Bench to bedside: Multiple facets of cannabinoid control in epilepsy

Highlights

• Cannabinoid control modulate neural excitability through presynaptic inhibition.

• Endocannabinoid system was spatiotemporally perturbed in epilepsy.

• Intervention of cannabinoid receptors or endocannabinoids could affect seizures.

• Cannabidiol as an add-on treatment could reduce seizures in clinic.

Abstract

Epilepsy is a neurological disease recognized as the consequence of excessive neuronal excitability. Endocannabinoid system, the critical regulator of synaptic inhibition in brain, was supposed to be closely involved in epilepsy. Cannabinoid receptors mostly locate on presynaptic terminals of both excitatory and inhibitory neurons, but with characteristic distribution varying in different brain areas and synapses. Endocannabinoids are synthesized in postsynaptic neurons and retrogradely act on presynaptic cannabinoid receptors. Accumulating evidence suggest that the expression of cannabinoid receptors and synthesis or breakdown of endocannabinoids were cell-type specifically altered and spatiotemporally regulated in seizures, and intervention of the expression of cannabinoid receptors or the level of endocannabinoids could affect seizure actions. Further in clinic, cannabidiol as an add-on treatment could reduce seizures in patients with treatment-resistant epilepsy, but the underlying mechanisms are still unclear and independent of the endocannabinoid system. Therefore, we review recent advances from bench to bedside, to address the cannabinoid control on seizures, discuss the existing confusion in current studies and provide directions for further research, which may be clinically important for the design of cannabinoid-based precise therapeutic interventions for epilepsy.

Introduction

Epilepsy is characterized by recurrent spontaneous seizures and commonly recognized as the consequence of excessive neuronal excitability (Bernard et al., 2003; Thijs et al., 2019). However, in addition to the inhibitory GABAergic system and excitatory glutamatergic system (Wang et al., 2018), the endocannabinoid system also has been appreciated as an important modulator for neural excitability mostly through presynaptic inhibition of transmitter release and was supposed to be involved in the control of epilepsy (Cristino et al., 2020; Kilaru and Chapman, 2020; O'Connell et al., 2017). In the past decades, accumulating evidence has suggested that the expression of cannabinoid receptors and synthesis or breakdown of endocannabinoids were spatiotemporally regulated and cell-type specifically disrupted during seizures, and intervention of the expression of cannabinoid receptors or the level of endocannabinoids could affect seizure actions (Cheung et al., 2019; Gaston and Friedman, 2017; Soltesz et al., 2015). In clinic trials, Cannabis has been used to treat seizures for centuries (Devinsky et al., 2014; McCall, 2015; Miller et al., 2020), and cannabidiol as an add-on treatment was proved to reduce seizures in patients with epilepsy (Devinsky et al., 2016; Friedman et al., 2019). However, although it was generally recognized that activation of cannabinoid receptors or increasing the level of endocannabinoids could protect against acute excitotoxicity and have the potential to suppress seizure (Marsicano et al., 2003), we canont ignore their multiple facets also with seizure-promoting actoins (Lutz, 2004).seizure (). The underlying mechanisms have been not clear yet. Therefore, in this review, we provide an overview of the endocannabinoid system, then summarize the multiple facets of the on-demand cannabinoid control on seizures and discuss the therapeutic potential of cannabinoids in epilepsy.