Jo,irnd zyxwvutsrqponml cd Ncrrroi lienii\lry zyxwvutsrqponmlkj Raven Pres. New York zyxwvutsrqponm G 1986 International Society for Neurochemistry Content of Quinolinic Acid and of Other Tryptophan Metabolites Increases in Brain Regions of Rats Used as Experimental Models of Hepatic Encephalopathy F. Moroni, G. Lombardi, V. Carla, D. Pellegrini, *G. L. Carassale, and *C. Cortesini Department zyxwvutsrq of Preclinicnl find Clinical Phnrmcicology and *Depnrtment zyxwv of Surgery, University of Florence, Florence, Itril! Abstract: The content of the tryptophan metabolites quinolinic acid (QUIN), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) was measured in various brain areas of rats bearing a portocaval anas- tomosis (PCA) for zyxwvutsr 4 weeks, zyxwvutsr using mass fragmentography or HPLC. In these animals, the content of the excitotoxic compound QUIN increased by 75% in the cortex and 125% in the cerebellum. The content of 5-HT increased by 27% in the brainstem. No changes occurred in other brain areas. On the other hand, the content of 5-HIAA increased by 66% in the cortex, 65% in the caudate, 64% in the hippocampus, 120% in the diencephalon. and 185% in the brainstem. Probenecid administration caused a larger increase of 5-HIAA accumulation in various brain areas of PCA-bearing rats than in those of sham-operated controls. The cortical content of QUIN and 5-HIAA in- creased after administration of ammonium acetate (7 mmol/kg), whereas an equimolar amount of sodium ace- tate was inactive. These results confirm that profound changes in the disposition of tryptophan occur in the brains of experimental animals used as models of hepatic encephalopathy. Furthermore, this study adds the exci- totoxic compound QUIN to the list of molecules possibly involved in the pathogenesis of this brain disorder. Key Words: Portocaval anastomosis- Hepatic encephalo- pathy-Quinolinic acid-Tryptophan-5-Hydroxytryp- tamine. Moroni F. et al. Content of quinolinic acid and of other tryptophan metabolites increases in brain regions of rats used as experimental models of hepatic encephalop- athy. J. Ncwocliiwi. 46, 869-874 (1986). An increased amount of tryptophan in plasma, CSF, or brain of patients affected by hepatic en- cephalopathy or hepatic coma has been shown re- peatedly (Hirayama. 1971; Young et al., 1975: Ono et al., 1978; Sourkes, 1978; Weiser et al., 1978; Sal- ern0 et al., 1982). Similarly, in several experimental models of acute or chronic hepatic failure, the con- centration of tryptophan is increased both in plasma and in various brain areas (Curzon et al., 1973. 1975; Cummings et al., 1976; Mans et al., 1979: Tricklebank et al., 1978; Martin et al., 1983). A relatively large dose of tryptophan adminis- tered to Eck-fistula-bearing dogs causes a symptom- atology similar to hepatic coma (Ogihara et al.. 1966), and the infusion of solutions containing large amounts of tryptophan and tyrosine causes coma in normal dogs (Rossi-Fanelli et al., 1982). This sug- gests that tryptophan is in some way involved caus- ally in the neurological alterations occurring during liver diseases. Most of the symptoms related to increased tryp- tophan in the brain are usually ascribed to changes in function of 5-hydroxytryptamine (5-HT)-re- leasing neurons. However, tryptophan is the pre- cursor of several other electrophysiologically active compounds, including quinolinic acid (QUIN), which has been demonstrated recently in the brain (Wolfensberger et al., 1983; Moroni et al.. 1984a). This compound is a convulsant agent (Lapin. 1982). it excites the neurons acting on receptors for exci- tatory amino acids (Stone and Perkins. 1981), and, under appropriate conditions, it may also cause neuronal degeneration (Schwarcz et al.. 1983). Tryptophan administration to rats increases the zy ~___ ~ Received April 10. IY85: revised September 24. 1985: accepted September 27. 1985. Address correspondence and reprint requests to Prof. F. Mo- roni at Department of Preclinical and Clinical Pharmacology. University of Florence. Vide Morgagni. 65. 50134 Florence. Italy. Ahhrerinlimi.5 itsrd: 5-HIAA. Z-hydroxyindoleacetic acid: 5- HT. Shydroxytryptamine: PCA, portocaval anastomo\is: QUIN. quinolinic acid. 86 9