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Further Studies on the Hypothesis of PARP-1 Inhibition as a Strategy for Lessening the Long-Term Effects Produced by Perinatal Asphyxia: Effects of Nicotinamide and Theophylline on PARP-1 Activity in Brain and Peripheral Tissue

Nicotinamide and Theophylline on PARP-1 Activity

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Abstract

Oxygen interruption leads to death when re-oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of biochemical events for restoring function at the cost of improper homeostasis. The effects observed long after perinatal asphyxia (PA) have been explained by over-expression of sentinel proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1), competing for NAD+ during re-oxygenation, leading to the idea that sentinel protein inhibition constitutes a therapeutic strategy. We studied the effects of nicotinamide and theophylline on PARP-1 activity assayed in brain and peripheral (heart) rat tissue 1–24 h after birth, as well as on changes in behaviour and monoamine neurotransmission in adult rats. PA was induced by immersing rat foetuses into a water bath for 0 or 21 min. After resuscitation, the pups were treated with nicotinamide (0.8 mmol/kg, i.p.), theophylline (0.14 mmol/kg, i.p.) or saline (0.9% NaCl) and nurtured by surrogate dams, pending behavioural and microdialysis experiments, or euthanised after birth for assaying PARP-1 activity. To estimate the in vivo distribution of a single dose of nicotinamide or theophylline into brain and peripheral compartment, a series of animals were implanted with microdialysis probes, one into the brain and other subcutaneously, 1 h after birth, assaying the drugs with a HPLC–UV system. Nicotinamide, but not theophylline prevented the long-term effects induced by PA. Only nicotinamide produced a consistent decrease in PARP-1 activity in brain and heart, whether assayed in control or asphyxia-exposed pups. The present results support the idea that the long-term effects induced by PA imply PARP-1 over-activation.

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Abbreviations

AIF:

Apoptosis inducing factor

AS:

Asphyxia-exposed saline treated

ATP:

Adenosine triphosphate

CNS:

Central nervous system

CS:

Caesarean-delivered saline treated

DA:

Dopamine

DOPAC:

3,4-Dihydroxyphenylacetic acid

ERCC2:

Excision repair cross-complementing rodent repair group 2

5-HIAA:

5-Hydroxyindolacetic acid

5-HT:

5-Hydroxytryptamine

HIF:

Hypoxia-inducible factor

HPLC:

High performance liquid chromatography

HRE:

Hypoxia responsive elements

HVA:

Homovanillic acid

NAD:

Nicotinamide adenine dinucleotide

NADH:

Reduced nicotinamide adenine dinucleotide

NF-κB:

Nuclear factor-κB

PARG:

Poly-ADP-ribose glycohydrolase

PARylated PARP:

Poly-ADP-ribosylated PARP

PARPs:

Poly(ADP-ribose) polymerases

PBS:

Phosphate buffered saline

ROS:

Reactive oxygen species

Strep-HRP:

Strepavidine-horse-radish-peroxidase

TH:

Tyrosine hydroxylase

XRCC1:

X-ray Cross Complementary Factor 1

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Acknowledgments

This study was supported through contract grant sponsors: FONDECYT-Chile (contracts: 1080447; 11070192; 1110263) (MH-M, PM); CONICYT/DAAD (contract: 1378-090529) (PJG-H; MH-M); Millenium Institute (BNI P09-015-F, Mideplan, Chile); BMBF (NGFN + TP9); and DAAD (415/alechile) (PJ G-H). C A-C, P E-M, E R-M and M A G-H are CONICYT fellows; T N is a MECESUP (UCh 0714) fellow. The excellent technical and secretarial help from Mr. Juan Santibañez, Ms. Carmen Almeyda and Ms Ana Maria Mendez are gratefully acknowledged.

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Authors and Affiliations

  1. Programme of Molecular & Clinical Pharmacology, ICBM, BNI, Medical Faculty, University of Chile, P.O. Box 70.000, Santiago 7, Chile

    C. Allende-Castro, P. Espina-Marchant, D. Bustamante, E. Rojas-Mancilla, T. Neira, M. A. Gutierrez-Hernandez, D. Esmar, J. L. Valdes, P. Morales & M. Herrera-Marschitz

  2. Department of Psychopharmacology, Central Institute of Mental Health J5, Mannheim, Germany

    P. J. Gebicke-Haerter

  3. Programme of Physiology & Biophysics, ICBM, BNI, Medical Faculty, University of Chile, Santiago 7, Chile

    J. L. Valdes

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  1. C. Allende-Castro
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  2. P. Espina-Marchant
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  3. D. Bustamante
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  4. E. Rojas-Mancilla
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  5. T. Neira
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  6. M. A. Gutierrez-Hernandez
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  8. J. L. Valdes
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  9. P. Morales
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  10. P. J. Gebicke-Haerter
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  11. M. Herrera-Marschitz
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Correspondence to M. Herrera-Marschitz.

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The contribution of C. Allende-Castro and P. Espina-Marchant has been equally relevant.

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Allende-Castro, C., Espina-Marchant, P., Bustamante, D. et al. Further Studies on the Hypothesis of PARP-1 Inhibition as a Strategy for Lessening the Long-Term Effects Produced by Perinatal Asphyxia: Effects of Nicotinamide and Theophylline on PARP-1 Activity in Brain and Peripheral Tissue. Neurotox Res 22, 79–90 (2012). https://doi.org/10.1007/s12640-012-9310-2

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