Further studies on the hypothesis of PARP-1 inhibition as a strategy for lessening the long-term effects produced by perinatal asphyxia

• Verfasst von: Allende-Castro, Camilo [VerfasserIn]
• Verfasst von: Gebicke-Härter, Peter J. [VerfasserIn]
• Titel: Further studies on the hypothesis of PARP-1 inhibition as a strategy for lessening the long-term effects produced by perinatal asphyxia
• Titelzusatz: effects of nicotinamide and theophylline on PARP-1 activity in brain and peripheral tissue : nicotinamide and theophylline on PARP-1 activity
• Verf.angabe: 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
• E-Jahr: 2012
• Jahr: 4 February 2012
• Umfang: 12 S.
• Fussnoten: Gesehen am 17.05.2018
• Titel Quelle: Enthalten in: Neurotoxicity research
• Ort Quelle: New York, NY : Springer, 1999
• Jahr Quelle: 2012
• Band/Heft Quelle: 22(2012), 1, Seite 79-90
• ISSN Quelle: 1476-3524
• DOI: doi:10.1007/s12640-012-9310-2
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1575281058

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.