Immuno-modulator inter-alpha inhibitor proteins ameliorate complex auditory processing deficits in rats with neonatal hypoxic-ischemic brain injury

Threlkeld, Steven W.; Lim, Yow‐Pin; Rue, Molly La; Gaudet, Cynthia M.; Stonestreet, Barbara S.

doi:10.1016/j.bbi.2017.03.004

Cited by 21 publications

(40 citation statements)

References 59 publications

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“…Recent work has also shown that exogenous treatment with IAIPs in neonates exposed to HI reduces neuronal cell death, improves neuronal plasticity, ameliorates complex auditory processing deficits, cognitive function, and behavioral outcomes (Gaudet et al, 2016; Threlkeld et al, 2014, 2017). Administration of urinary bikunin, the light chain of IAIPs demonstrated neuroprotective properties by reducing pro‐inflammatory mediators and resulting in milder ischemia related brain injury in young piglets (Wang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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

Disdier

Zhang

Fukunaga

et al. 2017

Intl J of Devlp Neuroscience

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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.

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Section: Introductionmentioning

confidence: 99%

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

Disdier

Zhang

Fukunaga

et al. 2017

Intl J of Devlp Neuroscience

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“…Neonatal brain injury is known to result in auditory deficits that contribute to language comprehension and learning difficulties [69,70]. Rats treated with IAIPs after neonatal HI, when tested as adults (23 weeks after injury), exhibited significantly better auditory discrimination capacity compared with untreated counterparts after injury [71]. These results demonstrate that short-term treatment with exogenous IAIPs after HI in neonatal subjects has the potential to provide cognitive improvements that persist into later life.…”

Section: Neurobehavioral Effectsmentioning

confidence: 73%

“…Future studies are required to determine whether the efficacy of treatment with IAIPs is sex-specific. Initial studies identifying neuroprotection by IAIPs in neonatal rodents exposed to HI investigated mainly male subjects [64,68,71]. More recent studies investigating both male and female subjects suggest that, although brain infarct volumes were reduced in both sexes after treatment with IAIPs given soon after HI [40,63], when treatment was delayed, males exhibited greater reductions in infarct volumes than female neonatal rodents [63].…”

Section: Sex-specific Efficacymentioning

confidence: 99%

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

Koehn

Chen

Logsdon

et al. 2020

IJMS

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Perinatal hypoxia-ischemia (HI) is a major cause of brain injury and mortality in neonates. Hypoxic-ischemic encephalopathy (HIE) predisposes infants to long-term cognitive deficits that influence their quality of life and place a large burden on society. The only approved treatment to protect the brain after HI is therapeutic hypothermia, which has limited effectiveness, a narrow therapeutic time window, and is not considered safe for treatment of premature infants. Alternative or adjunctive therapies are needed to improve outcomes of full-term and premature infants after exposure to HI. Inter-alpha inhibitor proteins (IAIPs) are immunomodulatory molecules that are proposed to limit the progression of neonatal inflammatory conditions, such as sepsis. Inflammation exacerbates neonatal HIE and suggests that IAIPs could attenuate HI-related brain injury and improve cognitive outcomes associated with HIE. Recent studies have shown that intraperitoneal treatment with IAIPs can decrease neuronal and non-neuronal cell death, attenuate glial responses and leukocyte invasion, and provide long-term behavioral benefits in neonatal rat models of HI-related brain injury. The present review summarizes these findings and outlines the remaining experimental analyses necessary to determine the clinical applicability of this promising neuroprotective treatment for neonatal HI-related brain injury.

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“…This heavy chain-to-hyaluronan interaction is facilitated by Tumor necrosis factor-inducible gene 6 (TSG-6) and is currently the only known interaction of the ITI heavy chain [ 60 ], serving to cross-link molecules within the ECM and enhance ECM rigidity [ 61 ]. ITIH-family proteins have been revealed to modulate peripheral inflammatory responses in multiple diseases [ 62 ]. The formation of extracellular or cell surface ITIH-HA complexes promotes the adhesion of leukocytes [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Endothelial Progenitor Cells Modulate Inflammation-Associated Stroke Vasculome

Acosta

Lee

Nguyen

et al. 2019

Stem Cell Rev and Rep

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Stroke remains a major unmet clinical need that warrants novel therapies. Following an ischemic insult, the cerebral vasculature secretes inflammatory molecules, creating the stroke vasculome profile. The present study evaluated the therapeutic effects of endothelial cells on the inflammation-associated stroke vasculome. qRT-PCR analysis revealed that specific inflammation-related vasculome genes BRM, IκB, Foxf1, and ITIH-5 significantly upregulated by oxygen glucose deprivation (OGD. Interestingly, co-culture of human endothelial cells (HEN6) with human endothelial cells (EPCs) during OGD significantly blocked the elevations of BRM, IκB, and Foxf1, but not ITIH-5. Next, employing the knockdown/antisense technology, silencing the inflammation-associated stroke vasculome gene, IκB, as opposed to scrambled knockdown, blocked the EPC-mediated protection of HEN6 against OGD. In vivo, stroke animals transplanted with intracerebral human EPCs (300,000 cells) into the striatum and cortex 4 h post ischemic stroke displayed significant behavioral recovery up to 30 days post-transplantation compared to vehicle-treated stroke animals. At 7 days post-transplantation, quantification of the fluorescent staining intensity in the cortex and striatum revealed significant upregulation of the endothelial marker RECA1 and a downregulation of the stroke-associated vasculome BRM, IKB, Foxf1, ITIH-5 and PMCA2 in the ipsilateral side of cortex and striatum of EPC-transplanted stroke animals relative to vehicle-treated stroke animals. Altogether, these results demonstrate that EPCs exert therapeutic effects in experimental stroke possibly by modulating the inflammation-plagued vasculome.

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Immuno-modulator inter-alpha inhibitor proteins ameliorate complex auditory processing deficits in rats with neonatal hypoxic-ischemic brain injury

Cited by 21 publications

References 59 publications

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

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

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

Endothelial Progenitor Cells Modulate Inflammation-Associated Stroke Vasculome

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