Significance: Perinatal brain injury is caused by hypoxia-ischemia (HI) in term neonates, perinatal arterial stroke, and infection/inflammation leading to devastating long-term neurodevelopmental deficits. Therapeutic hypothermia is the only currently available treatment but is not successful in more than 50% of term neonates suffering from hypoxic-ischemic encephalopathy. Thus, there is an urgent unmet need for alternative or adjunct therapies. Reactive oxygen species (ROS) are important for physiological signaling, however, their overproduction/accumulation from mitochondria and endoplasmic reticulum (ER) during HI aggravate cell death. Recent Advances and Critical Issues: Mechanisms underlying ER stress-associated ROS production have been primarily elucidated using either non-neuronal cells or adult neurodegenerative experimental models. Findings from mature brain cannot be simply transferred to the immature brain. Therefore, age-specific studies investigating ER stress modulators may help investigate ER stress-associated ROS pathways in the immature brain. New therapeutics such as mitochondrial site-specific ROS inhibitors that selectively inhibit superoxide (O2•-)/hydrogen peroxide (H2O2) production are currently being developed. Future Directions: Because ER stress and oxidative stress accentuate each other, a combinatorial therapy utilizing both antioxidants and ER stress inhibitors may prove to be more protective against perinatal brain injury. Moreover, multiple relevant targets need to be identified for targeting ROS before they are formed. The role of organelle-specific ROS in brain repair needs investigation. Antioxid. Redox Signal. 31, 643-663.
Keywords: antioxidants; endoplasmic reticulum; mitochondria; neonatal hypoxia–ischemia; reactive oxygen species; sirtuins.