p. ) given for 10 days normalized the enhanced SBP determined in a mouse model for the Williams-Beuren syndrome [ 21 ].…”

“…Importantly, 2-AG released in response to vasoconstrictors (e.g., phenylephrine) acts protectively against enhanced vascular tone via CB 1 receptor-mediated vasorelaxation; this mechanism has also been determined in mesenteric arteries of SHR [ 19 ]. The MAGL inhibitor JZL184 decreased HR, but not BP, in pithed rats [ 20 ]; its chronic administration diminished the enhanced BP in a mouse model of the Williams–Beuren syndrome (i.e., a genetic disorder affecting the heart, the face and many other parts of the body; [ 21 ]). It is also worth noting that in normotensive rats the 2-AG levels are higher than those of AEA not only in the brain [ 22 ], but also in the heart [ 23 , 24 ] and in the blood vessels [ 19 ].…”

Sub-chronic peripheral CB1R inhibition enhances cognitive performance and induces hippocampal synaptic plasticity changes in naïve mice

“…The elevated plus maze test was performed as previously described (Navarro-Romero et al, 2022). The test consisted of a black Plexiglas apparatus with four arms (29 cm long × 7 5 cm wide) set in cross from a neutral central square (5 cm × 5 cm) elevated 40 cm above the floor.…”

“…Locomotor activity was assessed for 30 min after 7 days of treatment 24 h after the last drug administration as previously described (Navarro-Romero et al, 2022). Individual locomotor activity boxes (9 × 20 × 11 cm) (Imetronic) were used in a low luminosity environment.…”

Endocannabinoid System: Chemical Characteristics and Biological Activity

“…Male mice showed hypersocial behaviors, memory deficits, enlarged hearts, and differences in the function of CB1R. These mutant mice received JZL184, an MAGL inhibitor, which improved their social and memory symptoms and cardiovascular function [ 121 ]. These studies show that the modulation of eCB hyperactivity is a promising therapeutic approach for cognitive deficits associated with genetic syndromes.…”