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Perinatal kynurenine 3-hydroxylase inhibition in rodents: Pathophysiological implications
- Source :
- Journal of Neuroscience Research. 85:845-854
- Publication Year :
- 2007
- Publisher :
- Wiley, 2007.
-
Abstract
- The kynurenine pathway (KP) of tryptophan degradation contains three neuroactive metabolites: the neuroinhibitory agent kynurenic acid (KYNA) and, in a competing branch, the free radical generator 3-hydroxykynurenine (3-HK) and the excitotoxin quinolinic acid (QUIN). These three "kynurenines" derive from a common precursor, L-kynurenine, and are recognized for their role in brain physiology and pathophysiology. Inhibition of kynurenine 3-hydroxylase, the enzyme responsible for 3-HK formation, shifts KP metabolism in the mature brain toward enhanced KYNA formation. We now tested the cerebral effects of kynurenine 3-hydroxylase inhibition in immature rodents. Rat pups treated with the kynurenine 3-hydroxylase inhibitor UPF 648 (30 mg/kg, i.p.) 10 min after birth showed substantial increases in cerebral and liver kynurenine and KYNA levels up to 24 hr later, whereas 3-HK and QUIN levels were simultaneously decreased. Administered to pregnant rats or mice on the last day of gestation, UPF 648 (50 mg/kg, i.p.) produced qualitatively similar changes (i.e., large increases in kynurenine and KYNA and reductions in 3-HK and QUIN) in the brain and liver of the offspring. Rat pups delivered by UPF 648-treated mothers and immediately exposed to neonatal asphyxia showed further enhanced brain KYNA levels. These studies demonstrate that acute kynurenine 3-hydroxylase inhibition effectively shifts cerebral KP metabolism in neonatal rodents toward increased KYNA formation. Selective inhibitors of this enzyme may therefore provide neuroprotection in newborns and will also be useful for the experimental evaluation of the long-term effects of perinatal KP impairment.
- Subjects :
- Cyclopropanes
medicine.medical_specialty
Kynurenine pathway
Offspring
3-Hydroxykynurenine
Biology
Kynurenic Acid
Neuroprotection
Drug Administration Schedule
Rats, Sprague-Dawley
Mice
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Kynurenine 3-Monooxygenase
Kynurenic acid
Pregnancy
Internal medicine
medicine
Animals
Enzyme Inhibitors
Kynurenine
Brain Chemistry
Parturition
Metabolism
Quinolinic Acid
Embryo, Mammalian
Rats
Endocrinology
Animals, Newborn
Liver
chemistry
Prenatal Exposure Delayed Effects
Female
Metabolic Networks and Pathways
Deoxycholic Acid
Quinolinic acid
Subjects
Details
- ISSN :
- 10974547 and 03604012
- Volume :
- 85
- Database :
- OpenAIRE
- Journal :
- Journal of Neuroscience Research
- Accession number :
- edsair.doi.dedup.....09617956c4f96b71934ce15cca2bb566
- Full Text :
- https://doi.org/10.1002/jnr.21183