Perinatal asphyxia: CNS development and deficits with delayed onset

Abstract

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.

Keywords: behavior; cognition; development; neonatal hypoxic ischemic encephalopathy; obstetric complications; plasticity; poly(ADP-ribose) polymerase; sentinel proteins.

Figure 1

Antagonistic molecular and cell cascades elicited by perinatal asphyxia. There are two important molecular and cell cascades elicited by perinatal hypoxic insults, one leading to removal of cells damaged by the reduced supply of oxygen, implying activation of ubiquitination, peroxisomal, and caspase pathways, resulting in apoptosis or necrosis, the latter encompassing mild to severe inflammation. The other cascade is activated for compensating cell loss by multiple mechanisms of DNA repair. Naturally occurring nicotinamide with its various mechanisms of action could support these compensatory mechanisms if given systemically as a therapeutic means. In any case, both cell loss and cell rescue eventually entail more or less subtle consequences on brain development, neuronal wiring, and neuron glia interactions. These tentatively negative consequences are probably reinforced by additional negative impact during development (puberty and adolescence), resulting in psychiatric disorders if not aggravating neurological deficits.

Figure 2

Transcriptional activation of pro-inflammatory signaling in tandem with PARP-1 overactivation. Perinatal asphyxia decreases oxygen saturation in blood, leading to a switch from aerobic to a less efficient anaerobic metabolism involving lactate accumulation, acidosis and cell death. Re-oxygenation is essential for survival. Nevertheless, re-oxygenation induces oxidative stress, damaging several biomolecules including DNA. In response to DNA damage, PARP-1 increases its activity, recruiting the DNA repair machine. PARP-1 overactivation modifies several target proteins via poly (ADP-ribose) polymers (pADPr). One of the targets of pADPr ribosylation is NF-κB, whose p65 subunit is translocated to the nucleus, activating the transcription of pro-inflammatory (e.g., TNF-α, IL-1β, and IL-6), but also anti-inflammatory (e.g., IL-4, IL-10; IL-13) cytokines. The balance between pro- and anti-inflammatory cytokines is crucial for determining cell survival or death.