Leucine blocks lipopolysaccharide-induced depression-like behavior by interfering with kynurenine influx into the brain.

Abstract

Inflammation activates the tryptophan-kynurenine metabolism pathway. Circulating kynurenine is transported into the brain at the vascular blood–brain barrier (BBB) by the large amino-acid transporter LAT-1, where it is further metabolized into neurotoxic metabolites responsible for depressive symptoms. LAT-1 transports tryptophan, kynurenine and the amino acid leucine. We sought to competitively inhibit kynurenine blood-to-brain transport with leucine in order to attenuate lipopolysaccharide-induced depression-like behavior in CD-1 mice. Given that the concentration of circulating kynurenine is 100 fold less than kynurenine, we hypothesized that leucine should inhibit kynurenine more than tryptophan transport. We had already demonstrated that inflammation increases luminal-to-abluminal transport of tryptophan using an in vitro model of BBB transport. Here we show that lipopolysaccharide-treated mice (0.83 mg/kg, ip) develop depression-like behavior at 24 h (reduced sucrose preference and increased forced swim test immobility; p p p p