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 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 suitable therapeutic strategy. Asphyxia induces transcriptional activation of proinflammatory
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 foetuses 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 it constitutes a lead for
exploring compounds with similar or better pharmacological profiles