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 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 Received: 22 July 2011 / Revised: 5 January 2012 / Accepted: 5 January 2012 / Published online: 4 February 2012 Ó Springer Science+Business Media, LLC 2012 Abstract Oxygen interruption leads to death when re- oxygenation is not promptly re-established. Re-oxygena- tion 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 strat- egy. We studied the effects of nicotinamide and theoph- ylline 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 implan- ted 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 nic- otinamide produced a consistent decrease in PARP-1 The contribution of C. Allende-Castro and P. Espina-Marchant has been equally relevant. C. Allende-Castro Á P. Espina-Marchant Á D. Bustamante Á E. Rojas-Mancilla Á T. Neira Á M. A. Gutierrez-Hernandez Á D. Esmar Á J. L. Valdes Á P. Morales Á M. Herrera-Marschitz (&) Programme of Molecular & Clinical Pharmacology, ICBM, BNI, Medical Faculty, University of Chile, P.O. Box 70.000, Santiago 7, Chile e-mail: mh-marschitz@med.uchile.cl P. Espina-Marchant e-mail: pa_espina@med.uchile.cl D. Bustamante e-mail: dbustama@med.uchile.cl E. Rojas-Mancilla e-mail: eseba21@gmail.com T. Neira e-mail: tanyaneira@gmail.com M. A. Gutierrez-Hernandez e-mail: manugut@med.uchile.cl D. Esmar e-mail: daniela.esmar@gmail.com J. L. Valdes e-mail: jlvaldes@med.uchile.cl P. Morales e-mail: pmorales@med.uchile.cl J. L. Valdes Programme of Physiology & Biophysics, ICBM, BNI, Medical Faculty, University of Chile, Santiago 7, Chile P. J. Gebicke-Haerter Department of Psychopharmacology, Central Institute of Mental Health J5, Mannheim, Germany e-mail: peter.gebicke@zi-mannheim.de 123 Neurotox Res (2012) 22:79–90 DOI 10.1007/s12640-012-9310-2