Cannabidiol precursor produces anti-convulsant effects in preliminary study
A study shows that cannabidiol (CBD) precursor olivetolic acid had protective effects against fever-induced seizures in Dravet syndrome mice. These effects were comparable to those previously reported with CBD in this model, suggesting that olivetolic acid may have the potential to reduce seizures in Dravet syndrome and other seizure-related disorders.
Further studies are needed to better understand the molecule's mechanism of action and whether it protects against other types of seizures, the researchers noted.
THEsurvey, entitled " Olivetolic acid, a cannabinoid precursor in Cannabis sativa,“, was published in the Journal of Cannabis Research.
The cannabis plant, which contains more than 140 natural cannabinoids, was used to treat epilepsy and commonly prescribed by doctors for this indication before prohibition. Cannabinoids are chemical messenger molecules that bind to cannabinoid receptors in the brain and body, thereby regulating several functions in the body.
A previous study by Australian researchers showed that cannabigerolic acid (CBGA), a major precursor of CBD, protected against spontaneous seizures and those induced by high temperatures (hyperthermia) in a Dravet mouse model. These effects were greater than those previously reported for CBD in this model.
However, "CBGA's low brain penetration and chemical instability limit its potential as an [anti-seizure] therapy," the researchers wrote.
The same team has now assessed whether CBGA methyl ester – a more stable version of CBGA – and olivetolic acid, a precursor to CBGA, have better pharmacological and anti-hyperthermia-induced seizure properties in the same model. of mouse.
These mice lacked a copy of the SCN1A gene, which mutated in most Dravet cases, and exhibited key features of the disease, such as susceptibility to hyperthermia-induced seizures, or febrile seizures.
The animals received CBGA methyl ester or olivetolic acid at a dose of 10, 30 or 100 mg/kg body weight, similar doses to those used for CBGA in the previous study.
The results showed that both molecules had a limited ability to reach the brain, with CBGA methyl ester showing 13% brain exposure and olivetolic acid 1%. Nevertheless, the stable version of CBGA exhibited greater brain penetration than GBGA (2%) in the previous study, suggesting that it may lead to greater therapeutic effects.
However, ACBG methyl ester treatment “had no effect on hyperthermia-induced seizures at any dose tested,” the team wrote.
In contrast, olivetolic acid showed a modest but significant anti-seizure effect at a dose of 100 mg/kg. Specifically, it increased by about 0,4 C (0,72 F) the temperature threshold that the animals were able to endure without experiencing hyperthermia-induced seizures.
The researchers wrote that this result was “comparable to the temperature threshold increase of approximately 0,5°C caused by 100 mg/kg of CBD” in a previous study using the same mouse model.
It was, however, less than the almost 1 C increase in temperature threshold obtained previously with CBGA at the same dose.
Further analyzes performed on lab-grown human cells showed that neither CBGA methyl ester nor olivetolic acid interacted with two known CBGA seizure targets – G-protein-coupled receptor 55. and T-type calcium channels – suggesting that the benefits of olivetolic acid may involve other molecules.
Future studies are needed to better understand the mechanism of action of olivetolic acid and whether it acts on other seizure targets common to CBD and CBGA, such as GABAA receptors, TRPV1 and channels. voltage-dependent sodium.
The researchers noted that it's also possible that the anticonvulsant effects of olivetolic acid are due to an active metabolite, or byproduct, of the molecule.
Further research "could determine the metabolic profile of olivetolic acid and explore time-dependent studies to assess the anticonvulsant [anti-seizure] potential of possible metabolites," the team wrote.
It could also “examine whether the anticonvulsant activity of olivetolic acid extends to other animal models of epilepsy,” the researchers add.
The results also suggest that a specific chemical region, called the carboxylic acid moiety, may be important for the anticonvulsant effects of cannabinoids, since AGCB and olivetolic acid have it, but AGCB methyl ester does not. .
However, this region is highly unstable and is thought to be responsible for the low penetration of these molecules into the brain, posing "a challenge to the development of these [cannabinoids] as mainstream pharmaceuticals," wrote Researchers.
Future work could focus on potential chemical modifications to improve the physicochemical properties, brain penetration and stability of these cannabinoids, they added.
