Cannabindiol (CBD) and erythropoietin (EPO) blokc the ativity of P glycoprotein (P-gp) linked to drug resistance in refractory epilepsies.

MERELLI A; RAMOS AJ; LAZAROWSKI A; AUZMENDI J

San José de Costa Rica

Congreso; X Congreso Latinoamericano de Epilepsia; 2018

ILAE-IBE

Cannabindiol (CBD) obtained from the Cannabis sativa plant has beneficial properties for the treatment of different pathologies in the central nervous system (CNS). In the CNS, the expression of the glycoprotein P (P-gp) is limited to the blood-brain barrier, although stressful stimuli such as seizures or hypoxia promote its expression in both astrocytes and neurons, facilitating the acquisition of the drug-resistant phenotype. In addition, these stimuli promote the expression of the erythropoietin receptor that antagonizes the function of P-gp, so that erythropoietin (EPO) could play an important role in the control of refractory epilepsies. In this work we aimed to evaluate the effect of CBD and recombinant human EPO (hrEPO) on the activity of P-gp. We designed a functional experiment on primary cultures of cortical cells using Rhodamine 123 (Rho123) as a substrate for P-gp. The cultures were obtained from Wistar rats. At 10 days in vitro the expression of P-gp was induced by a treatment with CoCl2 (0.3 mM) for 6 h. The loss-of-function experiments were performed with different concentrations of CBD (5, 50 and 100 μM) and hrEPO (30; 100; 300 IU) for 30 minutes. The positive control was performed with the specific P-gp Tariquidar blocker (5 μM). Then it was incubated with Rho123 (1 μM) for 30 minutes. Fluorescence was determined using fluorescence microscopy. Functional tests showed that CBD blocks P-gp activity in concentration-dependent mode. On the other hand, hrEPO blocked the activity of P-gp independently of the concentration. No additive or synergistic effects were observed. The expression of P-gp was confirmed by immunofluorescence. Both CBD and hrEPO blocked the activity of P-gp, presumably in different ways suggesting that both could have a role in the control of refractory crises.