Perinatal hypoxia-ischemia (HI) is the most common cause of various neurological disabilities in children with high societal cost. Hypoxic-ischemic brain damage is an evolving process and ample evidence suggests distinct difference between the immature and mature brain in the pathology and consequences of brain injury. Therefore, it is of utmost importance to better understand the mechanisms underlying the hypoxic-ischemic injury in neonatal brain to devise effective therapeutic strategies. Nonetheless, the mechanism(s) involved in this pathology in the developing brain remain inadequately understood. Effective neuroprotective strategies will include either inhibition of the death effector pathways or induction of their regulatory and survival promoting cellular proteins. Neuronal pentraxins (NPs) define a family of novel proteins "long pentraxins" that are exclusively expressed in the central neurons, and are homologous to the C-reactive and acute-phase proteins in the immune system. NPs have been shown to be involved in the excitatory synaptic remodeling. We found that the neuronal protein 'neuronal pentraxin 1' (NP1) is induced in neonatal rat brain following HI, and NP1 induction preceded the time of actual tissue loss in 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 NP1 is part of a death program triggered by HI. Most importantly, our findings of specific interactions of NP1 with the excitatory glutamate receptors AMPA GluR1 subunit and their co-localization suggest a role for this novel neuronal protein NP1 in the excitotoxic cascade. Blockade of AMPA-induced neuronal death following inhibition of NP1 expression further implicates a regulatory interaction between NP1 and AMPA glutamate receptors. Subsequent experiments using NP1 loss-of-function strategies, we have demonstrated specific requirements of NP1 induction in HI-induced neuronal death. Together our findings clearly identify a novel role for NP1 in the coupling between HI and cerebral cell death. Thus, NP1 could be a new molecular target in the central neurons for preventing hypoxic-ischemic neuronal death in developing brain. These very novel results could lead to more effective neuroprotective strategies against hypoxic-ischemic brain injury in neonates.