Hemopexin alleviates cognitive dysfunction after focal cerebral ischemia-reperfusion injury in rats

Dong, Beibei; Yang, Yanmin; Zhang, Zhishen; Xie, Keliang; Su, Lin; Yu, Yonghao

doi:10.1186/s12871-019-0681-2

Cited by 26 publications

(23 citation statements)

References 26 publications

(16 reference statements)

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“…Therefore, Hpx could potentially be applied as a human blood-derived product similar to other plasma proteins, such as albumin, α1-antitrypsin or immunoglobulins, which are well-established therapies (34). Hpx has already been tested in numerous animal models and showed beneficial effect in most of the tested parameters [ (10,13,14,19,20,23,29,33,(35)(36)(37)(38)(39)(40)(41); Table 2].…”

Section: Discussionmentioning

confidence: 99%

Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation

et al. 2020

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Hemopexin is the main plasmatic scavenger of cell-free heme, released in the context of intravascular hemolysis or major cell injury. Heme is indispensable for the oxygen transport by hemoglobin but when released outside of the erythrocytes it becomes a danger-associated molecular pattern, contributing to tissue injury. One of the mechanisms of pro-inflammatory action of heme is to activate the innate immune complement cascade. Therefore, we hypothesized that injection of hemopexin will prevent hemolysis-induced complement activation. Human plasma-derived hemopexin is compatible with the heme clearance machinery of the mice. 100 or 500 mg/kg of hemopexin was injected in C57Bl/6 mice before treatment with phenylhydrazine (inducer of erythrocytes lysis) or with PBS as a control. Blood was taken at different timepoints to determine the pharmacokinetic of injected hemopexin in presence and absence of hemolysis. Complement activation was determined in plasma, by the C3 cleavage (western blot) and in the kidneys (immunofluorescence). Kidney injury was evaluated by urea and creatinine in plasma and renal NGAL and HO-1 gene expression were measured. The pharmacokinetic properties of hemopexin (mass spectrometry) in the hemolytic mice were affected by the target-mediated drug disposition phenomenon due to the high affinity of binding of hemopexin to heme. Hemolysis induced complement overactivation and signs of mild renal dysfunction at 6 h, which were prevented by hemopexin, except for the NGAL upregulation. The heme-degrading capacity of the kidney, measured by the HO-1 expression, was not affected by the treatment. These results encourage further studies of hemopexin as a therapeutic agent in models of diseases with heme overload.

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Section: Discussionmentioning

confidence: 99%

Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation

et al. 2020

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“…Based on its lipophilic nature, heme may induce lipid peroxidation and subsequent membrane injury, which finally results in apoptosis. Indeed, scavenging of heme by intracerebroventricularly applied hemopexin reduced the infarct volumes, improved neurological function and cognitive function after focal ischemia (62,63). We therefore think that the decreased HO activity, which is caused by CA, results in neuronal deficits.…”

Section: Discussionmentioning

confidence: 96%

Motor Cortex and Hippocampus Display Decreased Heme Oxygenase Activity 2 Weeks After Ventricular Fibrillation Cardiac Arrest in Rats

et al. 2020

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“…This protective effect was also linked to HO1 activity because it was reversed by the HO1 inhibitor, zinc-PPIX [119]. In a similar experimental approach, HPX was protective after cerebral ischemia/reperfusion injury and protection was lost when zinc-PPIX was given [119].…”

Section: Hemopexin Protects the Blood-brain Barriermentioning

confidence: 98%

“…Using a model of cerebral ischemia-reperfusion injury in rats, focal cerebral ischemic and reperfusion, Dong and colleagues [119] showed that HPX alleviated cognitive dysfunction rapidly when injected intracerebro-ventricularly once reperfusion was initiated. This protective effect was also linked to HO1 activity because it was reversed by the HO1 inhibitor, zinc-PPIX [119]. In a similar experimental approach, HPX was protective after cerebral ischemia/reperfusion injury and protection was lost when zinc-PPIX was given [119].…”

Section: Hemopexin Protects the Blood-brain Barriermentioning

confidence: 99%

What Is Next in This “Age” of Heme-Driven Pathology and Protection by Hemopexin? An Update and Links with Iron

2019

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This review provides a synopsis of the published literature over the past two years on the heme-binding protein hemopexin (HPX), with some background information on the biochemistry of the HPX system. One focus is on the mechanisms of heme-driven pathology in the context of heme and iron homeostasis in human health and disease. The heme-binding protein hemopexin is a multi-functional protectant against hemoglobin (Hb)-derived heme toxicity as well as mitigating heme-mediated effects on immune cells, endothelial cells, and stem cells that collectively contribute to driving inflammation, perturbing vascular hemostasis and blood–brain barrier function. Heme toxicity, which may lead to iron toxicity, is recognized increasingly in a wide range of conditions involving hemolysis and immune system activation and, in this review, we highlight some newly identified actions of heme and hemopexin especially in situations where normal processes fail to maintain heme and iron homeostasis. Finally, we present preliminary data showing that the cytokine IL-6 cross talks with activation of the c-Jun N-terminal kinase pathway in response to heme-hemopexin in models of hepatocytes. This indicates another level of complexity in the cell responses to elevated heme via the HPX system when the immune system is activated and/or in the presence of inflammation.

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Hemopexin alleviates cognitive dysfunction after focal cerebral ischemia-reperfusion injury in rats

Cited by 26 publications

References 26 publications

Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation

Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation

Motor Cortex and Hippocampus Display Decreased Heme Oxygenase Activity 2 Weeks After Ventricular Fibrillation Cardiac Arrest in Rats

What Is Next in This “Age” of Heme-Driven Pathology and Protection by Hemopexin? An Update and Links with Iron

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