Rats treated with
oxindole (10-100 mg/kg i.p.), a putative
tryptophan metabolite, showed decreased spontaneous locomotor activity, loss of the righting reflex,
hypotension, and reversible
coma. Brain
oxindole levels 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 the neurological symptoms associated with
acute liver failure, we measured the changes of its concentration in the brain after massive liver damage, and we investigated the possible metabolic pathways leading to its synthesis. Rats treated with either
thioacetamide (0.2 and 0.4 g/kg 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 concentrations (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
tryptophan (300-1,000 mg/kg p.o.) caused a twofold increase, whereas administration of
indole (10-100 mg/kg p.o.) caused a 200-fold increase, of
oxindole content in liver, blood, and brain, thus suggesting that
indole formation from
tryptophan is a limiting step in
oxindole synthesis.
Oral administration of
neomycin, a broad-spectrum, locally acting
antibiotic agent able to reduce intestinal flora, significantly decreased brain
oxindole content. Taken together, our data show that
oxindole is a neurodepressant
tryptophan metabolite and suggest that it may play a significant role in the neurological symptoms associated with acute liver impairment.