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Vulnerability to a Metabolic Challenge Following Perinatal Asphyxia Evaluated by Organotypic Cultures: Neonatal Nicotinamide Treatment

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Abstract

The hypothesis of enhanced vulnerability following perinatal asphyxia was investigated with a protocol combining in vivo and in vitro experiments. Asphyxia-exposed (AS) (by 21 min water immersion of foetuses containing uterine horns) and caesarean-delivered control (CS) rat neonates were used at P2-3 for preparing triple organotypic cultures (substantia nigra, neostriatum and neocortex). At DIV 18, cultures were exposed to different concentrations of H2O2 (0.25–45 mM), added to the culture medium for 18 h. After a 48-h recovery period, the cultures were either assessed for cell viability or for neurochemical phenotype by confocal microscopy. Energy metabolism (ADP/ATP ratio), oxidative stress (GSH/GSSG) and a modified ferric reducing/antioxidant power assay were applied to homogenates of parallel culture series. In CS cultures, the number of dying cells was similar in substantia nigra, neostriatum and neocortex, but it was several times increased in AS cultures evaluated under the same conditions. A H2O2 challenge led to a concentration-dependent increase in cell death (>fourfold after 0.25 mM of H2O2) in CS cultures. In AS cultures, a significant increase in cell death was only observed after 0.5 mM of H2O2. At higher than 1 mM of H2O2 (up to 45 mM), cell death increased several times in all cultures, but the effect was still more prominent in CS than in AS cultures. The cell phenotype of dying/alive cells was investigated in formalin-fixed cultures exposed to 0 or 1 mM of H2O2, co-labelling for TUNEL (apoptosis), MAP-2 (neuronal phenotype), GFAP (astroglial phenotype) and TH (tyrosine hydroxylase; for dopamine phenotype), counterstaining for DAPI (nuclear staining), also evaluating the effect of a single dose of nicotinamide (0.8 nmol/kg, i.p. injected in 100 μL, 60 min after delivery). Perinatal asphyxia produced a significant increase in the number of DAPI/TUNEL cells/mm3, in substantia nigra and neostriatum. One millimolar of H202 increased the number of DAPI/TUNEL cells/mm3 by ≈twofold in all regions of CS and AS cultures, an effect that was prevented by neonatal nicotinamide treatment. In substantia nigra, the number of MAP-2/TH-positive cells/mm3 was decreased in AS compared to CS cultures, also by 1 mM of H202, both in CS and AS cultures, prevented by nicotinamide. In agreement, the number of MAP-2/TUNEL-positive cells/mm3 was increased by 1 mM H2O2, both in CS (twofold) and AS (threefold) cultures, prevented by nicotinamide. The number of MAP-2/TH/TUNEL-positive cells/mm3 was only increased in CS (>threefold), but not in AS (1.3-fold) cultures. No TH labelling was observed in neostriatum, but 1 mM of H2O2 produced a strong increase in the number of MAP-2/TUNEL-positive cells/mm3, both in CS (>2.9-fold) and AS (>fourfold), decreased by nicotinamide. In neocortex, H2O2 increased the number of MAP-2/TUNEL-positive cells/mm3, both in CS and AS cultures (≈threefold), decreased by nicotinamide. The ADP/ATP ratio was increased in AS culture homogenates (>sixfold), compared to CS homogenates, increased by 1 mM of H202, both in CS and AS homogenates. The GSH/GSSG ratio was significantly decreased in AS, compared to CS cultures. One millimolar of H2O2 decreased that ratio in CS and AS homogenates. The present results demonstrate that perinatal asphyxia induces long-term changes in metabolic pathways related to energy and oxidative stress, priming cell vulnerability with both neuronal and glial phenotype. The observed effects were region dependent, being the substantia nigra particularly prone to cell death. Nicotinamide administration in vivo prevented the deleterious effects observed after perinatal asphyxia in vitro, a suitable pharmacological strategy against the deleterious consequences of perinatal asphyxia.

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Abbreviations

ADP:

Adenosine diphosphate

AIF:

Apoptosis-inducing factor

AM:

Calcein-acetoxymethyl ester

AS:

Asphyxia-exposed rats

ATP:

Adenosine triphosphate

BCA:

Bicinchoninic acid

Bcl-2:

B-cell lymphoma 2

Bnip3:

BCL2 interacting protein 3

CS:

Caesarean-delivered rats

Cx:

Neocortex

DAPI:

4′6-Diamidino-2-phenylindole

DIV:

Days in vitro

DMEM:

Dulbecco’s modified Eagle medium

DTNB:

5,5′-Dithiobis-2-nitrobenzoic acid

EthD-1:

Ethidium-homodimer

G:

Gestation day

GFAP:

Glial fibrillary acidic protein

GSH:

Reduced glutathione

GSSG:

Oxidized glutathione

HIF-1α:

Hypoxia induced factor-1α

i.p.:

Intraperitoneal

MAP-2:

Microtubule-associated protein-2

NAD+ :

Nicotinamide adenine dinucleotide

NADPH:

Nicotinamide adenine dinucleotide phosphate

NAM:

Nicotinamide, niacinamide, vitamine B3

Nix:

BCL2/adenovirus E1B interacting protein 3-like

NMDA:

N-methyl-d-aspartate

nNOS:

Neuronal nitric oxide synthase

NO:

Nitric oxide

Noxa:

Phorbol-12-myristate-13-acetate-induced protein 1

PA:

Perinatal asphyxia

PARP-1:

Poly(ADP-ribose) polymerase-1

PBS:

Phosphate-buffered saline

PLS:

Partial least squares

RFU:

Relative fluorescence units

ROS:

Reactive oxidative species

RNS:

Reactive nitrosylated species

SN:

Substantia nigra

Str:

Neostriatum

TH:

Tyrosine hydroxylase

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labelling

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Acknowledgements

We would like to than the following contract grant sponsors: FONDECYT-Chile; Millenium Institute Initiative (BNI P09-015-F) and MHMarschitz Foundation, Sweden. RPL (#21130739), CLR (#21140281), ATB (#21151232) and EP (#21171433) are CONICYT-Chile fellows. VVM was a MECESUP-Chile fellow (UCH0704).

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

    R. Perez-Lobos, C. Lespay-Rebolledo, A. Tapia-Bustos, E. Palacios, V. Vío, D. Bustamante, P. Morales & M. Herrera-Marschitz

  2. Escuela de Tecnologia Medica, Facultad de Medicina, Universidad Andres Bello, Av. República, Santiago, PO Box 8370146, Chile

    R. Perez-Lobos

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  1. R. Perez-Lobos
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  2. C. Lespay-Rebolledo
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  3. A. Tapia-Bustos
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  4. E. Palacios
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  5. V. Vío
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  6. D. Bustamante
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  8. M. Herrera-Marschitz
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Correspondence to M. Herrera-Marschitz.

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Perez-Lobos, R., Lespay-Rebolledo, C., Tapia-Bustos, A. et al. Vulnerability to a Metabolic Challenge Following Perinatal Asphyxia Evaluated by Organotypic Cultures: Neonatal Nicotinamide Treatment. Neurotox Res 32, 426–443 (2017). https://doi.org/10.1007/s12640-017-9755-4

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  • DOI: https://doi.org/10.1007/s12640-017-9755-4

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