The Long-Term Impairment in Redox Homeostasis Observed in the Hippocampus of Rats Subjected to Global Perinatal Asphyxia (PA) Implies Changes in Glutathione-Dependent Antioxidant Enzymes and TIGAR-Dependent Shift Towards the Pentose Phosphate Pathways: Effect of Nicotinamide

  • C. Lespay-Rebolledo
  • A. Tapia-Bustos
  • D. Bustamante
  • P. MoralesEmail author
  • M. Herrera-MarschitzEmail author
Original Article


We have recently reported that global perinatal asphyxia (PA) induces a regionally sustained increase in oxidized glutathione (GSSG) levels and GSSG/GSH ratio, a decrease in tissue-reducing capacity, a decrease in catalase activity, and an increase in apoptotic caspase-3-dependent cell death in rat neonatal brain up to 14 postnatal days, indicating a long-term impairment in redox homeostasis. In the present study, we evaluated whether the increase in GSSG/GSH ratio observed in hippocampus involves changes in glutathione reductase (GR) and glutathione peroxidase (GPx) activity, the enzymes reducing glutathione disulfide (GSSG) and hydroperoxides, respectively, as well as catalase, the enzyme protecting against peroxidation. The study also evaluated whether there is a shift in the metabolism towards the penthose phosphate pathway (PPP), by measuring TIGAR, the TP53-inducible glycolysis and apoptosis regulator, associated with delayed cell death, further monitoring calpain activity, involved in bax-dependent cell death, and XRCC1, a scaffolding protein interacting with genome sentinel proteins. Global PA was induced by immersing fetus-containing uterine horns removed by a cesarean section from on term rat dams into a water bath at 37 °C for 21 min. Asphyxia-exposed and sibling cesarean-delivered fetuses were manually resuscitated and nurtured by surrogate dams. Animals were euthanized at postnatal (P) days 1 or 14, dissecting samples from hippocampus to be assayed for glutathione, GR, GPx (all by spectrophotometry), catalase (Western blots and ELISA), TIGAR (Western blots), calpain (fluorescence), and XRCC1 (Western blots). One hour after delivery, asphyxia-exposed and control neonates were injected with either 100 μl saline or 0.8 mmol/kg nicotinamide, i.p., shown to protect from the short- and long-term consequences of PA. It was found that global PA produced (i) a sustained increase of GSSG levels and GSSG/GSH ratio at P1 and P14; (ii) a decrease of GR, GPx, and catalase activity at P1 and P14; (iii) a decrease at P1, followed by an increase at P14 of TIGAR levels; (iv) an increase of calpain activity at P14; and (v) an increase of XRCC1 levels, but only at P1. (vi) Nicotinamide prevented the effect of PA on GSSG levels and GSSG/GSH ratio, and on GR, GPx, and catalase activity, also on increased TIGAR levels and calpain activity observed at P14. The present study demonstrates that the long-term impaired redox homeostasis observed in the hippocampus of rats subjected to global PA implies changes in GR, GPx, and catalase, and a shift towards PPP, as indicated by an increase of TIGAR levels at P14.


Pentose phosphate pathway TIGAR Glutathione reductase Glutathione peroxidase Catalase Neonatal hippocampus Perinatal asphyxia XRCC1 Calpain Delayed cell death Rat 







Apoptosis inducing factor


Asphyxia-exposed rats


Arbitrary units


Bcl-2 associated X protein apoptosis regulator


BH3 interacting domain death agonist


Bicinchoninic acid


Bovine serum albumin




Control saline rats


5, 5′-Dithio-bis-[2-nitrobenzoic acid]




Changes in absorbance per minute


Ethylenediaminetetraacetic acid


Ethylene glycol-bis (β-aminoethylether)-N, N, N′, N′-tetraacetic acid


Enzyme-linked immunosorbent assay


Glutathione peroxidase


Glutathione reductase


Reduced glutathione


Oxidized glutathione


Gestation day 22




Hypoxic-ischemia encephalopathy


Horseradish peroxidase


Hydrogen peroxide


Distillated water


Hexokinase 2


Intraperitoneal injection

IgG (H + L)

Immunoglobulin type G (Heavy + Light chains)


Milliunits enzymatic per milliliter


Sodium chloride


Oxidized nicotinamide adenine dinucleotide


Reduced nicotinamide adenine dinucleotide


Oxidized β-Nicotinamide adenine dinucleotide 2′-phosphate


Reduced β-Nicotinamide adenine dinucleotide 2′-phosphate


NAD+ kinase


Sodium fluoride


Nicotinamide phosphoribosyltransferase




Nicotinamide mononucleotide adenyltransferase


Nicotinamide mononucleotide


Perinatal asphyxia


Poly(ADP-ribose) polymerase 1


Phosphate buffer saline


Pyruvate kinase


Phenylmethylsulfonyl fluoride


Phosphofructokinase 1


Pentose phosphate pathway


Postnatal day


Tumor protein p53


Cellular tumor antigen p53


Reticulum endoplasmic


Radio-immune precipitation assay buffer


Reactive oxygen species




Standard error of the means


Superoxide dismutase


Sodium dodecyl sulfate


Sodium dodecyl sulfate polyacrylamide gel


Single-strand break DNA


TP53-induced glycolysis and apoptosis regulator


Tris(hydroxymethyl)aminoethane-chloride acid buffer


Tris-buffered saline containing 0.1% Tween-20


Tumor necrosis factor alpha


Units enzymatic per milliliter




Western blots


X-linked inhibitor of apoptosis protein


X-ray repair cross-complementing protein 1



Contract grant sponsors: FONDECYT-Chile (no. 1120079, MHM; 1180042, YI, PMR, MHM; 1190562, PMR). CONICYT Operational Support no. 21140281 (LRC) and no. 21151232 (TBA). CONICYT-Chile fellowships: no. 21140281 (LRC) and no. 21151232 (TBA).

Compliance with ethical standards

Ethic statement

All procedures were conducted in accordance with the animal care and use protocol established by a Local Ethics Committee for experimentation with laboratory animals at the Medical Faculty, University of Chile (Protocol CBA no. 0722 FMUCH) and by an ad hoc commission of the Chilean Council for Science and Technology Research (CONICYT), endorsing the principles of laboratory animal care (NIH; No. 86-23; revised 1985). Animals were permanently monitored (on 24 h basis) regarding well being, following the ARRIVE guidelines for reporting animal studies (


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Programme of Molecular & Clinical Pharmacology, ICBM, Medical FacultyUniversity of ChileSantiagoChile
  2. 2.Department of Neuroscience, Medical FacultyUniversity of ChileSantiagoChile

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