Abstract
Neural hyperexcitability in the event of damage during early life, such as hyperthermia, hypoxia, traumatic brain injury, status epilepticus, or a pre-existing neuroinflammatory condition, can promote the process of epileptogenesis, which is defined as the sequence of events that converts a normal circuit into a hyperexcitable circuit and represents the time that occurs between the damaging event and the development of spontaneous seizure activity or the establishment of epilepsy. Epilepsy is the most common neurological disease in the world, characterized by the presence of seizures recurring without apparent provocation. Cannabidiol (CBD), a phytocannabinoid derived from the subspecies Cannabis sativa (CS), is the most studied active ingredient and is currently studied as a therapeutic strategy: it is an anticonvulsant mainly used in children with catastrophic epileptic syndromes and has also been reported to have anti-inflammatory and antioxidant effects, supporting it as a therapeutic strategy with neuroprotective potential. However, the mechanisms by which CBD exerts these effects are not entirely known, and the few studies on acute and chronic models in immature animals have provided contradictory results. Thus, it is difficult to evaluate the therapeutic profile of CBD, as well as the involvement of the endocannabinoid system in epileptogenesis in the immature brain. Therefore, this review focuses on the collection of scientific data in animal models, as well as information from clinical studies on the effects of cannabinoids on epileptogenesis and their anticonvulsant and adverse effects in early life.
Highlights
Seizure disorders are common during childhood; they are causes of morbidity (Glass et al, 2018), and a large percentage of them have a poor response to current first-line anticonvulsant drugs (ADs; Glass et al, 2012)
The synthesis of endocannabinoids is mediated by an increase in intracellular Ca2+ generated by neuronal hyperexcitability and the demand for membrane phospholipid diacylglycerol lipase (DAGL) and for glutamate and acetylcholine (Wallace et al, 2003; Rosenberg et al, 2017)
Previous experimental studies have reported that the anticonvulsant effect of CBD is linked to the modulating effects on neuronal hyperexcitability through the antagonism of G protein-coupled receptor 55 (GPR55), of which CBD is a negative allosteric modulator (Laprairie et al, 2015), desensitization of transient receptor potential vanilloid receptor (TRPV1) (Chen and Hackos, 2015) and inhibition of adenosine reuptake by blocking equilibrative nucleotide transporter 1 (ENT1), which increases the concentration of extracellular adenosine (Pandolfo et al, 2011)
Summary
Seizure disorders are common during childhood; they are causes of morbidity (Glass et al, 2018), and a large percentage of them have a poor response to current first-line anticonvulsant drugs (ADs; Glass et al, 2012). Previous experimental studies have reported that the anticonvulsant effect of CBD is linked to the modulating effects on neuronal hyperexcitability through the antagonism of G protein-coupled receptor 55 (GPR55), of which CBD is a negative allosteric modulator (Laprairie et al, 2015), desensitization of TRPV1 (Chen and Hackos, 2015) and inhibition of adenosine reuptake by blocking equilibrative nucleotide transporter 1 (ENT1), which increases the concentration of extracellular adenosine (Pandolfo et al, 2011). These mechanisms decrease intracellular Ca2+ flux and regulate neuronal hyperexcitability. Such studies will provide a broader picture to test the efficacy of drugs in epilepsy and study the adverse effects of drugs derived from cannabis
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