TRANSCRIPTIONS AND NEUROPROTECTION

Perinatal hypoxic-ischemic (HI) brain injury is a major cause of mortality and morbidity in infants for whom there is no effective treatment. The understanding of the effects of ontogeny on HI brain injury in relation to the transcriptional activation leading to pro-survival gene expressions is important, particularly as it pertains to the development of new therapeutic intervention. Here, we highlight the function and regulation of transcription factors that potentially could promote neuro-survival signaling in the immature brain.

The transcriptional factors, cAMP-response-element-binding protein (CREB), nuclear factor-κB (NF-êB) and hypoxia-inducible factor 1 (HIF-1), are developmentally regulated in neural system, and all are necessary in the induction of neuroprotective preconditioning against ischemia or hypoxic/ischemia through transcriptional activation of their pro-survival genes. CREB and NF-êB are also involved in the regulation of synaptic plasticity, and learning and memory formation. CREB phosphorylation and subsequently activation of its regulated gene expression is a sufficient and necessary signal for neuro-survival in adult and immature neurons. The NF-êB's role in brain injury as a pro- and anti-apoptotic role has been controversial. It is highly likely that activation of NF-κB in neurons promotes survival and plasticity, whereas activation of NF-κB in glial cells promotes neuronal death by inducing inflammatory processes, enhancing reactive oxygen molecules and neurotoxin production. Although HIF-1 is necessary for activating neuro-survival genes during hypoxic preconditioning, paradoxically, in the absence of preconditioning, HIF-1 might promote ischemia-induced neuronal death. Erythropoietin (EPO), one of the prominent HIF-1targeted genes, has potent neuroprotective properties in adult and immature brain. Since the wide use of EPO in premature newborns, this agent may be potentially beneficial in treating newborns with HI brain damage.

Drugs that activate the specific signaling pathway, such as cAMP-CREB cascades, leading to the transcriptional activation of pro-survival genes would provide novel therapeutic approaches for the treatment of HI brain injury in high-risk newborns. The continuing investigation of the transcriptional mechanisms of neuronal survival and tolerance is likely to reveal other novel transcription factors whose activation by small molecule drugs will complement current medication in activating salutary gene program. However, due to the multi-potent activity of the transcription factors, whether strategies can be designed that achieves the desired therapeutic effect without incurring undesired side effects is a major concern.