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
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...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
4 February 2012
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| In: |
Neurotoxicity research
Year: 2012, Volume: 22, Issue: 1, Pages: 79-90 |
| ISSN: | 1476-3524 |
| DOI: | 10.1007/s12640-012-9310-2 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1007/s12640-012-9310-2 Verlag, Volltext: https://link-springer-com.ezproxy.medma.uni-heidelberg.de/article/10.1007/s12640-012-9310-2 
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| Author Notes: | C. Allende-Castro, P. Espina-Marchant, D. Bustamante, E. Rojas-Mancilla, T. Neira, M.A. Gutierrez-Hernandez, D. Esmar, J.L. Valdes, P. Morales, P.J. Gebicke-Haerter, M. Herrera-Marschitz |
| Summary: | 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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| Item Description: | Gesehen am 17.05.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1476-3524 |
| DOI: | 10.1007/s12640-012-9310-2 |