Studies on the Pharmacological Properties of Oxindole (2-Hydroxyindole) and 5-Hydroxyindole: Are They Involved in Hepatic Encephalopathy?

Abstract

It has been repeatedly described that plasma or CSF tryptophan concentrations increase in experimental animal models of liver impairment and in patients suffering from hepatic encephalopathy or hepatic coma (Hirayama, 1971; Curzon et al. 1973; Sourkes, 1978; ONO et al. 1996). It has also been demonstrated that the administration of large doses of tryptophan to patients affected by hepatic disorders or to dogs with a portocaval shunt may lead to coma (Sherlock, 1975; Rossi-Fanelli et al. 1982). On the basis of the widely agreed assumption that increased brain tryptophan concentrations signify increased 50Htryptamine turnover, several years ago, a number of investigators proposed that an increased stimulation of 50H-tryptamine receptors plays a key role in the neurological and psychiatric symptoms associated with liver diseases (Cummings et al. 1976). Tryptophan may be metabolized not only into 50H-tryptamine, but also into quinolinic or kynurenic acids, neuroactive compounds which are able to interact with glutamate receptors of the NMDA type (see: Stone, 1993 for a review). Approximately ten years ago, we observed that quinolinic acid was indeed increased in the rat brain with portocaval anastomosis or in patients who had died in hepatic coma (Moroni et al. 1986; Moroni et al. 1986a). We therefore proposed that “..quinolinic acid should be added to the list of compounds possibly involved in the pathogenesis and symptomatology of brain disorders associated to liver failure.” Other groups have recently confirmed that quinolinic acid is indeed increased in the blood and brain of rat models suffering from either acute or chronic liver failure. The concentration of quinolinic acid in the brain, however, does not seem to correlate with the neurological symptoms observed in these liver disorders. Furthermore, it is possible that quinolinic acid synthesis occurs mostly in macrophages or other periphalopathy may be “minor” (Bergquist et al. 1995; Basile et al. 1995).