Pharmacological and biochemical analysis of interactions between N-acetylcysteine and some antiepileptic drugs on experimental seizures in mice.

PURPOSE: In view of a putative role of oxidative stress in the pathophysiology of seizures, this study addressed the interactions between N-acetylcysteine (NAC), a potent antioxidant and two antiepileptic drugs sodium valproate (SVP) and phenytoin (PHT) on experimental seizures in mice.

METHODS

The interaction was studied at three fixed ratio combinations (i.e., 1:1, 1:3, and 3:1) in the mouse maximal electroshock (MES) test using isobolographic analysis. Markers of oxidative stress (reduced glutathione [GSH] and malondialdehyde [MDA]) were estimated in the cortex of mice pretreated with either of these drugs alone or their 3:1 ratio combinations at the experimentally determined ED(50) values (ED(50 exp) values). The grip strength and spontaneous alternation behavior (SAB) were also assessed. In addition, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and calcium levels were estimated.

RESULTS

We found an anticonvulsant action of NAC in the MES test. Further, the ED(50 exp) values for the combinations of PHT and NAC did not differ from the theoretically calculated ED(50) values indicating additive effects. In case of SVP and NAC, however, the ED(50 exp) values were lower than the theoretically calculated ED(50) values. The interaction of SVP with NAC at the fixed ratios of 1:3 and 3:1 was found to be synergistic. No significant changes were observed in the grip strength, SAB, cortical GSH and MDA levels, serum AST, ALT, ALP, or calcium levels.

CONCLUSION

Our results thus hold promise for the use of NAC as an adjunct to PHT and SVP therapy.