Cannabidivarin completely rescues cognitive deficits and delays neurological and motor defects in male Mecp2 mutant mice

Abstract

Background: Recent evidence suggests that 2-week treatment with the nonpsychotomimetic cannabinoid cannabidivarin (CBDV) could be beneficial towards neurological and social deficits in early symptomatic Mecp2 mutant mice, a model of Rett syndrome (RTT). Aim: To provide further insights into the efficacy of CBDV in Mecp2-null mice we used a lifelong treatment schedule (from 4 to 9 weeks of age) and evaluated its effect on recognition memory and neurological defects in both early and advanced stages of the phenotype progression. Methods: CBDV 0.2, 2, 20, 200 mg/kg/day was administered to Mecp2-null mice from 4 to 9 weeks of age. Cognitive and neurological defects were monitored during the whole treatment schedule. Biochemical analyses were carried out in brain lysates from 9-week-old wildtype and knockout mice to evaluate brainderived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) levels as well as components of the endocannabinoid system. Results: CBDV rescues recognition memory deficits in Mecp2 mutant mice and delays the appearance of neurological defects. At the biochemical level, it normalizes BDNF/IGF1 levels and the defective PI3K/AKT/mTOR pathway in Mecp2 mutant mice at an advanced stage of the disease. Mecp2 deletion 3 upregulates CB1 and CB2 receptor levels in the brain and these changes are restored after CBDV treatment. Conclusions: CBDV administration exerts an enduring rescue of memory deficits in Mecp2 mutant mice, an effect that is associated with the normalization of BDNF, IGF-1 and rpS6 phosphorylation levels as well as CB1 and CB2 receptor expression. CBDV delays neurological defects but this effect is only transient.

A systematic review of minor phytocannabinoids with promising neuroprotective potential

“…All in vivo cannabidivarin (CBDV) studies evaluated the anti‐epileptic properties of the compound in models of Rett syndrome and MES seizures (Amada, Yamasaki, Williams, & Whalley, 2013; Hill et al, 2012; Hill et al, 2013; Vigli et al, 2018; Zamberletti et al, 2019). Doses in these studies ranged from 0.2 to 400 mg·kg −1 per day in rodents with efficacy in reducing tremors was observed between 2 and 200 mg·kg −1 per day.…”

The endocannabinoidome as a substrate for noneuphoric phytocannabinoid action and gut microbiome dysfunction in neuropsychiatric disorders

“…Beneficial effects and/or increased survival were observed also at relatively low (eg, 2 mg/kg, intraperitoneal) doses. [80][81][82] Interestingly, in both the valproate model and Mecp2 mutant mice, CBDV reversed the alterations of eCBS proteins observed in the brain (such as the increased levels of CB 1 receptors). 80,82 In adults with ASD submitted to an MRS study, 83 CBDV (600 mg, single oral dose) produced, in the left basal ganglia, effects on glutamate-GABA signaling similar to those exerted by the same dose of CBD in the prefrontal cortex.…”

Termination of acute stress response by the endocannabinoid system is regulated through lysine‐specific demethylase 1‐mediated transcriptional repression of 2‐AG hydrolases ABHD6 and MAGL

“…Protein extraction from mouse hippocampus was performed as in Colombo et al, (2009). Immunodecoration methods to comparatively quantify protein levels in the different experimental groups is described elsewhere (Colombo et al, 2017; Zamberletti, Gabaglio, & Piscitelli, 2019). Hippocampal protein extracts were analyzed by a blind experimenter who received stressed and control hippocampi both from wild type and KO animals with a labeling whose code was only disclosed at the end of the analysis.…”

“…Protein extraction from mouse hippocampus was performed as in Colombo et al, (2009). Immunodecoration methods to comparatively quantify protein levels in the different experimental groups is described elsewhere (Colombo et al, 2017;Zamberletti, Gabaglio, & Piscitelli, 2019)…”