Effects of levetiracetam on astroglial release of kynurenine-pathway metabolites

BACKGROUND AND PURPOSE Several preclinical studies have demonstrated the unique profiles of levetiracetam (LEV), inhibits spontaneous absence epilepsy models but does not affect traditional convulsion models; however, the detailed pharmacological mechanisms of action of LEV remain to be clarified. EXPERIMENTAL APPROACH We determined the interaction between LEV and IFN gamma regarding astroglial release of anti-convulsive (kynurenic acid and xanthurenic acid), pro-convulsive (quinolinic acid) and anti-convulsive but pro-absence (cinnabarinic acid) kynurenine-pathway metabolites from rat cortical primary cultured astrocytes using ultra-HPLC equipped with MS. KEY RESULTS IFN gamma increased basal astroglial release of cinnabarinic acid and quinolinic acid but decreased that of kynurenic acid and xanthurenic acid. IFN gamma enhanced inositol 1,4,5-trisphosphate (IP3) receptor agonist (adenophostin A, AdA)-induced astroglial release of kynurenine-pathway metabolites, without affecting AMPA-induced release. LEV increased basal astroglial release of kynurenic acid and xanthurenic acid without affecting cinnabarinic acid or quinolinic acid. Chronic and acute LEV administration inhibited AMPA- and AdA-induced kynurenine-pathway metabolite release. Upon chronic administration, LEV enhanced stimulatory effects of IFN gamma on kynurenic acid and xanthurenic acid, and reduced its stimulatory effects on cinnabarinic acid and quinolinic acid. Furthermore, LEV inhibited stimulatory effects of chronic IFN gamma on AdA-induced release of kynurenine-pathway metabolites. CONCLUSIONS AND IMPLICATIONS This study demonstrated several mechanisms of LEV: (i) inhibition of AMPA- and AdA-induced astroglial release, (ii) inhibition of IFN gamma-induced IP3 receptor activation and (iii) inhibition of release of cinnabarinic acid and quinolinic acid with activation of that of kynurenic acid induced by IFN gamma. These combined actions of LEV may contribute to its unique profile.