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Abstract

Introduction: Intrauterine inflammation during pregnancy has been implicated in fetal/neonatalneuroinflammation and developmental disorders such as cerebral palsy. We hypothesize that maternal and fetal inflammation results in macrophage/microglial activation and increased tryptophan (TRP) metabolism through the kynurenine (KYN) pathway due to increased expression of the rate limiting enzymes indoleamine2,3 dioxygenase (IDO) and kynurenine mono-oxygenase (KMO), in activated macrophages/microglia, leading to increased formation of the neurotoxic metabolites 3-hydroxykynurenine and quinolinic acid and decreased serotonin (5HT) in the placenta and fetal brain. This may be associated with impaired development of serotonin regulated fibers in the parietal somatosensory cortex resulting in sensory impairment. Methods: Pregnant rabbits were administered 20,000 EU of E.coli endotoxin (endotoxin) or saline along the uterus on G28 (term=G31).Comparisons were made with naïve controls. Placenta and fetal brains were harvested after 24 hours (G29) and analyzed by HPLC for concurrent measurement of all TRP and KYN metabolites, and confirmed by Mass Spectrophotometer. Some of the rabbits were allowed to go to term and newborn rabbit brains were also evaluated for the metabolites as above. Fetal and newborn brains were also evaluated for microglial activation, neuronal loss and oxidative injury. Results: Our results demonstrate that maternal endotoxin exposure results in increased KYN and kynurenic acid (KYNA) with a decrease in 5HT in the periventricular region (PVR) of the fetal and newborn brain when compared to controls(n=4–5 kits /group). Endotoxin kits had significantly increased microglial activation with increased KMO expression in the PVR that mainly co-localized in CD11b staining activated microglia and increased neuronal loss by TUNEL and Floro-Jade staining. There was no difference in TRP levels between the groups. The newborn endotoxin rabbits had decreased sensory response to painful and tactile stimulation and a decreased aversion response to noxious olfactory stimuli when compared to the controls. This was associated with decreased serotonin concentration in the brain and decreased number of serotonin staining fibers in the parietal somatosensory cortex. Conclusions: In conclusion, this data suggests that maternal inflammation and fetal neuroinflammation results in increased tryptophan metabolism along the kynurenine pathway that is associated with increased microglial activation, neuronal injury and impaired development of the sensory cortex in the fetal and newborn rabbit brain.