Despite the approval of a considerable number of last generation
antiepileptic drugs (AEDs) (only in the last decade, six drugs have gained Food and Drug Administration approval), the global figures of seizure control have seemingly not improved, and available AED can still be regarded as symptomatic treatments. Fresh thinking in AEDs
drug discovery, including the development of drugs with novel mechanisms of action, is required to achieve truly innovative
antiepileptic medications. The transporter hypothesis proposes that inadequate penetration of AEDs across the blood-brain barrier, caused by increased expression of efflux transporters such as
P-glycoprotein (P-gp), contributes to
drug-resistant epilepsy.
Neuroinflammation due to high levels of
glutamate has been identified as one of the causes of P-gp upregulation, and several studies in animal models of
epilepsy suggest that antiinflammatory drugs might prevent P-gp overexpression and, thus, avoid the development of
refractory epilepsy. We have applied
ligand-based in silico screening to select compounds that exert dual
anticonvulsant and antiinflammatory effects. Five of the hits were tested in animal models of seizure, with protective effects. Later, two of them (
sebacic acid (SA) and
gamma-decanolactone) were submitted to the recently described MP23 model of
drug-resistant
seizures. All in all, SA displayed the best profile, showing activity in the maximal electroshock seizure (MES) and
pentylenetetrazol (PTZ) seizure models, and reversing resistance to
phenytoin (PHT) and decreasing the P-gp upregulation in the MP23 model. Furthermore, pretreatment with SA in the
pilocarpine status epilepticus (SE) model resulted in decreased histamine release in comparison with nontreated animals. This is the first report of the use of the MP23 model to screen for novel
anticonvulsant compounds that may avoid the development of P-gp-related drug resistance.