Montelukast potentiates the anticonvulsant effect of phenobarbital in mice: An isobolographic analysis

Abstract Although leukotrienes have been implicated in seizures, no study has systematically investigated whether the blockade of CysLT 1 receptors synergistically increases the anticonvulsant action of classic antiepileptics. In this study, behavioral and electroencephalographic methods, as well as isobolographic analysis, are used to show that the CysLT 1 inverse agonist montelukast synergistically increases the anticonvulsant action of phenobarbital against pentylenetetrazole-induced seizures. Moreover, it is shown that LTD 4 reverses the effect of montelukast. The experimentally derived ED 50mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital was 0.06 ± 0.02 μmol, whereas the additively calculated ED 50add value was 0.49 ± 0.03 μmol. The calculated interaction index was 0.12, indicating a synergistic interaction. The association of montelukast significantly decreased the antiseizure ED 50 for phenobarbital (0.74 and 0.04 μmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. The demonstration of a strong synergism between montelukast and phenobarbital is particularly relevant because both drugs are already used in the clinics, foreseeing an immediate translational application for epileptic patients who have drug-resistant seizures.