STRESS INDUCED BY EPILEPTIC SEIZURES MODIFIES THE EXPRESSION OF CANNABIDIOL (CBD) MOLECULAR TARGETS. IMPLICATIONS FOR THE MECHANISM OF ACTION OF CBD IN THE CONTROL OF DRUG-RESISTANT SEIZURES.

TABORDA GÓMEZ, CLAUDIA; FERNÁNDEZ, FLORENCIA; MOSCOVICZ, FRANCO; BORDA, NATALIA; LAZAROWSKI, ALBERTO; AUZMENDI, JERÓNIMO

Mar del Plata

Congreso; XLVIII reunion anual SAIC; 2023

Sociedad Argentina de Investigaciones Clínicas

Cannabidiol (CBD) is used as an adjuvant in the treatment for the control of drug-resistant epileptic seizures, increasing the plasmatic concentration of antiepileptic drugs (AEDs) presumably by blocking their metabolization. However, DAEs without hepatic metabolization are also increased. In previous work we demonstrated that CBD blocks ABCt. On the other hand, hypoxia and inflammation modify hepatic CYPs and ABCt levels. Since seizures produce a systemic hypoxic/inflammatory state, we hypothesized that the targets on which CBD presumably acts are modified as a consequence of seizures. Using databases (UniProt, PDB, Ensembl, CDD and RGD) we analyzed the correspondence between human-rat cytochromes by sequence homology and conservation of functional domains. We then employed the pilocarpine (30mg/kg) induced Status Epilepticus (SE) model and extracted liver RNA to evaluate the expression of CYPs (2C9, 2C19, 2D6 and 3A4) and ABCt (B1b and G2) by RT-PCR. In addition, we evaluated phenytoin consumption using hepatocytes in primary cultures obtained from the same animals. The human-rat sequence identities were between 78.89-84.51% with over 50% coverage. Despite this, the functional domains were conserved. SE induction had an efficiency of 81.1%, mean duration of 127±48 min and lethality of 9.51%. Evaluation of CYP expression showed a decreasing trend that was significant for CYP 2C9 (p=0.0029) and 3A4 (p=0.0212), while ABCt expression was significantly increased (p=0.0110) as a consequence of SE. Consistently phenytoin consumption was decreased 3-5% after SE. Our results show that SE induces a variation of CYPs and ABCt expression similar to those described for inflammatory/hypoxic conditions, suggesting that CBD could increase the plasma concentration of DAEs, in particular those without hepatic metabolism, by blocking ABCt.