Interactions of MRZ 2/576 with Felbamate, Lamotrigine, Oxcarbazepine and Topiramate in the Mouse Maximal Electroshock-Induced Seizure Model

Abstract

This study focused on the evaluation of interactions between MRZ 2/576 (8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazino(4,5-b)quinoline-5-oxide choline salt), an N-methyl-D-aspartate (NMDA) receptor antagonist acting at the NMDA receptor/glycine_B site and four newer antiepileptic drugs (felbamate, lamotrigine, oxcarbazepine, and topiramate) in the mouse maximal electroshock seizure model. Results indicate that MRZ 2/576 administered intraperitoneally, 5 min before the test, exerted a clear-cut anticonvulsant effect in the maximal electroshock seizure test in mice and its ED₅₀ value was 13.71 (11.95–15.73) mg/kg. In the subthreshold method, MRZ 2/576 (administered intraperitoneally, at a subthreshold dose of 5 mg/kg) significantly enhanced the anticonvulsant action of felbamate, oxcarbazepine and topiramate, by reducing their ED₅₀ values from 73.0 to 53.8 mg/kg (p < 0.05) for felbamate, from 10.77 to 7.48 mg/kg (p < 0.05) for oxcarbazepine, and from 49.3 to 28.7 mg/kg (p < 0.01) for topiramate. In contrast, MRZ 2/576 (5 mg/kg, i.p.) did not significantly affect the antiseizure effects of lamotrigine in the maximal electroshock seizure test in mice. Isobolographic transformation of data revealed that MRZ 2/576 (5 mg/kg, i.p.) exerted barely additive interactions with all investigated antiepileptic drugs in the maximal electroshock seizure test. In conclusion, the isobolographic analysis revealed that MRZ 2/576 additively cooperates with newer antiepileptic drugs in terms of suppression of maximal electroshock-induced seizures in mice.

Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice

“…By combining drugs with different or even similar pharmacologic actions, polytherapy allows for better therapeutic efficacy at lower and, thus, less toxic doses. This phenomenon is also often observed and studied under experimental conditions where one anticonvulsant agent in doses ineffective per se would potentiate anticonvulsant effects of other compounds or AEDs (Luszczki et al., 2006a, 2007a, 2008a,b). The present study shows that acetone behaves similarly to many classical and novel AEDs when administered in combinations.…”

Assessment of the Combined Treatment with Umbelliferone and Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

“…UMB and classical AEDs) allowed us to ascribe doses of drugs to their predicted anticonvulsant effects. After isobolographic transformation of data, as described in details elsewhere [33] , it was found that UMB combined with PB and VPA produced barely additive interaction in the mouse MES model. Thus, the observed enhancement of the anticonvulsant potency of PB and VPA by UMB was additive in nature.…”

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

“…This is the reason for calculating the fractions of the antiseizure effects produced by fixed doses of the tested naturally occurring compounds and fractions of the classic ASMs. Summation of fractions allowed for the precise characterization of interactions between the studied drugs (for more detailed information, see [ 28 , 29 ]). Due to the isobolographic transformation, we found that the observed potentiation of the antiseizure effects of PB by scoparone or borneol in the two-drug mixture was additive in the mouse MES model.…”

“…Calculation of fractions of the studied drugs (i.e., borneol, scoparone and classic ASMs) along with subsequent isobolographic transformation of data was conducted in strict accordance with the procedure as described earlier [ 42 ]. After summation of the fractions of the studied drugs in mixture (i.e., borneol, scoparone and the classic ASMs), the isobolographic characterization of interactions was possible, as reported elsewhere [ 28 , 29 ]. To graphically illustrate the studied interactions, polygonograms were drawn.…”