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Regionally Impaired Redox Homeostasis in the Brain of Rats Subjected to Global Perinatal Asphyxia: Sustained Effect up to 14 Postnatal Days

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Abstract

The present report evaluates the effect of global perinatal asphyxia on several parameters of oxidative stress and cell viability in rat brain tissue sampled at an extended neonatal period up to 14 days, a period characterised by intensive neuritogenesis, synaptogenesis, synaptic consolidation, pruning and delayed cell death. Perinatal asphyxia was induced by immersing foetus-containing uterine horns removed by a caesarean section from on term rat dams into a water bath at 37 °C for 21 min. Asphyxia-exposed and sibling caesarean-delivered foetuses were manually resucitated and nurtured by surrogate dams for 1 to 14 postnatal (P) days. Brain samples (mesencephalon, telencephalon and hippocampus) were assayed for glutathione (reduced and oxidated levels; spectrophotometry), tissue reducing capacity (potassium ferricyanide reducing assay, FRAP), catalase (the key enzyme protecting against oxidative stress and reactive oxygen species, Western blots and ELISA) and cleaved caspase-3 (the key executioner of apoptosis, Western blots) levels. It was found that global PA produced a regionally specific and sustained increase in GSSG/GSH ratio, a regionally specific decrease in tissue reducing capacity and a regionally and time specific decrease of catalase activity and increase of cleaved caspase-3 levels. The present study provides evidence for regionally impaired redox homeostasis in the brain of rats subjected to global PA, an effect observed up to P14, mainly affecting mesencephalon and hippocampus, suggesting a sustained oxidative stress after the posthypoxia period. The oxidative stress observed postnatally can in part be associated to a respiratory apneic-like deficit, since there was a statistically significant decrease in respiration frequency in AS compared to CS neonates, also up to P14, together with the signs of a decreased peripheral blood perfusion (pink-blue skin colour in AS, compared to the pink colour observed in all CS neonates). It is proposed that PA implies a long-term metabolic insult, triggered by the length of hypoxia, the resuscitation/reoxigenation manoevres, but also by the developmental stage of the affected brain regions, and the integrity of cardiovascular and respiratory physiological functions, which are fundamental for warrantying a proper development.

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Abbreviations

ADP/ATP ratio :

Adenosine diphosphate/adenosine triphosphate ratio

a.u.:

Arbitrary units

AS:

Asphyxia-exposed rats

BCA:

Bicinchoninic acid assay

Bcl-2:

Protooncogen Bcl-2 (B cell lymphoma 2)

β-NADPH:

β-Nicotinamide adenine dinucleotide 2′-phosphate

C:

Cerebellum

Cdk:

Cyclin-dependent kinase

CNS:

Central nervous system

CS:

Caesarean-delivered rat controls

DTNB:

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

EDTA:

Ethylenediaminetetraacetic acid

EGTA:

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

ELISA:

Enzyme-linked immunosorbent assay

FRAP:

Ferric reducing antioxidant power

Fe+2 :

Iron in oxidation state +2

GSH:

Reduced glutathione

GSSG:

Oxidised glutathione

G22:

Gestation day 22

H2O2 :

Hydrogen peroxide

HIE:

Hypoxic-ischemia encephalopathy

HI:

Hypoxic-ischemic

HRP:

Horseradish peroxidase

H2Od:

Destilated water

L:

Liver

O2 :

Oxygen

PA:

Perinatal asphyxia

PB:

Pink-blue

PKC:

Protein kinase C

P:

Postnatal day

PMSF:

Phenylmethylsulfonyl fluoride

RIPA Buffer:

Radio-immune precipitation assay buffer

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

SDS:

Sodium dodecyl sulfate

SEM:

Standard error of the mean

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

WB:

Western blots

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Acknowledgements

Contract grant sponsors: FONDECYT-Chile (#1120079; 1180042). CONICYT Operacional Support 21140281. LRC (#21140281), TBA (#21151232), PLR (#21130739), are CONICYT-Chile fellows. VV (UCH074; MECESUP-Chile).

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Authors and Affiliations

  1. Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Av. Independencia 1027, PO Box 8389100, Santiago, Chile

    Carolyne Lespay-Rebolledo, Ronald Perez-Lobos, Andrea Tapia-Bustos, Valentina Vio, Paola Morales & Mario Herrera-Marschitz

  2. Department Neuroscience, Medical Faculty, University of Chile, Santiago, Chile

    Paola Morales

Authors
  1. Carolyne Lespay-Rebolledo
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  2. Ronald Perez-Lobos
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  3. Andrea Tapia-Bustos
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  4. Valentina Vio
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  5. Paola Morales
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  6. Mario Herrera-Marschitz
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Corresponding author

Correspondence to Mario Herrera-Marschitz.

Ethics declarations

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# 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 wellbeing, following the ARRIVE guidelines for reporting animal studies (www.nc3rs.org.uk/ARRIVE).

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The authors declare that they have no conflict of interest.

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Lespay-Rebolledo, C., Perez-Lobos, R., Tapia-Bustos, A. et al. Regionally Impaired Redox Homeostasis in the Brain of Rats Subjected to Global Perinatal Asphyxia: Sustained Effect up to 14 Postnatal Days. Neurotox Res 34, 660–676 (2018). https://doi.org/10.1007/s12640-018-9928-9

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  • DOI: https://doi.org/10.1007/s12640-018-9928-9

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