Atividade anticrise de fitocomplexos derivados de Cannabis spp. e do canabidiol em um modelo de status epilepticus em camundongos

Abstract

Placebo-controlled clinical trials show that cannabidiol (CBD) reduces seizure frequency, both convulsive and non-convulsive, in patients with difficult-to-control epilepsy. Part of this effect depends on pharmacokinetic interactions since, in these studies, patients continue conventional antiseizure medication. Furthermore, the CBD mechanism that would reduce seizure frequency is still unknown, especially considering its affinity for endocannabinoid system receptors. Other phytocannabinoids, such as tetrahydrocannabinol (THC), modify the endocannabinoid system, altering synaptic transmission and neuronal excitability. Thus, this thesis evaluated the antiseizure potential of different phytocannabinoid profiles (phytocomplexes) of Cannabis spp. extracts on the status epilepticus (SE), comparing their responses with those observed after CBD. We worked with the hypothesis that phytocomplexes derived from Cannabis spp., as they contain a variety of secondary metabolites, would be more effective in controlling neuronal hyperexcitability than a pure phytocannabinoid (CBD). For this, we used electrophysiological and behavioral recordings of mice submitted to the SE model induced by intrahippocampal pilocarpine administration. Dose-response curves of two extracts, one with a CBD:THC concentration ratio greater than 1 (XT-CBD) and the other with a CBD:THC ratio less than 1 (XT-THC), were compared with conventional treatments (e.g., CBD and diazepam). The animals received the experimental compound intraperitoneally (i.p.) thirty minutes before pilocarpine. We used the ambulation between the two administrations to indicate possible sedative effects caused by the extracts. Our results show that XT-CBD reduced the duration and severity of behavioral SE at all evaluated doses (4, 36, and 360 mg/kg; n=6-9/group) compared to the control group (sterile corn oil solution, 10 mL/kg; n=24, p<0.05, Mann-Whitney test). XT-THC treatment showed a biphasic effect: the 10 mg/kg dose (n=7) increased the proportion of animals with generalized seizures, while higher doses (450 and 1000 mg/kg; n=6-9/group ) decreased the severity of seizures. However, the high doses of XT-THC produced strong sedation. Comparatively, the decrease in SE severity at high doses of XT-CBD and XT-THC was similar to that observed in groups treated with diazepam (5 mg/kg; n=6; p>0.05; Mann-Whitney test) and with CBD (200 mg/kg dose, n=11). Surprisingly, treatment with CBD, XT-THC, and XT-CBD did not change the electrophysiological expression of the seizure, considering the electrographic paroxysms' latency, duration, and power. Our results demonstrate that phytocomplexes are effective in modulating the behavioral expression of pharmacologically induced SE, and CBD-rich extracts are more effective than THC-rich extracts. Future experiments will be necessary to understand the dissociation between behavioral and electrographic expression of phytocannabinoids on SE induced by intrahippocampal administration of pilocarpine. This study contributed to a better understanding of the use of phytocannabinoids in seizure treatment.