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

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.

Effects of Cannabidiol on Innate Immunity: Experimental Evidence and Clinical Relevance

“…CBD’s ability to modulate PMN extravasation has been examined in several in vitro models of migration. For example, McHugh and colleagues found that CBD inhibited fMLP-induced migration of human PMNs in a concentration-dependent manner [ 153 ], and the results of this study were also confirmed in a similar model by Gómez and colleagues [ 154 ], Mukhopadhyay et al [ 155 ], and Mabou Tagne et al, who showed that CBD inhibits PMN migration after activation with IL-8, but not in resting cells, in a concentration-dependent manner [ 156 ]. This finding is, in our opinion, of extreme interest, because it seems to suggest that CBD’s anti-inflammatory effects are greater in pathological conditions, whereas this compound does not seem to exert an inhibitory effect on the immune system in physiological conditions, thus once again highlighting the safety and manageability of CBD.…”

“…Lastly, Gómez found that CBD triggered a significant decrease in oxygen uptake and H 2 O 2 generation but also increased ROS production. In order to explain this discrepancy, the authors postulated that CBD might activate different receptors present on PMNs, which in turn modulate different intracellular pathways, causing these apparently contradictory effects [ 154 ].…”

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

“…Previous literature shows that CBD inhibits neutrophil migration and infiltration in vivo and vitro ( Mabou Tagne et al, 2019 ; Gómez et al, 2021 ; Robaina Cabrera et al, 2021 ). Thus, treatment with CBD may ameliorate excessive inflammatory responses involving neutrophils.…”

Molecular and Cellular Mechanisms of Action of Cannabidiol

“…CBD interferes with the translocation of the NOX2 subunits to the membrane, preventing the oxidative burst and, consequently, the generation of O2− and H2O2 [ 104 ]. Additionally, CBD reduces neutrophil activation and degranulation [ 128 ].…”