Hypoxic-ischemic (HI)
brain injury is one of the most common neurological problems occurring in the perinatal period.
Hypothermia is the only approved intervention for neonatal HI
encephalopathy. However, this treatment is only partially protective, has a narrow therapeutic time window after birth and only can be used to treat full-term infants. Consequently, additional
therapies are critically needed.
Inflammation is an important contributing factor to the evolution of HI
brain injury in neonates.
Inter-alpha Inhibitor Proteins (IAIPs) are immunomodulatory
proteins with anti-inflammatory properties. We have previously shown that IAIPs reduce neuronal cell death and improve behavioral outcomes when given after carotid artery
ligation, but before
hypoxia in male neonatal rats. The objective of the current study was to investigate the
neuroprotective effects of treatment with IAIPs given immediately or 6 h after HI in both male and female neonatal rats. HI was induced with the Rice-Vannucci method in postnatal (P) day 7 rats. After
ligation of the right common carotid artery, P7 rats were exposed to 90 min of
hypoxia (8%
oxygen). Human plasma-derived IAIPs or placebo (
phosphate buffered saline) was given at zero, 24, and 48 h after HI. Brains were perfused, weighed and fixed 72 h after HI at P10. In a second,
delayed treatment group, the same procedure was followed except that IAIPs or placebo were given at 6, 24 and 48 h after HI. Separate
sham-operated, placebo-treated groups were exposed to identical protocols but were not exposed to carotid artery
ligation and remained in room air. Rat sex was recorded. The effects of IAIPs on HI
brain injury were examined using histopathological scoring and immunohistochemical analyses of the brain and by using
infarct volume measurements on frozen tissue of the entire brain hemispheres ipsilateral and contralateral to HI injury. IAIPs given immediately after HI improved (P < 0.050) histopathological
brain injury across and within the cingulate, caudate/putamen, thalamus, hippocampus and parietal cortex in males, but not in females. In contrast, IAIPs given immediately after HI reduced (P < 0.050)
infarct volumes of the hemispheres ipsilateral to HI injury in similarly both the males and females. Treatment with IAIPs also resulted in higher (P < 0.050) brain weights compared with the placebo-treated HI group, reduced (P < 0.050) neuronal and non-neuronal cell death in the cortex and total hemisphere, and also increased the total area of oligodendrocytes determined by
CNPase in the ipsilateral hemisphere and corpus callosum (P < 0.050) of male, but not female subjects exposed to HI.
Delayed treatment with IAIPs 6 h after HI did not improve histopathological
brain injury in males or females, but resulted in higher (P < 0.050) brain weights compared with the placebo-treated HI males. Therefore, treatment with IAIPs immediately after HI improved brain weights and reduced neuropathological
brain injury and cell death in male rats, and reduced
infarct volume in both male and female neonatal rats. We conclude that IAIPs exert
neuroprotective effects after exposure to HI in neonatal rats and may exhibit some sex-related differential effects.