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.