title: 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 CysLT1 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 CysLT1 inverse agonist montelukast synergistically increases the anticonvulsant action of phenobarbital against pentylenetetrazole-induced seizures. Moreover, it is shown that LTD4 reverses the effect of montelukast. The experimentally derived ED50mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital was 0.06±0.02 μmol, whereas the additively calculated ED50add 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 ED50 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.
authors: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil; University Hospital of Santa Maria, Federal University of Santa Maria, Santa Maria, RS, Brazil; Pharmacy Department, Center of Health Sciences, Franciscan University Center, RS, Brazil.
authors: Juliana
authors: J
authors: Fleck
authors: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors: Joseane Righes
authors: JR
authors: Marafiga
authors: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors: Ana Cláudia
authors: AC
authors: Jesse
authors: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors: Leandro Rodrigo
authors: LR
authors: Ribeiro
authors: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
authors: Leonardo Magno
authors: LM
authors: Rambo
authors: Graduate Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil. Electronic address: cf.mello@smail.ufsm.br.
authors: Carlos Fernando
authors: CF
authors: Mello
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003292:Convulsants; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D010634:Phenobarbital / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013440:Sulfides
chemical_list: D000085:Acetates; D000927:Anticonvulsants; D003292:Convulsants; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D013440:Sulfides; C093875:montelukast; D010433:Pentylenetetrazole; D010634:Phenobarbital
keywords: Dimethyl sulfoxide (PubChem CID: 679); Isobolographic analysis; Leukotriene D(4) (PubChem CID: 6435286); Montelukast; Montelukast (PubChem CID: 5281040); Pentylenetetrazole (PubChem CID: 5917); Phenobarbital; Phenobarbital (PubChem CID: 23674889); Propylene glycol (PubChem CID: 1030); Seizure; Sodium chloride (PubChem CID: 5234)