Exogenous inter-α inhibitor proteins prevent cell death and improve ischemic stroke outcomes in mice

Abstract

Conflict of interest: YPL and BSS hold a patent on inter-α inhibitor protein (IAIP) (US patent no. 9,572,87). Purified IAIP for these studies was provided by ProThera Biologics. YPL is cofounder of and holds significant financial interest in ProThera Biologics.

Longitudinal Change of Serum Inter-<i>α</i>-Trypsin Inhibitor Heavy Chain H4 and its Relation with Inflammation, Disease Recurrence, and Mortality in Acute Ischemic Stroke Patients

“…In the present study, ITIH4 was decreased in AIS patients than in controls, which was in line with the previous study (Kashyap et al 2009). The potential explanations might be that: (1) ITIH4 might play a protective role in the central nervous system by suppressing the extent of cerebral infarction and neuron death (Kashyap et al 2009;McCullough et al 2021;Nayak et al 2012); thus, declined ITIH4 implied that the central nervous system got damaged, leading to the pathogenesis of AIS; (2) ITIH4 could inhibit the occurrence of atherosclerosis and consequently accelerate the pathogenesis of AIS (Malaud et al 2012); thereby, reduced ITIH4 might be related to a higher risk of atherosclerosis, which resulted in a higher possibility of AIS (Riggs et al 2022). Thus, declined ITIH4 was correlated with a higher risk of AIS.…”

Inter‐alpha‐trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis

“…Inter‐alpha inhibitor proteins (IAIPs), a family of serine proteases inhibitors, comprise of inter‐alpha inhibitor (2 heavy chains and 1 light chain) and pre‐alpha inhibitor (1 heavy chain and 1 light chain). 14 , 15 Several studies disclose the anti‐inflammatory properties of IAIPs in some inflammation‐implicated diseases, such as sepsis, enterocolitis, stroke, recurrent pregnancy loss, and allergic contact dermatitis 16 , 17 , 18 , 19 , 20 In terms of inter‐alpha‐trypsin inhibitor heavy chain 4 (ITIH4), a plasma glycoprotein produced by liver, belongs to the family of IAIPs. 21 , 22 Like other IAIP family members, ITIH4 also has systemic anti‐inflammatory properties in some complex diseases, including Alzheimer's disease, acute ischemic stroke, etc.…”

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

“…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.…”