Cannabidiol (CBD) Alters the Functionality of Neutrophils (PMN). Implications in the Refractory Epilepsy Treatment

Claudia Taborda Gómez,Amalia Merelli,Jerónimo Auzmendi,Alberto Lazarowski,Marisa Repetto,Miren Ettcheto,Fabiana Lairion

doi:10.3390/ph14030220

Abstract

Cannabidiol (CBD), a lipophilic cannabinoid compound without psychoactive effects, has emerged as adjuvant of anti-epileptic drugs (AEDs) in the treatment of refractory epilepsy (RE), decreasing the severity and/or frequency of seizures. CBD is considered a multitarget drug that could act throughout the canonical endocannabinoid receptors (CB1-CB2) or multiple non-canonical pathways. Despite the fact that the CBD mechanism in RE is still unknown, experiments carried out in our laboratory showed that CBD has an inhibitory role on P-glycoprotein excretory function, highly related to RE. Since CB2 is expressed mainly in the immune cells, we hypothesized that CBD treatment could alter the activity of polymorphonuclear neutrophils (PMNs) in a similar way that it does with microglia/macrophages and others circulating leukocytes. In vitro, CBD induced PMN cytoplasmatic vacuolization and proapoptotic nuclear condensation, associated with a significantly decreased viability in a concentration-dependent manner, while low CBD concentration decreased PMN viability in a time-dependent manner. At a functional level, CBD reduced the chemotaxis and oxygen consumption of PMNs related with superoxide anion production, while the singlet oxygen level was increased suggesting oxidative stress damage. These results are in line with the well-known CBD anti-inflammatory effect and support a potential immunosuppressor role on PMNs that could promote an eventual defenseless state during chronic treatment with CBD in RE.

Highlights

Epilepsy is a neurological disease affecting about 50 million people worldwide, and nearly 30–40% of patients will develop a multidrug-resistant (MDR) phenotype defined as refractory epilepsy (RE), characterized by high recurrence of seizures that cannot be controlled by at least two well-tolerated antiepileptic drugs (AEDs) appropriate for the particular epilepsy type [1,2,3]
When the polymorphonuclear neutrophils (PMNs) were incubated with dimethyl sulfoxide (DMSO) as vehicle (DMSO was added at same concentration as CBD a 10−3 M) a PMN’s viability of 10% at 60 min (Figure 1B, black line) was observed
Intermediate and very pronounced loss of viability were observed with CBD at 10−5 M and 10−3 M, respectively (Figure 1B)

Summary

Introduction

Epilepsy is a neurological disease affecting about 50 million people worldwide, and nearly 30–40% of patients will develop a multidrug-resistant (MDR) phenotype defined as refractory epilepsy (RE), characterized by high recurrence of seizures that cannot be controlled by at least two well-tolerated antiepileptic drugs (AEDs) appropriate for the particular epilepsy type [1,2,3]. Several alternative therapies such as ketogenic diet and vagal stimulation have been applied with variable results. In this context, the treatment with cannabinoids compounds such as cannabidiol (CBD) have emerged as a promising adjuvant therapy for seizure control [6]. Several reports showed a decrease in the seizures frequency and intensity [7,8,9]

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Discussion

Conclusion