Avaliação dos efeitos do canabigerol e do canabinol nas crises agudas induzidas pelo pentilenotetrazol em camundongos

Abstract

Phytocannabinoids, secondary metabolites produced by Cannabis plants, modulate cellular excitability and present promising effects in adjunctive treatment for refractory epilepsies. Tetrahydrocannabinol (THC) and cannabidiol (CBD), two phytocannabinoids with the highest concentration in Cannabis sp. inflorescences, have similar mass and molecular structure, but distinct pharmacological effects: THC has a clear psychotropic and pro-convulsant effect, while CBD does not affect behavior or perception, despite notable anti-seizure activity in clinical and preclinical studies. On the other hand, little is known about the pharmacological effects of other phytocannabinoids, such as cannabigerol (CBG, a precursor molecule of THC and CBD) and cannabinol (CBN, which results from the abiotic degradation of THC and CBD). CBG and CBN interact with different molecular targets, such as receptors of the endocannabinoid system (CB1r), but their pharmacological effects on neuronal hyperexcitability are unknown. In this study, we evaluated the antiseizure effect of CBG and CBN in a model of chemically-induced acute seizures by pentylenetetrazol (PTZ) in mice (CEUA/UFRN #043/2022). PTZ administration (60 mg/kg, s.c.) produced spasms, myoclonic jerks, and in some animals, generalized limbic seizures. Pretreatment (1 h before PTZ) with CBG or CBN at doses of 3, 30, or 300 mg/kg (i.p.) did not modify the latency, quantity, or severity of PTZ-induced ictal behaviors compared to the control group (CTR, animals receiving vehicle, i.e., corn oil; p>0.05, ANOVA). On the other hand, pretreatment with diazepam (5 mg/kg, a traditional anti-seizure drug, used here as positive control) increased the latency to the first spasm and the first myoclonus and significantly reduced the number of events compared to the control group (p<0.05, unpaired t-test). Surprisingly, the pretreatment with CBG or CBN increased the proportion of animals experiencing limbic seizures, regardless of the dose. The proportion of animals with seizures in the CTR group was 2/16 (13%), while in the CBG group, it was 8/17 (47%, CTR vs CBG, chi-square=4.66, p=0.031) and in the CBN group it was 5/16 (31%, CTR vs CBN, chi-square=1.65, p>0.05). Our results demonstrate that CBG and CBN do not have antiseizure activity in the PTZ-induced acute seizure model and suggest that these phytocannabinoids promote the expression of limbic seizures. We believe this study expands our understanding of the potential and limitations of the endocannabinoid system in controlling neuronal excitability.