Modulation by kynurenine of extracellular kynurenate and glutamate in cerebral cortex of rats with acute liver failure

Abstract

Background: Kynurenic acid (KYNA) modulates the glutamatergic tone by controlling neuronal glutamate (GLU) release. The present study tested the potential of the KYNA precursor, kynurenine (KYN) to counter increased extracellular GLU associated with the pathogenesis of hepatic encephalopathy accompanying acute liver failure (ALF).

Methods: ALF was induced in adult rats by administration of a hepatotoxin, thioacetamide. KYNA and GLU were measured in the cerebral cortical microdialysates of control (saline-treated) and ALF rats using HPLC. The expression of mRNA coding for kynurenine aminotransferase II (KAT-II), the astrocytic enzyme converting KYN to KYNA, was assayed by real-time PCR.

Results: Cerebral cortical extracellular KYNA was increased in ALF rats not treated with KYN, consistent with a previously observed increase of cerebral cortical KATII activity in this ALF model. Single intraperitoneal administration of KYN (50 mg/kg, 120 min before microdialysate collection), produced a further substantial increase of extracellular KYNA, paralleled by a decrease of extracellular GLU. In cultured cerebral cortical astrocytes, the cells which in situ are the primary target of blood-derived ammonia and other toxins liberated due to ALF, elevation of KAT-II mRNA expression was noted upon their incubation with KYN and the KYN precursor, tryptophan (Trp), which is normally elevated by ALF.

Conclusions: Administration of exogenous KYN to stimulate KYNA synthesis may help correcting excessive extracellular accumulation of GLU in cerebral cortex caused by ALF. The therapeutic potential of KYN in ALF appears to be fostered by increased expression of KAT-II in astrocytes upon exposure to KYN or Trp.

Keywords: Cultured astrocytes; Glutamate; Hepatic encephalopathy; Kynurenic acid; Kynurenine.