The kynurenine pathway: a missing piece in the puzzle of valproate action?

Abstract

The present study was designed to determine the role of the kynurenine pathway (KP) in the mechanism of action of valproate (VPA). Therefore, we investigated changes in the concentrations of tryptophan (TRP), kynurenic acid (KYNA), and kynurenine (KYN) in the brain and plasma following VPA administration (50, 250 and 500mg/kg i.p.). The most important findings of our study were that VPA administration produced a progressive and strong increase in the central concentrations of KYNA, KYN and TRP. Simultaneously, the TRP level in plasma declined, while the peripheral increase of KYNA in plasma was weaker and occurred earlier than in the hippocampus. Bearing in mind that the observed effect may be a result of a strong VPA-induced displacement of TRP from its binding sites to plasma albumin, we checked the effect of ibuprofen (IBU) administration (a prototypic drug used to study drug binding to serum albumin) on the KP. We found that IBU evoked a similar pattern of change in the KP activity as VPA. These new findings indicate the existence of a mechanism that could stimulate the production of KYNA in the brain after VPA administration, and may partially contribute to the mechanisms of VPA action. The results of our experiment indicate that an increase in the brain's KYNA level may be achieved by TRP displacement from its binding site on plasma albumin with the administration of different drugs, including VPA, IBU, or short-chain fatty acids, with important clinical consequences.