Perinatal asphyxia: CNS development and deficits with delayed onset.
Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted. The primary insult relates to the duration of the period lacking oxygenation, leading to death if not re-established. Re-oxygenation leads to a secondary insult, related to a cascade of biochemical events required for restoring proper function. Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated to mental and neurological diseases with delayed clinical onset, by mechanisms not yet clarified. In the experimental scenario, the effects observed long after perinatal asphyxia have been explained by overexpression 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 suitable therapeutic strategy. Asphyxia induces transcriptional activation of pro-inflammatory factors, in tandem with PARP-1 overactivation, and pharmacologically induced PARP-1 inhibition also down-regulates the expression of proinflammatory cytokines. Nicotinamide has been proposed as a suitable PARP-1 inhibitor. Its effect has been studied in an experimental model of global hypoxia in rats. In that model, the insult is induced by immersing rat fetus into a water bath for various periods of time. Following asphyxia, the pups are delivered, treated, and nursed by surrogate dams, pending further experiments. Nicotinamide rapidly distributes into the brain following systemic administration, reaching steady state concentrations sufficient to inhibit PARP-1 activity for several hours, preventing several of the long-term consequences of perinatal asphyxia, supporting the idea that nicotinamide constitutes a lead for exploring compounds with similar or better pharmacological profiles.
Millenium Institute BNI-Chile Santiago, Chile ; Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile.
Mario
M
Herrera-Marschitz
Millenium Institute BNI-Chile Santiago, Chile ; Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile ; Department of Chemical-Biological Science, University Bernardo O'Higgins Santiago, Chile.
Tanya
T
Neira-Pena
Millenium Institute BNI-Chile Santiago, Chile.
Edgardo
E
Rojas-Mancilla
Millenium Institute BNI-Chile Santiago, Chile.
Pablo
P
Espina-Marchant
Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile.
Daniela
D
Esmar
Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile.
Ronald
R
Perez
Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile.
Valentina
V
Muñoz
Millenium Institute BNI-Chile Santiago, Chile.
Manuel
M
Gutierrez-Hernandez
Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile.
Benjamin
B
Rivera
Department of Biomedical Sciences, Section of Neuropsychopharmacology, Cagliari University Cagliari, Italy.
Nicola
N
Simola
Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile.
Diego
D
Bustamante
Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile.
Paola
P
Morales
Department of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile Santiago, Chile ; Department of Psychopharmacology, Central Institute of Mental Health J5 Mannheim, Germany.
Peter J
PJ
Gebicke-Haerter
behavior; cognition; development; neonatal hypoxic ischemic encephalopathy; obstetric complications; plasticity; poly(ADP-ribose) polymerase; sentinel proteins