Inter-alpha-inhibitors in Hypoxic-Ischemic Brain Injury

Lim, Yow-Pin

Abstract

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. Cerebral oxygen deprivation and/or reduced blood flow due to umbilical cord occlusion, prolonged labor, and/or intracranial hemorrhage produce an inflammatory response contributing to neuronal cell death. Unfortunately, current treatment and prevention strategies in newborns are lacking and inadequate. There are no currently available therapies to prevent/treat and/or attenuate brain damage in premature infants 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 molecules that have been shown to play an important role in modulating inflammatory response by down-regulating pro-inflammatory cytokines in several experimental models of newborn and adult systemic inflammation and in models of inflammation- induced premature labor. Moreover, decreased IAIP has been shown to accurately predict the development of sepsis in premature infants and decreases in IAIP have been detected following induced ischemia in the ovine fetus brains. Thus, exogenous treatment with IAIP is likely to attenuate inflammation-induced brain injury in neonatal incidences of cerebral ischemia. Our recent data strongly demonstrate the beneficial effects of early administration of IAIP in established models of HI injury in the ovine fetus, neonatal rats and adult mice. Not only does IAIP treatment reduce neuroanatomical injury in the brain of experimental animals, but long-term improvement on learning and memory tasks was achieved. The goal of this Phase I SBIR project is to confirm and obtain proof-of-concept of the neuroprotective effects of IAIP in newborn brain injuries. We hypothesize that IAIP treatment will reduce neuronal death and attenuate the development of ischemic-reperfusion injury in the brain.
The Specific Aims of the study are to examine the therapeutic effects and long-term behavioral outcome of delayed IAIP treatment in neonatal rat hypoxic-ischemic brain injury model. The proposed studies have significant translational potential to develop IAIP as a novel agent to prevent/attenuate brain damage in infants at risk for mental retardation.

Public Health Relevance

Cerebral hypoxia-ischemia (HI) and associated inflammation is a profound neurological problem in neonatal infants leading to poor health conditions. This proposal will advance public health by developing novel therapeutic strategy based on novel anti-inflammatory treatment following HI injury.