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Plasticity of basal ganglia neurocircuitries following perinatal asphyxia: effect of nicotinamide

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Abstract

The potential neuroprotection of nicotinamide on the consequences of perinatal asphyxia was investigated with triple organotypic cultures. Perinatal asphyxia was induced in vivo by immersing foetuses-containing uterine horns removed from ready-to-deliver rats into a water bath for 20 min. Sibling caesarean-delivered pups were used as controls. Three days later tissue from substantia nigra, neostriatum and neocortex was dissected and placed on a coverslip. After a month, the cultures were processed for immunocytochemistry and phenotyped with markers against the NMDA receptor subunit NR1, tyrosine hydroxylase (TH), or neuronal nitric oxide synthase (nNOS). Some cultures were analysed for cell viability. Nicotinamide (0.8 mmol/kg, i.p.) or saline was administered to asphyxia-exposed and caesarean-delivered control pups 24, 48 and 72 h after birth. Perinatal asphyxia produced a decrease of cell viability in substantia nigra, but not in neostriatum or neocortex. Immunocytochemistry confirmed the vulnerability of the substantia nigra, demonstrating that there was a significant decrease in the number of NR1 and TH-positive (+) cells/mm2, as well as a decrease in the length of TH+ processes, suggesting neurite atrophy. In control cultures, many nNOS+ cells were seen, with different features, regional distribution and cell body sizes. Following perinatal asphyxia, there was an increase in the number of nNOS+ cells/mm2 in substantia nigra, versus a decrease in neostriatum including reduced neurite length, and no apparent changes in neocortex. The main effect of nicotinamide was seen in the neostriatum, preventing the asphyxia-induced decrease in the number of nNOS+ cells and neurite length. Nicotinamide also prevented the effect of perinatal asphyxia on TH-positive neurite length. The present results support the idea that nicotinamide can prevent the effects produced by a sustained energy-failure condition, as occurring during perinatal asphyxia.

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Abbreviations

AIF:

Apoptosis-inducing factor

AN:

Nicotinamide-treated, asphyxia-exposed

AS:

Saline-treated, asphyxia-exposed

BCIP/NBT:

5-Bromo-4-chloro-3-indolyl phosphate/nitroblue tetrazolium

BSA:

Bovine serum albumin

Calcein-AM:

Calcein-acetoxymethyl ester

CN:

Nicotinamide-treated, caesarean-delivered

CS:

Saline-treated, caesarean-delivered

Cx:

Neocortex

DA:

Dopamine

DIV:

Days in vitro

DMEM:

Dulbecco’s modified Eagle medium

ERCC2:

Excision repair cross-complementary rodent repair group 2

EthD-1:

Ethidium-homodimer

H:

Kruskal–Wallis factor for multiple comparison test

NADPH-d:

Nicotinamide adenine dinucleotide phosphate diaphorase

NF-κB:

Nuclear factor κB

NMDA:

N-methyl-D-aspartate

NO:

Nitric oxide

eNOS:

Endothelial NO synthase

iNOS:

Inducible NOS

nNOS:

Neuronal NOS

NR1:

Subunit 1 of the NMDA receptor

PARP:

Poly(ADP-ribose) polymerase

PBS:

Phosphate-buffered saline

PF:

Para-formaldehyde

SN:

Substantia nigra

Str:

Neostriatum

TH:

Tyrosine hydroxylase

TNF-α:

Tumoral necrosis factor α

XRCC1:

X-ray cross complementary factor 1

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Acknowledgments

This study was supported by grants from FONDECYT-Chile (1030521) and DID (I2–02/8–2). We are grateful for the excellent technical and secretarial help from Mr. Juan Santibañez, Ms. Carmen Almeyda and Ms. Ana Maria Mendez. We thank Prof. Piers Emson, Barbrahan Institute, Cambridge University, Cambridge, UK for generous supply of NOS antiserum.

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Authors and Affiliations

  1. Programme of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, PO Box 70000, Santiago 7, Chile

    Verena Klawitter, Paola Morales, Diego Bustamante & Mario Herrera-Marschitz

  2. Department of Neuroscience, Faculty of Medicine, University of the Basque Country, 48940, Leioa, Biscay, Spain

    Sonia Gomez-Urquijo

  3. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Tomas Hökfelt

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  1. Verena Klawitter
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  2. Paola Morales
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Correspondence to Mario Herrera-Marschitz.

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The contribution of VK and PM has been equally relevant.

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Klawitter, V., Morales, P., Bustamante, D. et al. Plasticity of basal ganglia neurocircuitries following perinatal asphyxia: effect of nicotinamide. Exp Brain Res 180, 139–152 (2007). https://doi.org/10.1007/s00221-006-0842-7

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