title: Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins.
abstract: Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD(+) tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care.
authors.affiliation: Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, P.O. Box 70.000, Santiago 7, Chile. mh-marschitz@med.uchile.cl
authors.forename: Mario
authors.initials: M
authors.lastname: Herrera-Marschitz
authors.forename: Paola
authors.initials: P
authors.lastname: Morales
authors.forename: Lisette
authors.initials: L
authors.lastname: Leyton
authors.forename: Diego
authors.initials: D
authors.lastname: Bustamante
authors.forename: Verena
authors.initials: V
authors.lastname: Klawitter
authors.forename: Pablo
authors.initials: P
authors.lastname: Espina-Marchant
authors.forename: Camilo
authors.initials: C
authors.lastname: Allende
authors.forename: Francisco
authors.initials: F
authors.lastname: Lisboa
authors.forename: Gabriel
authors.initials: G
authors.lastname: Cunich
authors.forename: Antonella
authors.initials: A
authors.lastname: Jara-Cavieres
authors.forename: Tanya
authors.initials: T
authors.lastname: Neira
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Gutierrez-Hernandez
authors.forename: Victor
authors.initials: V
authors.lastname: Gonzalez-Lira
authors.forename: Nicola
authors.initials: N
authors.lastname: Simola
authors.forename: Andrea
authors.initials: A
authors.lastname: Schmitt
authors.forename: Micaela
authors.initials: M
authors.lastname: Morelli
authors.forename: R
authors.initials: R
authors.lastname: Andrew Tasker
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gebicke-Haerter
mesh_terms: D000818:Animals; D001238:Asphyxia Neonatorum / Q000378:metabolism* / Q000517:prevention & control*; D016503:Drug Delivery Systems; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D051759:Xeroderma Pigmentosum Group D Protein / Q000096:biosynthesis
chemical_list: D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human