Brain Quinolinic Acid in Chronic Experimental Hepatic Encephalopathy: Effects of an Exogenous Ammonium Acetate Challenge

Abstract

Elevated brain concentrations of the neurotoxin and NMDA receptor agonist quinolinic acid (QUIN) have been demonstrated in portacaval‐shunted (PCS) rats, a chronic hepatic encephalopathy (HE) model. Increased brain QUIN levels have also been shown in acute hyperammonemic rats. In the present study, the plasma and brain (neocortical) QUIN levels in chronic PCS rats were investigated. The study also included a single exogenous ammonium acetate (NH4Ac; 5.2 mmol/kg, i.p.) challenge to precipitate a reversible hepatic coma. Compared with sham‐operated controls, chronic PCS rats exhibited decreased rather than increased plasma and brain QUIN levels. The plasma‐to‐brain QUIN ratio was not found to be altered. The NH4Ac administration induced coma in all of the PCS rats 20–25 min after the challenge, and this coma was resolved within 60–75 min. No relevant temporal relationship between changes in brain QUIN levels and the neurological status in the PCS rats was observed. Therefore, our results do not support the contention that increased brain QUIN levels per se are involved in the pathogenesis of HE.

Pharmacology of the kynurenine pathway

“…Holt et al [37] have demonstrated raised levels of quinolinic acid in the brains of dogs with porto-systemic shunts, emphasising the possible role of the kynurenine pathway in the associated cerebral dysfunction. It should be noted that this latest report conflicts with earlier failures to detect raised levels of quinolinic acid in hepatic encephalopathy in humans or animal models [38][39][40][41][42].…”

Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

“…It is therefore reasonable to suppose that tryptophan or its metabolites play an important role in the pathophysiology of brain changes occurring when liver function is impaired. In the past several decades, the tryptophan metabolite most studied in relation to the neurological and psychiatric symptoms associated to liver diseases has been 5-hydroxytryptamine (see references in Bengtsson, 1987;Bergqvist et al, 1995a). Other metabolites that have been studied in relation to liver failure are quinolinic or kynurenic acid (Moroni et al, 1986a,b;Basile et al, 1995;Bergqvist et al, 1995a), neuroactive compounds able to interact with glutamate receptors of the NMDA type (for review, see Stone, 1993), and tlyptamine, a biogenic amine having an increased turnover rate in the brain of hepatic encephalopathy patients (Young and Lal, 1980).…”

Long‐Term Effects of Portacaval Anastomosis on the 5‐Hydroxytryptamine, Histamine, and Catecholamine Neurotransmitter Systems in Rat Brain

“…Furthermore, Trp serves as a precursor for the synthesis of tryptamine and 5-HT and is involved in the biosynthesis of kynurenines, including the potentially toxic quinolinic acid. Increased concentrations of these compounds have been observed in humans with hepatic encephalopathy (Moroni et a!., 1986;al-Mardini et al, 1993;Mousseau et al, 1994;Bergqvist et al, 1995).…”