Perinatal brain injury and regulation of transcription

Abstract

Perinatal hypoxic-ischemic brain injury is a major cause of mortality and morbidity in infants. The understanding of transcription factor activation leading to prosurvival gene expression is important as it pertains to the development of new therapy. Here, we highlight the regulation of transcription factors that potentially could promote neuro-survival in the immature brain. cAMP response element binding protein (CREB), nuclear factor-kappaB (NF-kappaB) and hypoxia-inducible factor 1 (HIF-1) are developmentally regulated in the neural system, and are necessary for the induction of preconditioning against hypoxic-ischemia. CREB and NF-kappaB are also involved in the regulation of synaptic plasticity, and learning and memory. CREB phosphorylation is sufficient and necessary for survival in adult and immature neurons, and NF-kappaB activation in neurons could promote survival, whereas activation in glial cells enhances neuronal death. Although HIF-1 is necessary for hypoxic preconditioning, paradoxically, in the absence of preconditioning, this factor promotes ischemia-induced neuronal death. Erythropoietin, one of the HIF-1 targeted genes, is potently neuroprotective and may be beneficial in treating newborns with hypoxic-ischemic brain damage. Drugs that activate the specific signaling leading to the transcriptional activation of prosurvival genes may provide therapy for the treatment of perinatal hypoxic-ischemic brain injury. Investigation of the transcriptional mechanisms of neuro-survival is likely to reveal other novel transcription factors whose activation by small molecules or drugs will complement current medication in activating the salutary gene program.