Cannabidivarin helps with motor skills, cognition in female Rett mice
Study findings highlight potential of cannabis compound as a therapeutic agent
Cannabidivarin (CBDV), a non-psychoactive compound found in cannabis, preserves cognitive function and improves motor coordination in a female mouse model of Rett syndrome, a study suggests.
“These findings provide new insights into the role of CBDV in [Rett] and support for future research, highlighting its potential as a … therapeutic agent,” researchers wrote in the study, “Cannabidivarin mitigates motor and cognitive impairments in a female mouse model of Rett syndrome,” which was published in Life Sciences.
Most Rett studies biased toward using male mouse models
Most cases of Rett are caused by mutations in the MECP2 gene, which severely affect brain function. Almost exclusively affecting girls, the disorder is characterized by developmental delays in early childhood, followed by a rapid regression of acquired skills, including communication and fine motor function. Other features include repetitive hand movements, irregular breathing, heart complications, and seizures.
CBDV is similar in structure to cannabidiol, also known as CBD, the active ingredient in Epidiolex, an approved medication to treat seizures in children with Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex.
In preclinical studies, CBDV rescued memory deficits and delayed the onset of neurological and motor defects in a male Rett mouse model. In a Phase 1 study, the cannabis-based therapy was well tolerated and reduced the monthly frequency of seizures in five girls with Rett.
Most preclinical Rett studies are biased toward using male mouse models due to the rapid onset of symptoms (about three weeks old). In contrast, female Rett mice develop disease with variable severity, and at an older age (about four months old).
“Despite CBDV’s potential preclinical and clinical beneficial effects, the impact of CBDV in a female mouse model of [Rett] has never been addressed,” wrote a team led by researchers at the University of Lisbon in Portugal, who assessed the impact of daily CBDV treatment in a female Rett mouse model.
Cannabidivarin treatment rescues cognitive impairments in Rett mice
Animals, with and without Rett, received a single daily injection of CBDV into the abdomen before symptom onset (21 to 24 weeks old), followed by a battery of tests during the symptomatic stage (23 to 24 weeks old).
Initial experiments confirmed that daily CBDV treatment had no measurable effect on body weight in either Rett or healthy control mice, indicating that the cannabinoid was well tolerated and didn’t interfere with growth.
To assess motor coordination, mice were subjected to the rotarod test, which involves placing the animal on a rotating rod and measuring the time it takes for them to fall off. As expected, Rett mice fell from the rod more quickly than control mice. Rett mice treated with CBDV, in comparison, showed a trend toward improved performance, remaining on the rod longer than untreated Rett mice, “suggesting a partial rescue of motor coordination deficits,” the researchers wrote.
CBDV treatment also rescued cognitive impairments in Rett mice, as indicated by the novel object recognition test, which evaluated the ability to recognize a novel or previously presented object. Notably, healthy mice treated with CBDV failed to recognize the novel object, “suggesting that chronic exposure in healthy mice may exert unintended negative effects on cognitive function,” the team wrote.
CBDV had no impact on locomotion, as measured by the walking distance and speed of the mice.
Our findings underscore the importance of continued research that includes both male and female animal models, as well as human studies.
The researchers then examined the effect of CBDV on neural stem cells, or nerve cell precursors, in a brain region affected by Rett called the hippocampus, which plays a role in learning and memory.
After the onset of behavioral symptoms, Rett mice exhibited abnormal growth of neural stem cells, which was significantly reduced in CBDV-treated Rett mice, but not to the levels observed in healthy mice. Still, CBDV restored the differentiation of neural stem cells to mature nerve cells to levels comparable to those of healthy mice.
Finally, they looked at cannabinoid protein receptors, including CB1R and GPR55, which regulate processes such as neurodevelopment and how nerve cell connections adapt to activity, and are often disrupted in Rett patients. Experiments confirmed that CB1R and GPR55 production was impaired in Rett mice, while CBDV treatment restored CB1R and normalized GPR55 production to levels observed in healthy mice.
“Our findings underscore the importance of continued research that includes both male and female animal models, as well as human studies,” the researchers concluded. “Such research is crucial for further understanding the cellular and molecular mechanisms through which CBDV may offer therapeutic benefits for [Rett] patients.”
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