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

JERÓNIMO AUZMENDI; PABLO PALESTRO; AGUSTÍN BLACHMAN; LUCIANA GAVERNET; AMALIA MERELLI; ALAN TALEVI; GRACIELA CRISTINA CALABRESE; ALBERTO JAVIER RAMOS; ALBERTO LAZAROWSKI

Prime Archives in Neuroscience.

VIDE LEAF

Lugar: Hyderabad; Año: 2020; p. 1 - 28

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 ofthis MDR phenotype is the overexpression of ABC transporterssuch as P-glycoprotein (P-gp) in the neurovascular unit cells,limiting access of the AEDs to the brain. Recent clinical trialsand basic studies have shown encouraging results for the use ofcannabinoids in RE, although its mechanisms of action are stillnot fully understood. Here, we have employed astrocytes andvascular endothelial cell cultures subjected to hypoxia, to test theeffect 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 issimilar to that induced by the P-gp inhibitor Tariquidar (Tq).Noteworthy, this inhibition is like that registered in non-hypoxiaconditions. Additionally, docking studies predicted that CBDcould behave as a P-gp substrate by the interaction with severalresidues in the α-helix of the P-gp transmembrane domain.Overall, these findings suggest a direct effect of CBD on theRho-123 P-gp-dependent efflux activity, which might explainwhy the CBD add-on treatment regimen in RE patients results ina significant reduction in seizure frequency.