Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice.
- PMID : 31503547
Abstract
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in AS individuals are common, debilitating, and often drug-resistant. Therefore, there is an unmet need for better treatment options. Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS. Here we show that acute CBD (100 mg/kg) attenuated hyperthermia- and acoustically-induced seizures in a mouse model of AS. However, neither acute CBD nor a two-weeklong course of CBD administered immediately after a kindling protocol could halt the pro-epileptogenic plasticity observed in AS model mice. CBD had a dose-dependent sedative effect, but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS. Our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS, and will thus help guide the rational development of CBD as an AS treatment.
KEYWORDS : Epilepsy; Neuroscience; Pharmacology
INTRODUCTION
Deletions or mutations of the maternally inherited copy of the UBE3A gene cause Angelman syndrome (AS). Individuals with AS exhibit developmental delay, motor dysfunction, minimal speech, highly penetrant EEG abnormalities, and seizures (1, 2). Epilepsy in AS is common (80%–95%), polymorphic, and often resistant to available antiepileptics. The frequency, severity, and pharmacological intractability of the seizures exacts a heavy toll on individuals with AS and their caregivers (3-6). AS model mice lacking a functional maternal copy of the orthologous Ube3a gene (Ube3am–/p+) phenocopy many clinical aspects of AS, including seizure susceptibility, motor and behavioral impairments, as well as EEG abnormalities, thereby offering a preclinical model for developing new therapeutics (7-15).
Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is gaining attention for its antiepileptic, anxiolytic, and antipsychotic properties (16). In 2018, the FDA approved CBD (Epidiolex®) for the treatment of seizures associated with two rare and severe forms of epilepsy — Lennox-Gastaut syndrome and Dravet syndrome. While the interest and off-label medical use of CBD has largely outpaced the preclinical and clinical research, CBD provides a viable treatment for several other neurological disorders associated with epilepsy (17-20). However, little is known about the potential antiepileptic and other benefits of CBD in AS. The potential medicinal effects of CBD hold promise to simultaneously ameliorate behavioral deficits, EEG abnormalities, as well as seizures in AS (21).
In this study, we systematically tested the beneficial effects of CBD on seizures, motor deficits, and EEG abnormalities in mice that genetically model AS, with the expectation that this information will guide eventual clinical use. We report that acute treatment of CBD substantially attenuated audiogenic and hyperthermia-induced seizure severity, and normalized delta rhythms in AS model mice. The anticonvulsant dose of CBD (100 mg/kg) caused mild sedation, but had little effect on motor coordination or balance. While acute CBD could suppress seizure severity, CBD stopped short of being able to prevent the pro-epileptogenic plasticity observed in AS model mice. Our study provides a preclinical framework to better guide the rational development of CBD as either an adjunctive or monotherapy for AS.
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