CONICET | Buscador de Institutos y Recursos Humanos

Sociedad Argentina de Protozoología, Sociedad Argentina de Hematología, Sociedad Argentina de Fisiología, Sociedad Argentina de Farmacología Experimental, Sociedad Argentina de Biología, Sociedad Argentina de Biofísica, Sociedad Argentina de Investigación

Resumen:

About 30% of the patients with epilepsy do not respond to clinicallyestablished anticonvulsants, despite achieving effective concentrationsin plasma. One of the most accepted hypotheses to explainrefractory epilepsy is the overexpression of ABC transporters atblood-brain barrier level, which appears to be induced by glutamatethrough activation of the COX-2 pathway.Here, we have applied ligand-based in silico screening (basedon linear discriminant analysis and conformation-independent descriptors)to select compounds from the DrugBank and Sweetleaddatabases which, according to our computational models, displaycombined anticonvulsant and anti-inflammatory activity.5 of the hits from the in silico screening have been assayed in threeacute seizure models (MES, PTZ and MP). Those which showed anticonvulsantactivity in both MES and PTZ tests without neurotoxiceffects but did not in MP test (sebacic acid and γ-decanolactone)were evaluated in a pharmacoresistant seizure model in mice(MP23 model).The MP23 model consists in inducing daily clonic seizures during23 consecutive days through 3-mercaptopropionic acid (MP) administration.At the end of the treatment, mice are refractory to phenytoinand phenobarbital effects showing an increased P-glycoproteinbrain expression. Sebacic acid and γ-decanolactone were administered30 min before MP administration every day. On day 24 PHTresistance and P-gp expression were studied.All compounds selected by in silico screening showed anticonvulsantactivity in at last one of the acute seizure tests. Sebacic acidand γ-decanolactone administration before MP in the MP23 modelshowed a higher PHT effect in relation to MP alone (p