Avaliação do efeito anticonvulsivante de fitocanabinoides de grau farmacêutico nas crises agudas induzidas pela pilocarpina em ratos wistar

Abstract

The treatment of epilepsy is challenging due to the existence of forms resistant to pharmacological and surgical treatments, with refractoriness affecting 30% of patients, resulting in considerable morbidity and mortality. The present study evaluated the protective (inhibitory) effect of different formulations of pharmaceutical-grade phytocannabinoids in an oily vehicle and an aqueous formulation in nanoparticles on acute epileptic seizures, specifically in the form of Status Epilepticus (SE). Seventy adult male Wistar rats, sourced from the Bioterium of the Center for Reproductive Biology at UFJF, were used, subdivided into groups, in which the seizures were induced using the pilocarpine model via intraperitoneal injection. The intraperitoneal injection of the compounds compared the protective effect exerted by established antiepileptic drugs for the treatment of acute convulsive seizures with pharmaceutical-grade phytocannabinoids. The protective effect of different pharmaceuticalgrade phytocannabinoid formulations: (isolated Cannabidiol, Cannabidiol+Cannabigerol, Cannabidiol+Cannabigerol+THC, Cannabinol+Cannabichromene+Cannabigerol, and Cannabidiol+Cannabigerol+Cannabichromene in aqueous nanoparticles) was compared to Midazolam, considered a positive control, administered intraperitoneally before the induction of seizures. The evaluation included the incidence of SE, the latency to the onset of seizures, and the behavioral severity according to the Racine scale and colinergic simptons.. Among the phytocannabinoids used in the experiment, the combination of Cannabidiol, Cannabigerol, and THC demonstrated the most robust protective effect (80%), with a trend similar to Midazolam. On the other hand, isolated Cannabidiol showed 40% protection in the tested group, while the formulation in aqueous nanoparticles was the group that performed the worst, with only 30% protection and the shortest latency to the onset of seizures. The other phytocannabinoids combinations (Cannabidiol+Cannabigerol and Cannabinol+Cannabichromene Cannabigerol) showed intermediate protection (50%). The combination of phytocannabinoids, especially the one that includes THC in its pharmaceutical-grade formulation, can offer a significant protective effect against acute epileptic seizures, reinforcing the "entourage effect" hypothesis and indicating therapeutic potential for the management of refractory epilepsies and SE. The variation in efficacy between different formulations suggests that composition and bioavailability are crucial factors, and the lower efficacy of the formulation in aqueous nanoparticles can be explained by a possible inverted "U" dose-response curve, where altered bioavailability would result in concentrations outside the therapeutic window.