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Effects of Levetiracetam on Astroglial Release of Kynurenine-Pathway Metabolites

Effects of Levetiracetam on Astroglial Release of Kynurenine-Pathway Metabolites

Kouji Fukuyama, Motohiro Okada

Br J Pharmacol. 2018 Nov;175(22):4253-4265.

PMID: 30153331

Abstract:

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 (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 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 IP3 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.

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