Neonatal hypoxia-ischemia (HI) remains a major cause of acute perinatal brain injury, leading ultimately to neurologic dysfunction manifesting as cerebral palsy, mental retardation, and epilepsy. Unfortunately, current treatment and prevention strategies in newborns are limited. There are no currently available therapies to prevent/treat and/or attenuate brain damage in premature infants other than supportive care and the only available therapeutic intervention for full term infants is hypothermia, which is only partially protective. Inter- alpha Inhibitor Proteins (IAIP) are naturally derived glycoproteins that have been shown to play an important role in modulating inflammatory responses by down-regulating pro-inflammatory cytokines in several experimental models of newborn and adult systemic inflammation and in models of inflammation-induced premature labor. Our recent investigations strongly demonstrate that IAIP reduced neuroanatomical injury in the brain of neonatal rats and improves long-term behavioral indices of learning and memory tasks. In the Phase I SBIR study, we confirmed the beneficial effects of IAIP in neonatal rats after HI, particularly in male subjects. More recently, we obtained supporting evidence that IAIP also has long-term beneficial effects on behavioral function in female rats, suggesting that IAIP has durable neuroprotective effects in both males and females depending upon test and the duration after the HI insult. These findings suggest unique beneficial effects of IAIP on long-term outcomes in males and females, in spite our histopathological beneficial findings mainly in male neonatal rats. The goal of this Phase II SBIR project is to obtain robust preclinical and manufacturing process data of human plasma-derived IAIP to support the development as a novel adjunctive neuroprotective strategy to the current standard of care of hypothermia for the treatment of hypoxic-ischemic encephalopathy in newborns. We hypothesize that treatment with IAIP as an adjunctive therapy to hypothermia further enhances the effectiveness of hypothermia as a neuroprotective strategy and improves long-term outcomes after HI brain injury in neonates. The Specific Aims of the studies are: 1) to develop an efficient scalable bioprocess of plasma-derived IAIP and carry out formulation, viral safety and long-term stability studies of purified IAIP; 2a) to determine the pharmacokinetics (PK) of IAIP in male and female rats under conditions of hypoxic-ischemic (HI) and hypothermia (HT) and to perform dose-response studies; 2b) to assess the neuroprotective effects of IAIP as an adjunctive treatment strategy to HT in moderate or severe HI brain injury in newborn rats and 3) to determine the long-term neuroprotective efficacy of IAIP treatment with combined HT after HI in the newborn rats. The proposed studies have significant translational potential to develop IAIP as a novel agent to prevent/attenuate brain damage in full term as well as in preterm infants at risk for mental retardation.