Fig 2. Isobolograms presenting interactions between gabapentin (GBP), lacosamide (LCM), levetiracetam (LEV), pregabalin (PGB) and retigabine (RTG), whose dose-response relationship lines were mutually collateral one another, in the 6 Hz-corneal stimulation-induced seizure model in mice.

Isobolograms for various antiepileptic drugs combinations [PGB+LCM (A), GBP+LEV (B), PGB+LEV (C), GBP+RTG (D), LEV+RTG (E), PGB+GBP (F) and PGB+RTG (G)]. The ED₅₀ of antiepileptic drugs when used alone (with S.E.M. as the error bars) are placed on the abscissa and ordinate of the Cartesian plot system. On each graph, the line connecting the ED₅₀ values on both, X and Y axes illustrates the line of additivity. The point A reflects the ED_{50 add} value (with S.E.M. as the error bars) for the two-drug mixture that theoretically exerts additive interaction. The point M illustrates the ED_{50 exp} value (with S.E.M. as the error bars) for the two-drug combination that experimentally suppresses seizures in 50% of the animals tested. The dotted line crossing the points A and M illustrates the fixed drug dose ratio combination of 1:1. If the point M is placed significantly below the point A, the observed interaction is synergistic (unpaired Student’s t-test). *P<0.05, **P<0.01 and ***P<0.001 vs. the respective ED_{50 add} value. If the point M is placed close to the point A, the observed interaction is additive (unpaired Student’s t-test).