PMID- 31117076
OWN - NLM
STAT- MEDLINE
DCOM- 20200330
LR  - 20200522
IS  - 1421-9859 (Electronic)
IS  - 0378-5866 (Print)
IS  - 0378-5866 (Linking)
VI  - 41
IP  - 1-2
DP  - 2019
TI  - Assessment of Prenatal Kynurenine Metabolism Using Tissue Slices: Focus on the 
      Neosynthesis of Kynurenic Acid in Mice.
PG  - 102-111
LID - 10.1159/000499736 [doi]
AB  - Several lines of evidence support the hypothesis that abnormally elevated brain 
      levels of kynurenic acid (KYNA), a metabolite of the kynurenine pathway (KP) of 
      tryptophan degradation, play a pathophysiologically significant role in 
      schizophrenia and other major neurodevelopmental disorders. Studies in 
      experimental animal models suggest that KP impairments in these diseases may 
      originate already in utero since prenatal administration of KYNA's bioprecursor, 
      kynurenine, leads to biochemical and structural abnormalities as well as distinct 
      cognitive impairments in adulthood. As KP metabolism during pregnancy is still 
      insufficiently understood, we designed this study to examine the de novo 
      synthesis of KYNA and 3-hydroxykynurenine (3-HK), an alternative biologically 
      active product of kynurenine degradation, in tissue slices obtained from pregnant 
      mice on gestational day (GD) 18. Fetal brain and liver, placenta, and maternal 
      brain and liver were collected, and the tissues were incubated in vitroin the 
      absence or presence of micromolar concentrations of kynurenine. KYNA and 3-HK 
      were measured in the extracellular milieu. Basal and newly produced KYNA was 
      detected in all cases. As KYNA formation exceeded 3-HK production by 2-3 orders 
      of magnitude in the placenta and maternal brain, and as very little 3-HK 
      neosynthesis was detectable in fetal brain tissue, detailed follow-up experiments 
      focused on KYNA only. The fetal brain produced 3-4 times more KYNA than the 
      maternal brain and placenta, though less than the maternal and fetal liver. No 
      significant differences were observed when using tissues obtained on GD 14 and GD 
      18. Pharmacological inhibition of KYNA's main biosynthetic enzymes, kynurenine 
      aminotransferase (KAT) I and KAT II, revealed qualitative and quantitative 
      differences between the tissues, with a preferential role of KAT I in the fetal 
      and maternal brain and of KAT II in the fetal and maternal liver. Findings using 
      tissue slices from KAT II knockout mice confirmed these conclusions. Together, 
      these results clarify the dynamics of KP metabolism during pregnancy and provide 
      the basis for the conceptualization of interventions aimed at manipulating 
      cerebral KP function in the prenatal period.
CI  - (c) 2019 S. Karger AG, Basel.
FAU - Notarangelo, Francesca M
AU  - Notarangelo FM
AD  - Maryland Psychiatric Research Center, Department of Psychiatry, University of 
      Maryland School of Medicine, Baltimore, Maryland, USA, 
      fnotarangelo@som.umaryland.edu.
FAU - Beggiato, Sarah
AU  - Beggiato S
AD  - Maryland Psychiatric Research Center, Department of Psychiatry, University of 
      Maryland School of Medicine, Baltimore, Maryland, USA.
FAU - Schwarcz, Robert
AU  - Schwarcz R
AD  - Maryland Psychiatric Research Center, Department of Psychiatry, University of 
      Maryland School of Medicine, Baltimore, Maryland, USA.
LA  - eng
GR  - P50 MH103222/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190522
PL  - Switzerland
TA  - Dev Neurosci
JT  - Developmental neuroscience
JID - 7809375
RN  - 27723548JL (3-hydroxykynurenine)
RN  - 343-65-7 (Kynurenine)
RN  - EC 2.6.1.- (Transaminases)
RN  - EC 2.6.1.7 (kynurenine-oxoglutarate transaminase)
RN  - H030S2S85J (Kynurenic Acid)
SB  - IM
MH  - Animals
MH  - Brain/*metabolism
MH  - Female
MH  - Fetus
MH  - Kynurenic Acid/*metabolism
MH  - Kynurenine/analogs & derivatives/metabolism
MH  - Liver/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Organ Culture Techniques/methods
MH  - Placenta/*metabolism
MH  - Pregnancy
MH  - Transaminases/metabolism
PMC - PMC6732239
MID - NIHMS1033904
OTO - NOTNLM
OT  - Development
OT  - Kynurenine
OT  - Schizophrenia
COIS- Disclosure Statement The authors have no conflicts of interest to declare.
EDAT- 2019/05/23 06:00
MHDA- 2020/03/31 06:00
PMCR- 2020/05/22
CRDT- 2019/05/23 06:00
PHST- 2019/02/04 00:00 [received]
PHST- 2019/03/19 00:00 [accepted]
PHST- 2019/05/23 06:00 [pubmed]
PHST- 2020/03/31 06:00 [medline]
PHST- 2019/05/23 06:00 [entrez]
PHST- 2020/05/22 00:00 [pmc-release]
AID - 000499736 [pii]
AID - 10.1159/000499736 [doi]
PST - ppublish
SO  - Dev Neurosci. 2019;41(1-2):102-111. doi: 10.1159/000499736. Epub 2019 May 22.