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Cannabidiol attenuates generalized tonic–clonic and suppresses limbic seizures in the genetically epilepsy-prone rats (GEPR-3) strain

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Abstract

Background

Cannabidiol (CBD) has been of rapidly growing interest in the epilepsy research field due to its antiseizure properties in preclinical models and patients with pharmacoresistant epilepsy. However, little is known about CBD effects in genetic models of epilepsies. Here we assessed CBD dose–response effects in the Genetically Epilepsy Prone Rats (GEPR-3) strain, which exhibits two types of epileptic seizures, brainstem-dependent generalized tonic–clonic seizures and limbic seizures.

Methods

GEPR-3 s were submitted to the audiogenic seizure (AGS) protocol. Acute AGS are brainstem-dependent generalized tonic–clonic, while repeated AGS (or audiogenic kindling, AK), an epileptogenic process, leads to increased AGS severity and limbic seizure expression. Therefore, two different dose–response studies were performed, one for generalized tonic–clonic seizures and the other for limbic seizures. CBD time-course effects were assessed 2, 4, and 6 h after drug injection. GEPR-3 s were submitted to within-subject tests, receiving intraperitoneal injections of CBD (1, 10, 50, 100 mg/kg/ml) and vehicle.

Results

CBD dose-dependently attenuated generalized tonic–clonic seizures in GEPR-3 s; CBD 50 and 100 mg/kg reduced brainstem-dependent seizure severity and duration. In fully kindled GEPR-3 s, CBD 10 mg/kg reduced limbic seizure severity and suppressed limbic seizure expression in 75% of animals.

Conclusions

CBD was effective against brainstem and limbic seizures in the GEPR-3 s. These results support the use of CBD treatment for epilepsies by adding new information about the pharmacological efficacy of CBD in suppressing inherited seizure susceptibility in the GEPR-3 s.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors upon reasonable request.

Abbreviations

AK:

Audiogenic kindling

AGS:

Audiogenic seizures

CBD:

Cannabidiol

CB1R:

Cannabinoid receptors type 1

GEPR-3:

Genetically Epilepsy Prone Rats

KM:

Krushinsky–Molodkina

WAR:

Wistar Audiogenic Rat

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Funding

WLL holds Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES Brazil—Finance code 001) and CAPES-Print (Process No 88887.370299/2019–00) grants. The research was supported by R01NS097762 to PAF and R01 AA027660 to PN.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, Georgetown University, New Research Bldg., W209B, 3970 Reservoir Road NW, Washington, DC, 20007, USA

    Willian Lazarini-Lopes, Carolina Campos-Rodriguez & Patrick A. Forcelli

  2. Department of Neuroscience and Behavioral Sciences, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, SP, Brazil

    Willian Lazarini-Lopes & Norberto Garcia-Cairasco

  3. Department of Physiology, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, SP, Brazil

    Norberto Garcia-Cairasco

  4. Department of Physiology and Biophysics, Howard University School of Medicine, Washington, DC, 20059, USA

    Prosper N’Gouemo

  5. Department of Neuroscience, Georgetown University, Washington, DC, USA

    Patrick A. Forcelli

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  1. Willian Lazarini-Lopes
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Contributions

WLL, PAF, PN, and NGC designed the study. WLL, CCR, and PN performed experiments. WLL, CCR, PN, and PAF analyzed the data. WLL, PN, CCR, NGC, and PAF wrote the paper.

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Correspondence to Prosper N’Gouemo or Patrick A. Forcelli.

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Lazarini-Lopes, W., Campos-Rodriguez, C., Garcia-Cairasco, N. et al. Cannabidiol attenuates generalized tonic–clonic and suppresses limbic seizures in the genetically epilepsy-prone rats (GEPR-3) strain. Pharmacol. Rep 75, 166–176 (2023). https://doi.org/10.1007/s43440-022-00416-6

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