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

Abstract

Rats treated with oxindole (10-100 mg/kg 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 thioacetamidetreated 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.

The Endogenous Oxindoles 5-Hydroxyoxindole and Isatin Are Antiproliferative and Proapoptotic

“…Methods of increasing 5-hydroxyoxindole and isatin endogenous levels might be an alternative to exogenous administration, but better knowledge of their biosynthetic pathways would be required. 5-hydroxyoxindole and isatin result from hydroxylation in the liver (10,33) and intestinal bacteria also participate in 5-hydroxyoxindole and isatin biosynthesis, as shown by a significant fall in oxindole content in rat blood and brain during antibiotic treatment (34). Interestingly, brain isatin content is normal in germ-free rats, in contrast to urinary levels (35).…”

5‐hydroxyindole causes convulsions and increases transmitter release in the CA1 region of the rat hippocampus

“…Oxindole (2‐indolinone) and its analogue 5‐hydroxyindole (5‐OHi) are putative tryptophan metabolites requiring tryptophanase, an enzyme present in gut bacteria, for their synthesis (see: Figure 1 and Carpenedo et al ., 1998). Oxindole has sedative and anticonvulsant actions and, when tested in hippocampal slices, it significantly decreases neuronal excitability (Mannaioni et al ., 1998).…”

Amino acid dysbalance in liver failure is favourably influenced by recirculating albumin dialysis (MARS)

“…Plasma amino acid dysbalance in liver failure with low branched chain (BCAA) and increased aromatic amino acids (AAA) may lead to altered neurotransmitter levels as well as disturbed protein synthesis in the central nervous system, both possibly contributing to the development and maintenance of hepatic encephalopathy (1–6). To quantify the degree of this dysbalance, Fischer's index was defined as the ratio of BCAA and AAA concentrations (ΣBCAA/ΣAAA) (1, 2).…”