Open AccessMaternal Inflammation Results in Altered Tryptophan Metabolism in Rabbit Placenta and Fetal Brain
Author(s) -
Mónica Williams,
Zhang Zhi,
Elizabeth Nance,
Julia L. Drewes,
Wojciech G. Lesniak,
Sarabdeep Singh,
Diane C. Chugani,
Kannan Rangaramanujam,
David R. Graham,
Sujatha Kannan
Publication year - 2017
Publication title -
developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.893
H-Index - 82
eISSN - 1421-9859
pISSN - 0378-5866
DOI - 10.1159/000471509
Subject(s) - kynurenine pathway , kynurenine , serotonin , fetus , endocrinology , inflammation , quinolinic acid , medicine , placenta , biology , tryptophan , pregnancy , biochemistry , receptor , genetics , amino acid
Maternal inflammation has been linked to neurodevelopmental and neuropsychiatric disorders such as cerebral palsy, schizophrenia, and autism. We had previously shown that intrauterine inflammation resulted in a decrease in serotonin, one of the tryptophan metabolites, and a decrease in serotonin fibers in the sensory cortex of newborns in a rabbit model of cerebral palsy. In this study, we hypothesized that maternal inflammation results in alterations in tryptophan pathway enzymes and metabolites in the placenta and fetal brain. We found that intrauterine endotoxin administration at gestational day 28 (G28) resulted in a significant upregulation of indoleamine 2,3-dioxygenase (IDO) in both the placenta and fetal brain at G29 (24 h after treatment). This endotoxin-mediated IDO induction was also associated with intense microglial activation, an increase in interferon gamma expression, and increases in kynurenine and the kynurenine pathway metabolites kynurenine acid and quinolinic acid, as well as a significant decrease in 5-hydroxyindole acetic acid (a precursor of serotonin) levels in the periventricular region of the fetal brain. These results indicate that maternal inflammation shunts tryptophan metabolism away from the serotonin to the kynurenine pathway, which may lead to excitotoxic injury along with impaired development of serotonin-mediated thalamocortical fibers in the newborn brain. These findings provide new targets for prevention and treatment of maternal inflammation-induced fetal and neonatal brain injury leading to neurodevelopmental disorders such as cerebral palsy and autism.