Chronic cannabidiol (CBD) administration induces anticonvulsant and antiepileptogenic effects in a genetic model of epilepsy

Willian Lazarini-Lopes; Raquel A Do Val-da Silva; Rui M P da Silva-Júnior; Gleice K Silva-Cardoso; Christie R A Leite-Panissi; João P Leite; Norberto Garcia-Cairasco

doi:10.1016/j.yebeh.2021.107962

Chronic cannabidiol (CBD) administration induces anticonvulsant and antiepileptogenic effects in a genetic model of epilepsy

Epilepsy Behav. 2021 Jun:119:107962. doi: 10.1016/j.yebeh.2021.107962. Epub 2021 Apr 20.

Authors

Willian Lazarini-Lopes¹, Raquel A Do Val-da Silva², Rui M P da Silva-Júnior³, Gleice K Silva-Cardoso⁴, Christie R A Leite-Panissi⁵, João P Leite⁶, Norberto Garcia-Cairasco⁷

Affiliations

¹ Neuroscience and Behavioral Sciences Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil; Neurophysiology and Experimental Neuroethology Laboratory, Physiology Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: willian.lopes@usp.br.
² Neuroscience and Behavioral Sciences Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil.
³ Neurophysiology and Experimental Neuroethology Laboratory, Physiology Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: ruimiltonpsj@usp.br.
⁴ Psychology Department, Faculty of Phylosophy, Science, and Letters, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: cardoso.gkrs@usp.br.
⁵ Psychology Department, Faculty of Phylosophy, Science, and Letters, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: christie@usp.br.
⁶ Neuroscience and Behavioral Sciences Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: jpleite@fmrp.usp.br.
⁷ Neuroscience and Behavioral Sciences Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil; Neurophysiology and Experimental Neuroethology Laboratory, Physiology Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil. Electronic address: ngcairas@usp.br.

PMID: 33887676
DOI: 10.1016/j.yebeh.2021.107962

Abstract

Cannabidiol (CBD) is a marijuana compound implicated in epilepsy treatment in animal models and pharmacoresistant patients. However, little is known about chronic CBD administration's effects in chronic models of seizures, especially regarding its potential antiepileptogenic effects. In the present study, we combined a genetic model of epilepsy (the Wistar Audiogenic Rat strain - WARs), a chronic protocol of seizures (the audiogenic kindling - AuK), quantitative and sequential behavioral analysis (neuroethology), and microscopy imaging to analyze the effects of chronic CBD administration in a genetic model of epilepsy. The acute audiogenic seizure is characterized by tonic-clonic seizures and intense brainstem activity. However, during the AuK WARs can develop limbic seizures associated with the recruitment of forebrain and limbic structures. Here, chronic CBD administration, twice a day, attenuated brainstem, tonic-clonic seizures, prevented limbic recruitment, and suppressed limbic (kindled) seizures, suggesting CBD antiepileptogenic effects. Additionally, CBD prevented chronic neuronal hyperactivity, suppressing FosB immunostaining in the brainstem (inferior colliculus and periaqueductal gray matter) and forebrain (basolateral amygdala nucleus and piriform cortex), structures associated with tonic-clonic and limbic seizures, respectively. Chronic seizures increased cannabinoid receptors type 1 (CB1R) immunostaining in the hippocampus and the BLA, while CBD administration prevented changes in CB1R expression induced by the AuK. The neuroethological analysis provided details about CBD's protective effects against brainstem and limbic seizures associated with FosB expression. Our results strongly suggest chronic CBD anticonvulsant and antiepileptogenic effects associated with reduced chronic neuronal activity and modulation of CB1R expression. We also support the chronic use of CBD for epilepsies treatments.

Keywords: Anticonvulsant; CB1 receptors; Cannabidiol; Epilepsy; Neuronal activity; Preclinical model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acoustic Stimulation
Animals
Anticonvulsants* / therapeutic use
Cannabidiol*
Disease Models, Animal
Humans
Models, Genetic
Rats
Rats, Wistar

Substances

Anticonvulsants
Cannabidiol