Perinatal Programming of Neurodevelopment

Herrera-Marschitz M, Neira-Peña T, Rojas-Mancilla E, Morales P, Bustamante D, Leyton L, Gebicke-Haerter P, M. Herrera-Marschitz, T. Neira-Peña, L. Leyton, P. Gebicke-Haerter, E. Rojas-Mancilla, P. Morales, D. Bustamante, Herrera-Marschitz, M., Neira-Peña, T., Leyton, L., Gebicke-Haerter, P., Rojas-Mancilla, E., Morales, P., Bustamante, D.

Marta C. Antonelli

Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted. A primary insult is first produced by the length of the time without oxygenation, leading to hypoxia/ischemia and death if oxygenation is not promptly established. A second insult is produced by re-oxygenation, eliciting a cascade of biochemical events for restoring function, implying, however, improper homeostasis. The effects observed long after perinatal asphyxia can be explained by over-expression of sentinel proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1), competing for oxidised nicotinamide adenine dinucleotide (NAD(+)) during re-oxygenation. Asphyxia also induces transcriptional activation of pro-inflammatory factors, including nuclear factor κB (NFκB) and its subunit p65, whose translocation to the nucleus is significantly increased in brain tissue from asphyxia-exposed animals, in tandem with PARP-1 overactivation, leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy. It is proposed that PARP-1 inhibition also down-regulates the expression of pro-inflammatory cytokines.Nicotinamide is a suitable PARP-1 inhibitor, whose effects have been studied in an experimental model of global perinatal asphyxia in rats, inducing the insult by immersing rat foetuses into a water bath for various periods of time. Following asphyxia, the pups are delivered, immediately treated, or given to surrogate dams for nursing, pending further experiments. Systemic administration of nicotinamide 1 h after the insult inhibited PARP-1 overactivity in peripheral and brain tissue, preventing several of the long-term consequences elicited by perinatal asphyxia, supporting the idea that it constitutes a lead for exploring compounds with similar or better pharmacological profiles.