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Effects of levetiracetam on astroglial release of kynurenine‐pathway metabolites
Author(s) -
Fukuyama Kouji,
Okada Motohiro
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14491
Subject(s) - kynurenic acid , quinolinic acid , xanthurenic acid , kynurenine , kynurenine pathway , pharmacology , chemistry , ampa receptor , biochemistry , biology , receptor , glutamate receptor , amino acid , tryptophan
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 IFNγ 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 IFNγ increased basal astroglial release of cinnabarinic acid and quinolinic acid but decreased that of kynurenic acid and xanthurenic acid. IFNγ enhanced inositol 1,4,5‐trisphosphate (IP 3 ) 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 IFNγ on kynurenic acid and xanthurenic acid, and reduced its stimulatory effects on cinnabarinic acid and quinolinic acid. Furthermore, LEV inhibited stimulatory effects of chronic IFNγ 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 IFNγ‐induced IP 3 receptor activation and (iii) inhibition of release of cinnabarinic acid and quinolinic acid with activation of that of kynurenic acid induced by IFNγ. These combined actions of LEV may contribute to its unique profile.