Alterations in inter‐alpha inhibitor protein expression after hypoxic‐ischemic brain injury in neonatal rats

Abstract

Hypoxic-ischemic (HI) brain injury is frequently associated with premature and/or full-term birth-related complications that reflect widespread damage to cerebral cortical structures. Inflammation has been implicated in the long-term evolution and severity of HI brain injury. Inter-Alpha Inhibitor Proteins (IAIPs) are immune modulator proteins that are reduced in systemic neonatal inflammatory states. We have shown that endogenous IAIPs are present in neurons, astrocytes and microglia and that exogenous treatment with human plasma purified IAIPs decreases neuronal injury and improves behavioral outcomes in neonatal rats with HI brain injury. In addition, we have shown that endogenous IAIPs are reduced in the brain of the ovine fetus shortly after ischemic injury. However, the effect of HI on changes in circulating and endogenous brain IAIPs has not been examined in neonatal rats. In the current study, we examined changes in endogenous IAIPs in the systemic circulation and brain of neonatal rats after exposure to HI brain injury. Postnatal day 7 rats were exposed to right carotid artery ligation and 8% oxygen for 2h. Sera were obtained immediately, 3, 12, 24, and 48h and brains 3 and 24h after HI. IAIPs levels were determined by a competitive enzyme-linked immunosorbent assay (ELISA) in sera and by Western immunoblots in cerebral cortices. Serum IAIPs were decreased 3h after HI and remained lower than in non-ischemic rats up to 7days after HI. IAIP expression increased in the ipsilateral cerebral cortices 24h after HI brain injury and in the hypoxic contralateral cortices. However, 3h after hypoxia alone the 250kDa IAIP moiety was reduced in the contralateral cortices. We speculate that changes in endogenous IAIPs levels in blood and brain represent constituents of endogenous anti-inflammatory neuroprotective mechanism(s) after HI in neonatal rats.

Ontogeny of inter‐alpha inhibitor protein (IAIP) expression in human brain

“…Inflammatory responses in the fetal systemic and central nervous systems (CNSs) appear to contribute to the development of many types of brain injury in the newborn (Ferriero, 2004). Furthermore, we previously reported time-dependent changes in the endogenous expression of IAIPs in the brain after exposure to hypoxia-ischemia and hypoxia alone in neonatal rats (Disdier et al, 2018) and in the cerebral cortex and cerebellum of fetal sheep after exposure to brain ischemia (Spasova et al, 2017). Studies have also suggested that IAIPs could be important in neuroplasticity (Duman, Aghajanian, Sanacora, & Krystal, 2016;Gaudet, Lim, Stonestreet, & Threlkeld, 2016;Goldschmied & Gehrman, 2019;Normann, Schmitz, Furmaier, Doing, & Bach, 2007;Popoli, Gennarelli, & Racagni, 2002).…”

Potential biomarkers for neuroinflammation and neurodegeneration at short and long term after neonatal hypoxic-ischemic insult in rat

“…Post-ischemic neuroinflammation in the immature brain is a key pathophysiological factor in the development of HI-related injury [13–16]. However, the course of the inflammatory process has been investigated only partly in the neonatal setting [17, 18].…”

Novel Neuroprotective Agents to Treat Neonatal Hypoxic-Ischemic Encephalopathy: Inter-Alpha Inhibitor Proteins

“…HI decreases tight junctions at the BBB and increases barrier permeability to hydrophobic compounds in the fetal and neonatal brain [73][74][75][76]. Nonetheless, the level of exogenously administered IAIPs that could cross the BBB under conditions of HI could remain low relative to the quantity of IAIPs endogenously present within the brain parenchyma [77,78]. The presence of high levels of endogenous IAIPs within the brain parenchyma raises the question of whether influx transport systems exist for either IAIPs or certain IAIP subunits [39,79].…”