OXINDOLE, A SEDATIVE TRYPTOPHAN METABOLITE, ACCUMULATES IN BLOOD AND BRAIN OF RATS WITH ACUTE HEPATIC-FAILURE

Rats treated with oxindole (10-100 mg/kg i.p.), a putative tryptophan metabolite, showed decreased spontaneous locomotor activity, loss of t he righting reflex, hypotension, and reversible coma. Brain oxindole l evels were 0.05 +/- 0.01 nmol/g in controls and increased to 8.1 +/- 1 .7 or 103 +/- 15 nmol/g after its administration at doses of 10 or 100 mg/kg i.p., respectively. To study the role that oxindole plays in th e neurological symptoms associated with acute liver failure, we measur ed the changes of its concentration in the brain after massive liver d amage, and we investigated the possible metabolic pathways leading to its synthesis. Rats treated with either thioacetamide (0.2 and 0.4 g/k g i.p., twice) or galactosamine (1 and 2 g/kg i.p.) showed acute liver failure and a large increase in blood or brain oxindole concentration s (from 0.05 +/- 0.01 nmol/g in brains of controls to 1.8 +/- 0.3 nmol /g in brains of thioacetamide-treated animals). Administration of tryp tophan (300-1,000 mg/kg p.o.) caused a twofold increase, whereas admin istration of indole (10-100 mg/kg p.o.) caused a 200-fold increase, of oxindole content in liver, blood, and brain, thus suggesting that ind ole formation from tryptophan is a limiting step in oxindole synthesis . Oral administration of neomycin, a broad-spectrum, locally acting an tibiotic agent able to reduce intestinal flora, significantly decrease d brain oxindole content. Taken together, our data show that oxindole is a neurodepressant tryptophan metabolite and suggest that it may pla y a significant role in the neurological symptoms associated with acut e liver impairment.