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 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.
Programme of Molecular & Clinical Pharmacology, ICBM, BNI, Medical Faculty, University of Chile, P.O. Box 70.000, Santiago 7, Chile. allende.camilo@gmail.com
C
C
Allende-Castro
P
P
Espina-Marchant
D
D
Bustamante
E
E
Rojas-Mancilla
T
T
Neira
M A
MA
Gutierrez-Hernandez
D
D
Esmar
J L
JL
Valdes
P
P
Morales
P J
PJ
Gebicke-Haerter
M
M
Herrera-Marschitz
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001237:Asphyxia / Q000378:metabolism*; D001238:Asphyxia Neonatorum / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D017551:Microdialysis; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013806:Theophylline / Q000494:pharmacology*; D014803:Vitamin B Complex / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D014803:Vitamin B Complex; D009536:Niacinamide; D013806:Theophylline; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases