Inter-alpha Inhibitor Proteins Ameliorate Brain Injury and Improve Behavioral Outcomes in a Sex-Dependent Manner After Exposure to Neonatal Hypoxia Ischemia in Newborn and Young Adult Rats

Effects of Three Different Doses of Inter-Alpha Inhibitor Proteins on Severe Hypoxia–Ischemia-Related Brain Injury in Neonatal Rats

“…Treatment with doses of 30 mg/kg or greater were sufficient to attenuate this deficit ( Figure 3 A). These findings are somewhat consistent with our previous work, in which hIAIPs at a dose of 30 mg/kg attenuated deficits in the righting reflex after exposure to a more moderate amount of HI in male, but not female, neonatal rats [ 21 ]. Combined, the results from the present study and our previous publication suggest that restitution of righting reflex behaviors by treatment with hIAIPs can be observed in both males and females.…”

“…hIAIPs are a novel therapeutic candidate that has been shown to have important neuroprotective properties in preclinical rodent studies [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 26 ]. The optimal treatment regimen for hIAIPs needs to be ascertained before consideration of a potential clinical trial, in order to maximize their beneficial neuroprotective properties.…”

“…Producing IAIPs with recombinant techniques would be challenging because they are endogenously transcribed by four different genes localized on three different chromosomes [ 27 , 28 , 29 , 30 , 31 ]. Consequently, IAIPs are extracted and purified from human plasma, as described below in the section “Preparation of hIAIPs” [ 15 , 16 , 18 , 21 , 26 , 32 ]. Treatment with hIAIPs effectively reached the systemic circulation after the i.p.…”

“…Previous studies have shown that treatment with hIAIPs can improve behavioral performance in the water maze [ 17 , 19 ], on auditory discrimination [ 20 ], and wire hang tasks [ 21 ]. The righting reflex requires a combination of sensory perception for the rats to recognize that they are in a supine position, the innate cognitive capacity to realize that they prefer to be in a prone position, and motor function to return to the prone position.…”

“…IAIPs are endogenously present in the circulation and in many cell types [ 9 , 10 , 11 , 12 , 13 ], where they act to inhibit destructive proteases, decrease the quantity of damaging cytokines, and alter immune cell responses [ 14 ]. Treatment of neonatal rats with exogenous human IAIPs (hIAIPs) after exposure to HI has been shown to decrease infarct volumes in the brain, preserve neurons and oligodendrocytes, decrease the number of microglia, attenuate peripheral immune responses, and improve behavioral outcomes [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Therapeutic hIAIPs are isolated and purified from human plasma, which is a costly process and subject to human plasma availability.…”