Molecular determinants of hypoxic-ischemic injury in developing brain and potential strategies for neuroprotection

The developing brain is highly susceptible to hypoxic-ischemic injury leading to severe neurological disabilities in surviving infants and children affecting the life of all ages and populations worldwide. Neonatal brain injury has one of the very highest indices of burden of disease because of life-long consequences to the patient, care-takers and social institutions. Current treatment regimens are not optimal and there is a need for new therapeutic approaches. Cerebral hypoxia-ischemia (HI) at early childhood is intuitive and results in detrimental developmental brain pathology. Nonetheless, the mechanism(s) involved in this pathology in the developing brain has remained largely elusive. Therefore, it is of utmost importance to better understand the mechanism(s) underlying the hypoxic-ischemic injury in neonatal brain to devise effective therapy. Effective neuroprotective strategies will include either inhibition of the death effector pathways or induction of their regulatory and/or survival promoting cellular and molecular factors. The focus of this article is to discuss recent advances towards understanding the cellular and molecular determinants involved in neonatal brain injury mechanism(s). It is known that apoptotic and anti-apoptotic signaling pathways are activated after cerebral HI, and that a shift in the balance between apoptotic and anti-apoptotic cellular factors determines cells fate. Caspases and the inhibitors of apoptosis (IAP_s) family proteins are the crucial regulators that decide the fate of brain cells following HI. We reported a novel mechanism in which the neurotrophin factor =acidic fibroblast growth factor 1' (FGF-1) attenuates HI-induced neuronal death by intervening at the cellular pro-death factors concurrent with the activation of pro-survival molecules X-linked inhibitor of apoptosis (XIAP) and signaling pathways. More recently, we have identified a novel key neuronal molecule =neuronal pentraxin 1' (NP1), a member of a family of novel neuronal proteins "long pentraxins", which is induced following HI in the neonatal brain. In demonstrating this, we also found that NP1 gene silencing is neuroprotective against hypoxia-induced neuronal death. This is the first evidence for a pathophysiological function of NP1 in central neurons. Our results suggest that neuronal pentraxin NP1 can contribute to the death program triggered by HI, which may be clinically relevant against neonatal brain injury. Future strategies for neuroprotection against hypoxic-ischemic injury in the immature brain are likely to stem from our understanding of how brain responses to injury and repair that could lead to devise novel therapeutic drugs aiming at brain injury in neonates. Furthermore, a focus has been made to assess the potential of this novel neuronal pentraxin family of proteins in brain injury and neuroprotection,