Apoptosis and inflammation regulation after injury to the developing brain

Abstract

The brain shows greater plasticity in early life than in maturity, which paradoxically renders the organ more vulnerable to hypoxia-ischemia (HI)- and cranial irradiation (IR)- induced damage. Apoptosis after a HI insult is more pronounced in the immature vs. mature brain and develops over time; hence, blockade of the apoptotic cascade provides a target for delayed neuroprotective interventions aimed at reducing HI-provoked brain damage. Moreover, inflammation subsequent to the initial insult exacerbates HI-induced brain damage, and is also a target for interventions. Meanwhile, the profound progressive decrease in neurogenesis after IR is associated with the deleterious effects of chronic inflammation. The overall goal of this thesis was to investigate potential neuroprotective strategies to decrease brain injury through the regulation of apoptosis and inflammation. First, the impact of a cell-penetrating, Bax-inhibiting peptide (BIP) was assessed in a neonatal mouse model of HI. BIP administration moderated injury to the gray and white matter, and ameliorated sensorimotor and cognitive deficits. These actions were attributed to diminished Bax activation and decreased mitochondrial release of the pro-apoptotic proteins, cytochrome c and apoptosis-inducing factor (AIF). Next, the influence of delayed and extended systemic administration of a caspase inhibitor, Q-VD-OPh, was examined in neonatal HI. Consequently, Q-VD-OPh decreased the expression of pro-inflammatory chemokines, reduced signs of brain injury, and transiently overturned HI-induced sensorimotor deficits and hyperactivity. The present findings also revealed a novel mechanism amenable for therapeutic strategies after neural progenitor cell (NPC) transplantation into the brain, and showed that active cell death of NPCs plays a key role in the release of heat-stable, neuroprotective proteins. Specifically, conditioned medium (CM) originating from dying NPCs safeguarded hippocampal neurons against glutamate toxicity and trophic factor withdrawal in vitro, and exerted protective actions against ischemic brain damage in vivo. Finally, the current data demonstrated that peripheral macrophages do not contribute to the inflammatory response in the hippocampus after IR. Moreover, the microglial response was more pronounced and protracted in the juvenile vs. adult brain, and the inflammatory response appeared to be chronic, lasting at least 1 month after IR. Taken together, the observations presented herein provide insight into the control of apoptosis and inflammation after ischemic or IR injury to the developing brain.