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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
  • 14 Downloads

Abstract

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.

Keywords

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

Abbreviations

Ac-LLY-AFC

Ac-Leu-Leu-Tyr-7-amino-4-trifluoromethylcoumarin

AFC

7-amino-4-trifluoromethylcoumarin

AIF

Apoptosis inducing factor

AS

Asphyxia-exposed rats

a.u.

Arbitrary units

Bax

Bcl-2 associated X protein apoptosis regulator

Bid

BH3 interacting domain death agonist

BCA

Bicinchoninic acid

BSA

Bovine serum albumin

C

Cerebellum

CS

Control saline rats

DTNB

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

DTT

Dithiothreitol

ΔA

Changes in absorbance per minute

EDTA

Ethylenediaminetetraacetic acid

EGTA

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

ELISA

Enzyme-linked immunosorbent assay

GPx

Glutathione peroxidase

GR

Glutathione reductase

GSH

Reduced glutathione

GSSG

Oxidized glutathione

G22

Gestation day 22

HI

Hypoxic-ischemic

HIE

Hypoxic-ischemia encephalopathy

HRP

Horseradish peroxidase

H2O2

Hydrogen peroxide

H2Od

Distillated water

HK2

Hexokinase 2

i.p

Intraperitoneal injection

IgG (H + L)

Immunoglobulin type G (Heavy + Light chains)

mU/mL

Milliunits enzymatic per milliliter

NaCl

Sodium chloride

NAD+

Oxidized nicotinamide adenine dinucleotide

NADH

Reduced nicotinamide adenine dinucleotide

NADP+

Oxidized β-Nicotinamide adenine dinucleotide 2′-phosphate

NADPH

Reduced β-Nicotinamide adenine dinucleotide 2′-phosphate

NADK

NAD+ kinase

NaF

Sodium fluoride

NAMPT

Nicotinamide phosphoribosyltransferase

Nico

Nicotinamide

NMNAT

Nicotinamide mononucleotide adenyltransferase

NMN

Nicotinamide mononucleotide

PA

Perinatal asphyxia

PARP1

Poly(ADP-ribose) polymerase 1

PBS

Phosphate buffer saline

PK

Pyruvate kinase

PMSF

Phenylmethylsulfonyl fluoride

PFK1

Phosphofructokinase 1

PPP

Pentose phosphate pathway

P

Postnatal day

TP53

Tumor protein p53

p53

Cellular tumor antigen p53

RE

Reticulum endoplasmic

RIPA

Radio-immune precipitation assay buffer

ROS

Reactive oxygen species

R5P

Ribulose-5-phosphate

SEM

Standard error of the means

SOD

Superoxide dismutase

SDS

Sodium dodecyl sulfate

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel

SSBR

Single-strand break DNA

TIGAR

TP53-induced glycolysis and apoptosis regulator

Tris-HCl

Tris(hydroxymethyl)aminoethane-chloride acid buffer

TBST

Tris-buffered saline containing 0.1% Tween-20

TNF-alpha

Tumor necrosis factor alpha

U/ml

Units enzymatic per milliliter

Veh

Vehicle

WB

Western blots

XIAP

X-linked inhibitor of apoptosis protein

XRCC1

X-ray repair cross-complementing protein 1

Notes

Acknowledgements

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 (www.nc3rs.org.uk/ARRIVE).

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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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