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Background: Hypoxia-Ischemia (HI) is a condition in which the brain is deprived of adequate blood and oxygen supplies, resulting in a variety of neurodevelopmental morbidities in newborns. Inter-Alpha Inhibitor Proteins (IAIPs) are immunomodulatory proteins that have anti-inflammatory properties in systemic inflammatory disorders. The neuroprotective effects of treatment with IAIPs on apoptosis resulting from HI-related injury have not been examined yet.Objective: To investigate the effects of systemic treatment with IAIPs on apoptosis in HI-exposed neonatal rats.Design/Methods: Postnatal day 7 rats were randomly assigned to one of three groups: Placebo-Sham (PL-Sham, n=8), Placebo-HI (PL-HI, n=8) and IAIP-HI (n=8) groups. The PL-Sham group was not exposed to HI and received placebo intraperitoneally (0.9% NaCl); the PL-HI group was exposed to HI and received placebo (0.9% NaCl); the IAIP-HI group was exposed to HI and received IAIPs treatment (30 mg/kg). The Rice-Vannucci model was utilized to induce HI-related brain injury: unilateral carotid artery ligation followed by hypoxia (90 min in 8% O2). Rat sex was recorded. Placebo or IAIP treatment was given at 0, 24 and 48 hours after HI, and brains were perfused and fixed at 72 hours. Fixed brain tissues were immunohistochemically stained with TUNEL apoptotic cellular markers. Apoptotic cells were counted without knowledge of the group assignment using the StereoInvestigator 10.0, Fractionator probe (MBF Bioscience).Results: There were more TUNEL positive cells in the PL-HI group than in the PL-Sham group overall (female+male) as well as in males in the cortex, total hemisphere and hippocampus (all P<0.05), but not in females (P=0.11, P=0.30 and P=0.12, respectively). There appeared to be less apoptosis in the male IAIP-treated HI rats compared with the male placebo-treated HI rats (P=0.29 for hemisphere and cortex, P=0.51 for hippocampus).Conclusion: Apoptosis is significantly increased after HI in the total hemisphere, cortex, and hippocampus of male neonatal rats, but not in females. Further investigation is needed to determine the neuroprotective effects of IAIPs on apoptosis in HI-exposed neonatal rats, although preliminary data suggests a protective trend for male rats.