Olivetolic acid, a cannabinoid precursor in Cannabis sativa, but not CBGA methyl ester exhibits a modest anticonvulsant effect in a mouse model of Dravet syndrome

Abstract

Objective Cannabigerolic acid (CBGA), a precursor cannabinoid in Cannabis sativa, has recently been found to have anticonvulsant properties in the Scn1a+/- mouse model of Dravet syndrome. Poor brain penetration and chemical instability of CBGA limits its potential as an anticonvulsant therapy. Here, we examined whether CBGA methyl ester, a more stable analogue of CBGA, might have superior pharmacokinetic and anticonvulsant properties. In addition, we examined whether olivetolic acid, the biosynthetic precursor to CBGA with a truncated (des-geranyl) form, might possess minimum structural requirements for anticonvulsant activity. We also examined whether olivetolic acid and CBGA methyl ester retain activity at the epilepsy-relevant drug targets of CBGA: G-protein-coupled receptor 55 (GPR55) and T-type calcium channels. Methods The brain and plasma pharmacokinetic profiles of CBGA methyl ester and olivetolic acid were examined following 10 mg/kg intraperitoneal (i.p.) administration in mice (n = 4). The anticonvulsant potential of each was examined in male and female Scn1a+/- mice (n = 17–19) against hyperthermia-induced seizures (10–100 mg/kg, i.p.). CBGA methyl ester and olivetolic acid were also screened in vitro against T-type calcium channels and GPR55 using intracellular calcium and ERK phosphorylation assays, respectively. Results CBGA methyl ester exhibited relatively limited brain penetration (13%), although somewhat superior to that of 2% for CBGA. No anticonvulsant effects were observed against thermally induced seizures in Scn1a+/- mice. Olivetolic acid also showed poor brain penetration (1%) but had a modest anticonvulsant effect in Scn1a+/- mice increasing the thermally induced seizure temperature threshold by approximately 0.4°C at a dose of 100 mg/kg. Neither CBGA methyl ester nor olivetolic acid displayed pharmacological activity at GPR55 or T-type calcium channels. Conclusions Olivetolic acid displayed modest anticonvulsant activity against hyperthermia-induced seizures in the Scn1a+/- mouse model of Dravet syndrome despite poor brain penetration. The effect was, however, comparable to the known anticonvulsant cannabinoid cannabidiol in this model. Future studies could explore the anticonvulsant mechanism(s) of action of olivetolic acid and examine whether its anticonvulsant effect extends to other seizure types.

Cannabidiol Regulates PPARγ-Dependent Vesicle Formation as well as Cell Death in A549 Human Lung Cancer Cells

“…This so-called “entourage effect” could induce synergistic interactions among phytocannabinoids, and this effect could explain various pharmacokinetic properties, including substrate specificity, half-life, and regulatory functions with respect to target molecules [ 15 ]. CBDA concentrations were higher following cannabis extract administration than when administered as a single molecule in a mouse study, indicating that the crude extract provides a natural vehicle to substantially enhance CBDA concentrations [ 16 ].…”

Novel insights into the antibacterial activities of cannabinoid biosynthetic intermediate, olivetolic acid, and its alkyl-chain derivatives

“…The present study was designed to gain insights into the prospective therapeutic properties of 1b and its analogs. Only one phytochemical investigation of 1b was found in the literature [ 6 ]. In contrast, the antibacterial activities of 2b and 3b against S. aureus have been well studied [ 10 , 26 ].…”

“…A recent study revealed that despite its low brain penetration, the biosynthetic precursor molecule 1b exhibited a moderate anticonvulsant effect in a mouse model of Dravet syndrome, with comparable potency to the known anticonvulsant cannabinoid, CBD [ 6 ]. To the best of our knowledge, no other activity has been reported for 1b .…”

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“…This has inspired research addressing whether other less well characterized phytocannabinoids might similarly have anti-seizure properties. Indeed, recent studies have shown that several minor cannabinoids have anti-seizure effects in mouse models including CBGA, CBDVA, CBCA, and CBC ( Anderson et al, 2019b ; Anderson et al, 2021a ; Anderson et al, 2021b ; Anderson et al, 2022 ; Benson et al, 2022 ). However, the molecular mode of action of these compounds is poorly understood.…”

“…The introduction of CBD as an approved medicine has generated substantial interest in whether other phytocannabinoids might similarly be developed as novel anti-convulsants. We have recently reported that the lesser studied phytocannabinoids, cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA) and cannabichromene (CBC) were anti-convulsant in a mouse model of DS ( Anderson et al, 2021a ; Anderson et al, 2021b ; Anderson et al, 2022 ). However, the mode of action of these compounds remains enigmatic, particularly at epilepsy-relevant drug targets.…”