Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

Abstract

Stressful events during pregnancy adversely affect brain development and may increase the risk of psychiatric disorders later in life. Early changes in the kynurenine (KYN) pathway (KP) of tryptophan (TRP) degradation, which contains several neuroactive metabolites, including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), may constitute a molecular link between prenatal stress and delayed pathological consequences. To begin testing this hypothesis experimentally, we examined the effects of a 2-h restraint stress on KP metabolism in pregnant FVB/N mice on gestational day 17. TRP, KYN, KYNA, 3-HK, and QUIN levels were measured in maternal and fetal plasma and brain, as well as in the placenta, immediately after stress termination and 2 h later. In the same animals, we determined the activity of TRP 2,3-dioxygenase (TDO) in the maternal liver and in the placenta. Compared to unstressed controls, mostly transient changes in KP metabolism were observed in all of the tissues examined. Specifically, stress caused significant elevations of KYNA levels in the maternal plasma, placenta, and fetal brain, and also resulted in increased levels of TRP and KYN in the placenta, fetal plasma, and fetal brain. In contrast, 3-HK and QUIN levels remained unchanged from control values in all tissues at any time point. In the maternal liver, TDO activity was increased 2 h after stress cessation. Taken together, these findings indicate that an acute stress during the late gestational period preferentially affects the KYNA branch of KP metabolism in the fetal brain. Possible long-term consequences for postnatal brain development and pathology remain to be examined.

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

“…1A) (Ligam et al, 2005; Manuelpillai et al, 2005). In line with the expression of the KP enzymes, the metabolites of the pathway, including KYNA, 3-HK and QUIN, have been detected in the placenta (Beggiato et al, 2014a, 2015; Manuelpillai et al, 2005; Notarangelo and Schwarcz, 2014; Notarangelo et al, 2015). Regardless of the origin of kynur-enine in the fetus, the higher levels of the KP namesake in the fetal brain could in part also be responsible for higher levels of its me-tabolites KYNA and 3-HK (Beggiato et al, 2015; Ceresoli-Borroni and Schwarcz, 2000).…”

“…Maternal exposure to infection or stressful conditions adversely affects brain development and increases the risk for the offspring to develop psychiatric symptoms (Brown and Patterson, 2011; Fineberg and Ellman, 2013). In line with this notion, in rodents, both immune activation and stress during pregnancy cause rapid elevations of KP metabolites in the fetal brain (Notarangelo and Schwarcz, 2014; Notarangelo et al, 2015); however, the impact of these insults on long-lasting changes of KP in the offspring are still under investigation.…”

“…1B) (Beal et al, 1992; Ceresoli-Borroni and Schwarcz, 2000; Walker et al, 1999). Preclinical studies have reported high levels of KYNA in the fetal brain of monkeys (Beal et al, 1992), sheep (Walker et al, 1999), rats (Cannazza et al, 2001; Ceresoli-Borroni and Schwarcz, 2000; Pershing et al, 2015; Pocivavsek et al, 2014a) and mice (Beggiato et al, 2015; Notarangelo and Schwarcz, 2014). These results led to the speculation that high brain KYNA content may have a specific role during neurodevelopment.…”

“…As stress and infections are known to increase KP metabolism prenatally (Notarangelo and Schwarcz, 2014; Notarangelo et al, 2015) and during early postnatal development (Asp et al, 2010; Liu et al, 2014), several studies have attempted to model this phenotype by directly increasing kynurenine levels in the immature rodent brain (Table 1). The first paradigm that studied chronic elevation of kynurenine metabolism during pre- and postnatal development was continuous feeding of kynurenine-laced chow to pregnant rat dams from ED 15 to weaning (PND 21).…”

Redox Properties of Tryptophan Metabolism and the Concept of Tryptophan Use in Pregnancy

“…Social stress was proved to be associated with Trp metabolism in organisms. During pregnancy, restraint stress can induce the increase of some Trp metabolites along KP in maternal mouse and fetus [ 187 ]. An acute stress caused by restraint during the late gestational period can induce significant elevations of KYNA levels in the maternal plasma, placenta, and fetal brain, and raised levels of Trp and kynurenine in placenta, fetal plasma, and fetal brain [ 187 ].…”