Authors :
Presenting Author: Luisa Rocha, PhD – Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV)
Monserrat Fuentes-Mejía, PhD – Center for Research and Advanced Studies of the National Polytechnic Institute
Maximiliano Fallico, PhD – National University of la Plata
Alan Talevi, PhD – National University of la Plata
Luciana Gavernet, PhD – National University of la Plata
Sandra Orozco-Suárez, PhD – Specialty Hospital, "Dr. Bernardo Sepúlveda", National Medical Center "XXI Century"
Rationale:
Cannabidiol (CBD) decreases the expression of drug-resistant seizures. This research was conducted to investigate if subchronic administration of CBD with sodium channel blockers modifies the severity of clonic-tonic seizures and the development of the drug-resistant phenotype induced by subchronic administration of 3-mercaptopropionic acid (3-MP) in rats. These effects were compared with those elicited by antiseizure medications acting on the GABAA receptors. Methods:
Male Wistar rats were used to evaluate CBD combined with different antiseizure medications (phenobarbital, diazepam, valproic acid, lamotrigine and oxcarbazepine) at ED30 or ED50 during the repetitive administration of 3-MP. The seizure severity (mortality rate) and development of drug-resistant seizures were estimated. Computational experiments explored interactions between CBD and sodium channel blockers in the NaV1.7 receptor.
Results:
Control groups receiving coconut oil plus vehicle during the repetitive administration of 3-MP showed an elevated mortality rate. In contrast, coadministration of CBD and phenobarbital at ED30 or ED50 during the repetitive 3-MP administration resulted in 0% of mortality (p=0.0163 vs coconut oil plus vehicle for both doses). Similarly, coadministration of CBD and diazepam at ED50 avoided the mortality (0%, p=0.0433 vs coconut oil plus vehicle). On the other hand, a high mortality rate (41%) was obtained when animals received the subchronic administration of CBD plus oxcarbazepine at ED50. Other treatments did not significantly modify the mortality rate during the repetitive administration of 3-MP.
The drug-resistant assay carried out by the end of the experimental procedure revealed the high prevalence of drug-resistant seizures to the different ASMs in the experimental groups receiving repetitive coconut oil plus vehicle. Low prevalence of animals with phenobarbital-resistant seizures was found when applied CBD plus phenobarbital at ED30 (p=0.005 vs coconut oil plus phenobarbital at ED30) or ED50 (p=0.009 vs coconut oil plus phenobarbital at ED50). Similarly, coadministration of CBD and diazepam at ED50 reduced the prevalence of diazepam-resistant seizures (p=0.0286 vs coconut oil plus diazepam at ED50). Contrariwise, high prevalence (100%) of resistant seizures to oxcarbazepine (p=0.0163 vs coconut oil plus vehicle) was observed when animals received the subchronic administration of CBD plus oxcarbazepine at ED50. No significant changes were detected with other treatments.
Computational experiments suggested that CBD acting on NaV1.7 interferes with the action of sodium channel blockers and precludes their inhibitory effects.
Conclusions:
Our results indicate that repeated administration of CBD with GABAergic antiseizure medications, but not sodium channel blockers, may decrease seizure severity and prevent the development of the drug-resistant phenotype induced by repeatedly provoked severe seizures.
Funding:
This study was supported by the National Council of Science and Technology (CONAHCyT, Project A3-S-26782 and Scholarship 1009939 awarded to MFM). Cannabidiol was provided by HempMed. Bioquimed provided lamotrigine and oxcarbazepine.