Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

Rocha, Luisa; Frías‐Soria, Christian Lizette; Ortíz, José G.; Auzmendi, Jerónimo; Lazarowski, Alberto

doi:10.1002/epi4.12376

Cited by 21 publications

(19 citation statements)

References 144 publications

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“…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 ] and that correlates with an increased plasmatic AEDs concentration [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…It is known that CBD is a multi-target compound, acting on ionic channels, neurotransmitter receptors, and other transmembrane transporters, with different effects in each of them acting such as activator, modulator, agonist, antagonist, etc. Additionally, not only is CBD metabolized by the enzymatic cytochrome system, but it can also inhibit some of these enzymes, inducing a slowdown in the metabolism of more common AEDs, which is an alternative way of affecting their pharmacokinetics (Rocha et al, 2020). Therefore, CBD effects on ABC transporters are only one among multiple mechanisms through which this drug could have an impact on the MDR phenotype in RE patients.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol (CBD) Inhibited Rhodamine-123 Efflux in Cultured Vascular Endothelial Cells and Astrocytes Under Hypoxic Conditions

Auzmendi

Palestro

Blachman

et al. 2020

Front. Behav. Neurosci.

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Despite the constant development of new antiepileptic drugs (AEDs), more than 30% of patients develop refractory epilepsy (RE) characterized by a multidrug-resistant (MDR) phenotype. The "transporters hypothesis" indicates that the mechanism of this MDR phenotype is the overexpression of ABC transporters such as P-glycoprotein (P-gp) in the neurovascular unit cells, limiting access of the AEDs to the brain. Recent clinical trials and basic studies have shown encouraging results for the use of cannabinoids in RE, although its mechanisms of action are still not fully understood. Here, we have employed astrocytes and vascular endothelial cell cultures subjected to hypoxia, to test the effect of cannabidiol (CBD) on the P-gp-dependent Rhodamine-123 (Rho-123) efflux. Results show that during hypoxia, intracellular Rho-123 accumulation after CBD treatment is similar to that induced by the P-gp inhibitor Tariquidar (Tq). Noteworthy, this inhibition is like that registered in non-hypoxia conditions. Additionally, docking studies predicted that CBD could behave as a P-gp substrate by the interaction with several residues in the α-helix of the P-gp transmembrane domain. Overall, these findings suggest a direct effect of CBD on the Rho-123 P-gp-dependent efflux activity, which might explain why the CBD add-on treatment regimen in RE patients results in a significant reduction in seizure frequency.

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“…It is known that CBD is a multi-target compound, acting on ionic channels, neurotransmitter receptors, and other transmembrane transporters, with different effects in each of them acting such as activator, modulator, agonist, antagonist, etc. Additionally, not only is CBD metabolized by the enzymatic cytochrome system, but it can also inhibit some of these enzymes, inducing a slowdown in the metabolism of more common AEDs, which is an alternative way of affecting their pharmacokinetics [84]. Therefore, CBD effects on ABC transporters are only one among multiple mechanisms through which this drug could have an impact on the MDR phenotype in RE patients.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol (CBD) Inhibited Rhodamine-123 Efflux in Cultured Vascular Endothelial Cells and Astrocytes under Hypoxic Conditions

Auzmendi¹,

Palestro²,

Blachman³

et al. 2020

Prime Archives in Neuroscience

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Despite the constant development of new antiepileptic drugs (AEDs), more than 30% of patients develop refractory epilepsy (RE) characterized by a multidrug-resistant (MDR) phenotype. The -transporters hypothesis‖ indicates that the mechanism of this MDR phenotype is the overexpression of ABC transporters such as P-glycoprotein (P-gp) in the neurovascular unit cells, limiting access of the AEDs to the brain. Recent clinical trials and basic studies have shown encouraging results for the use of cannabinoids in RE, although its mechanisms of action are still not fully understood. Here, we have employed astrocytes and vascular endothelial cell cultures subjected to hypoxia, to test the effect of cannabidiol (CBD) on the P-gp-dependent Rhodamine-123 (Rho-123) efflux. Results show that during hypoxia, intracellular Rho-123 accumulation after CBD treatment is similar to that induced by the P-gp inhibitor Tariquidar (Tq). Noteworthy, this inhibition is like that registered in non-hypoxia conditions. Additionally, docking studies predicted that CBD could behave as a P-gp substrate by the interaction with several residues in the α-helix of the P-gp transmembrane domain. Overall, these findings suggest a direct effect of CBD on the Rho-123 P-gp-dependent efflux activity, which might explain why the CBD add-on treatment regimen in RE patients results in a significant reduction in seizure frequency.

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Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

Cited by 21 publications

References 144 publications

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

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

Cannabidiol (CBD) Inhibited Rhodamine-123 Efflux in Cultured Vascular Endothelial Cells and Astrocytes Under Hypoxic Conditions

Cannabidiol (CBD) Inhibited Rhodamine-123 Efflux in Cultured Vascular Endothelial Cells and Astrocytes under Hypoxic Conditions

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