Cell Death in the Developing Brain after Hypoxia-Ischemia

Abstract

Perinatal insults such as hypoxia–ischemia induces secondary brain injury. In order to develop the next generation of neuroprotective therapies, we urgently need to understand the underlying molecular mechanisms leading to cell death. The cell death mechanisms have been shown to be quite different in the developing brain compared to that in the adult. The aim of this review is update on what cell death mechanisms that are operating particularly in the setting of the developing CNS. In response to mild stress stimuli a number of compensatory mechanisms will be activated, most often leading to cell survival. Moderate-to-severe insults trigger regulated cell death. Depending on several factors such as the metabolic situation, cell type, nature of the stress stimulus, and which intracellular organelle(s) are affected, the cell undergoes apoptosis (caspase activation) triggered by BAX dependent mitochondrial permeabilzation, necroptosis (mixed lineage kinase domain-like activation), necrosis (via opening of the mitochondrial permeability transition pore), autophagic cell death (autophagy/Na+, K+-ATPase), or parthanatos (poly(ADP-ribose) polymerase 1, apoptosis-inducing factor). Severe insults cause accidental cell death that cannot be modulated genetically or by pharmacologic means. However, accidental cell death leads to the release of factors (damage-associated molecular patterns) that initiate systemic effects, as well as inflammation and (regulated) secondary brain injury in neighboring tissue. Furthermore, if one mode of cell death is inhibited, another route may step in at least in a scenario when upstream damaging factors predominate over protective responses. The provision of alternative routes through which the cell undergoes death has to be taken into account in the hunt for novel brain protective strategies.

A working model for hypothermic neuroprotection

“…. In neonatal rats, caspase, Bax and cytochrome c inhibitors all provide partial neuroprotection, supporting a pathological role for these intracellular mechanisms (Thornton et al . 2017).…”

“…Taken together, it is clear from these findings that brain metabolism can recover to normal or near‐normal levels after even severe HI, but multiple, inter‐related mechanisms are triggered that ultimately lead to delayed cellular death (Thornton et al . 2017).…”

“…These include activation of cell death pathways, withdrawal of trophic factors and secondary inflammation. In particular, the cell death pathways are activated through unregulated influx of calcium during anoxic depolarization, exposure to reactive oxidative species during reperfusion and other factors (Thornton et al . 2017).…”

“…Apoptosis can be triggered through intracellular and extracellular pathways (Fig. ; reviewed in detail by Thornton et al . 2017).…”

Analysis of long noncoding RNA expression profiles in the whole blood of neonates with hypoxic‐ischemic encephalopathy

“…Hypoxia‐ischemia can lead to cell death or cell apoptosis and further induce secondary brain damage . The pathogenesis of neonatal HIE is complex and not well understood.…”