Antiseizure Effects of Scoparone, Borneol and Their Impact on the Anticonvulsant Potency of Four Classic Antiseizure Medications in the Mouse MES Model—An Isobolographic Transformation

Abstract

Numerous botanical drugs containing coumarins and terpenes are used in ethnomedicine all over the world for their various therapeutic properties, especially those affecting the CNS system. The treatment of epilepsy is based on antiseizure medications (ASMs), although novel strategies using naturally occurring substances with confirmed antiseizure properties are being developed nowadays. The aim of this study was to determine the anticonvulsant profiles of scoparone (a simple coumarin) and borneol (a bicyclic monoterpenoid) when administered separately and in combination, as well as their impact on the antiseizure effects of four classic ASMs (carbamazepine, phenytoin, phenobarbital and valproate) in the mouse model of maximal electroshock-induced (MES) tonic-clonic seizures. MES-induced seizures were evoked in mice receiving the respective doses of the tested natural compounds and classic ASMs (when applied alone or in combinations). Interactions for two-drug and three-drug mixtures were assessed by means of isobolographic transformation of data. Polygonograms were used to illustrate the types of interactions occurring among drugs. The total brain content of ASMs was measured in mice receiving the respective drug treatments with fluorescent polarization immunoassay. Scoparone and borneol, when administered alone, exerted anticonvulsant properties in the mouse MES model. The two-drug mixtures of scoparone with valproate, borneol with phenobarbital and borneol with valproate produced synergistic interactions in the mouse MES model, while the remaining tested two-drug mixtures produced additivity. The three-drug mixtures of scoparone + borneol with valproate and phenobarbital produced synergistic interactions in the mouse MES model. Verification of total brain concentrations of valproate and phenobarbital revealed that borneol elevated the total brain concentrations of both ASMs, while scoparone did not affect the brain content of these ASMs in mice. The synergistic interaction of scoparone with valproate observed in the mouse MES model is pharmacodynamic in nature. Borneol elevated the brain concentrations of the tested ASMs, contributing to the pharmacokinetic nature of the observed synergistic interactions with valproate and phenobarbital in the mouse MES model.

Imperatorin interacts additively with novel antiseizure medications in the mouse maximal electroshock-induced seizure model: an isobolographic transformation

“…Although IMP potentiated the antiseizure effects of some novel ASMs, the isobolography revealed only additive interactions proving that only this method can correctly classify the interactions observed in preclinical conditions. The superiority of isobolographic analysis over the subthreshold method used in experimental epileptology has been previously confirmed [ 26 , 29 ]. Considering the anticonvulsant potential of all naturally-occurring coumarins tested, it should be stated that IMP possesses the best anticonvulsant profile potentiating the effects of several ASMs in the mouse MES model, in contrast to osthole, umbelliferone, xanthotoxin, and scoparone (Supplementary Table 1).…”

“…Of note, any antagonistic interaction in terms of seizure suppression is unfavorable, from a pharmacological viewpoint, due to the decrease in the anticonvulsant potential of the drugs in a mixture [ 31 , 32 ]. In the case of scoparone, this naturally occurring coumarin exerted additive interactions with CBZ, PHT, PB, and VPA in the mouse MES model [ 26 ]. Unfortunately, the anticonvulsant effects for the combinations of classic ASMs with osthole, umbelliferone, and xanthotoxin have not been isobolographically transformed and the exact types of interactions for these drug combinations are unknown as yet.…”

“…The interactions between IMP and the tested drugs in the mouse MES model were characterized by the isobolographic transformation. The constant doses of IMP (25 and 50 mg/kg) in mixtures were illustrated graphically as parallel lines to the Y-axis, whereas the increasing doses of each ASM allowed creating the isoboles, as reported earlier [ 26 ].…”

The (–)-Borneol Effect on Addiction/Abstinence by Morphine in Mice

“…One of the reported pharmacological activities of (-)-BOR is its anticonvulsive property [54,55], probably due to its ability to positively modulate GABAARs acting as a partial agonist [27]. Perhaps the effect on GABAAR may explain, in part, how (-)-BOR reduced the preference for the compartment in which the animals were paired.…”