Abstract
Perinatal hypoxia-ischemia (HI) is a major cause of brain injury and mortality in neonates. Hypoxic-ischemic encephalopathy (HIE) predisposes infants to long-term cognitive deficits that influence their quality of life and place a large burden on society. The only approved treatment to protect the brain after HI is therapeutic hypothermia, which has limited effectiveness, a narrow therapeutic time window, and is not considered safe for treatment of premature infants. Alternative or adjunctive therapies are needed to improve outcomes of full-term and premature infants after exposure to HI. Inter-alpha inhibitor proteins (IAIPs) are immunomodulatory molecules that are proposed to limit the progression of neonatal inflammatory conditions, such as sepsis. Inflammation exacerbates neonatal HIE and suggests that IAIPs could attenuate HI-related brain injury and improve cognitive outcomes associated with HIE. Recent studies have shown that intraperitoneal treatment with IAIPs can decrease neuronal and non-neuronal cell death, attenuate glial responses and leukocyte invasion, and provide long-term behavioral benefits in neonatal rat models of HI-related brain injury. The present review summarizes these findings and outlines the remaining experimental analyses necessary to determine the clinical applicability of this promising neuroprotective treatment for neonatal HI-related brain injury.
Highlights
Reductions in oxygenated blood flow to the fetal or neonatal brain can result in mortality or severe long-term cognitive impairment
Systemic Inter-alpha inhibitor proteins (IAIPs) levels are reduced in neonatal sepsis [24,32] and necrotizing enterocolitis (NEC) [38], suggesting that these proteins may be decreased during systemic inflammation in premature infants
The therapeutic potential of IAIPs in models of neonatal inflammation coupled with the role of inflammation in hypoxic-ischemic encephalopathy (HIE)-related brain injury suggests that IAIPs could be very promising therapeutic drug candidates for this disorder [35,60,62]
Summary
Reductions in oxygenated blood flow to the fetal or neonatal brain can result in mortality or severe long-term cognitive impairment. Hypoxia-ischemia (HI) limits nutrient and energy supply to the brain and stimulates brain parenchymal and systemic inflammatory responses [1,2,3,4] These abnormalities predispose patients to neurological cell death, cellular dysfunction, and neurodevelopmental deficits, which comprise hypoxic-ischemic encephalopathy (HIE). Neonatal cardiopulmonary abnormalities after birth, including hemorrhage, pulmonary disorders, or apnea, can predispose infants to hypoxic- or HI-related brain injury. Therapeutic hypothermia is the only clinically approved neuroprotective treatment strategy for newborns exposed to HI [8] This therapy is not approved to treat premature infants, the population with the highest incidence of HI-related brain injury and abnormal neurodevelopmental outcomes.
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