Apotransferrin, C1‐esterase inhibitor, and alpha 1‐acid glycoprotein for cerebral protection during experimental hypothermic circulatory arrest

Heikkinen, Jouni; Koskenkari, Juha; Kaakinen, Timo; Dahlbacka, Sebastian; Kiviluoma, Kai; Salomäki, Timo; Laurila, Päivi; Hirvonen, J.; Biancari, Fausto; Parkkinen, Jaakko; Juvonen, Tatu

doi:10.1080/14017430410028618

Cited by 3 publications

(2 citation statements)

References 27 publications

(27 reference statements)

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“…This was actually proved by the fact that exogenous hATf administered to rats does not generate iron-bound species of human Tf in rat serum either at 1 h (not shown) or 24 h later. The therapeutic efficacy of the administration of ATf (Low TSAT) we report here was not observed in a previous report in which authors used a lower ATf dose in a model of global ischemia by circulatory arrest in pigs, and in which TSAT was not determined [46] . However, a circulatory arrest, in contrast with focal stroke models we have used, produces global brain ischemia.…”

Section: Discussioncontrasting

confidence: 90%

Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage

DeGregorio-Rocasolano

Martí-Sistac

Ponce

et al. 2018

Redox Biology

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Despite transferrin being the main circulating carrier of iron in body fluids, and iron overload conditions being known to worsen stroke outcome through reactive oxygen species (ROS)-induced damage, the contribution of blood transferrin saturation (TSAT) to stroke brain damage is unknown. The objective of this study was to obtain evidence on whether TSAT determines the impact of experimental ischemic stroke on brain damage and whether iron-free transferrin (apotransferrin, ATf)-induced reduction of TSAT is neuroprotective. We found that experimental ischemic stroke promoted an early extravasation of circulating iron-loaded transferrin (holotransferrin, HTf) to the ischemic brain parenchyma. In vitro, HTf was found to boost ROS production and to be harmful to primary neuronal cultures exposed to oxygen and glucose deprivation. In stroked rats, whereas increasing TSAT with exogenous HTf was detrimental, administration of exogenous ATf and the subsequent reduction of TSAT was neuroprotective. Mechanistically, ATf did not prevent extravasation of HTf to the brain parenchyma in rats exposed to ischemic stroke. However, ATf in vitro reduced NMDA-induced neuronal uptake of HTf and also both the NMDA-mediated lipid peroxidation derived 4-HNE and the resulting neuronal death without altering Ca2+-calcineurin signaling downstream the NMDA receptor. Removal of transferrin from the culture media or blockade of transferrin receptors reduced neuronal death. Together, our data establish that blood TSAT exerts a critical role in experimental stroke-induced brain damage. In addition, our findings suggest that the protective effect of ATf at the neuronal level resides in preventing NMDA-induced HTf uptake and ROS production, which in turn reduces neuronal damage.

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Section: Discussioncontrasting

confidence: 90%

Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage

DeGregorio-Rocasolano

Martí-Sistac

Ponce

et al. 2018

Redox Biology

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“…The biological implication of such observation may be connected with the protective effects of orosomucoid against a number of noxious stimuli [69][70][71][72], including resistance to Gramnegative infection [73].…”

Section: Biological Aspectsmentioning

confidence: 98%

Serum protein pattern during cow pregnancy: Acute‐phase proteins increase in the peripartum period

et al. 2006

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Serum collected in a time-course mode during the pregnancy of a group of heifers was analyzed by 2-DE under various experimental conditions to optimize resolution of all protein spots. Changes in the levels of some components were detected during the last phase of pregnancy and early postpartum. These included a decrease of alpha2-HS-glycoprotein, an increase of alpha1-antichymotrypsin and, with a much larger and more abrupt variation, of orosomucoid and haptoglobin. These findings associate the weeks preceding calving with an acute-phase reaction. Analysis of individual animal's sera by 1-DE demonstrated a higher level of orosomucoid in the sera of cows developing postpartum endometritis during the 2 wk after calving (i.e., in the course of the infection) but a lower level during the 2 wk before calving. This observation could represent an important tool for the prepartum detection of animals prone to develop postpartum endometritis and lead to a more accurate peripartum management of those animals.

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C1 inhibitor: molecular and clinical aspects

Cicardi

Zingale

Zanichelli

et al. 2005

Springer Semin Immun

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C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement, contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three beta-sheets and an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE). The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there are several pathological conditions such as ischemia-reperfusion, septic shock, capillary leak syndrome, and pancreatitis, in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH, produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting C1-INH as a therapeutic agent.

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Apotransferrin, C1‐esterase inhibitor, and alpha 1‐acid glycoprotein for cerebral protection during experimental hypothermic circulatory arrest

Abstract: Although the small size of the study groups may affect the present findings, none of the metabolic and hemodynamic parameters as well as outcome endpoints indicate a substantial therapeutic efficacy of Apo-Tf, AGP, and C1-INH as neuroprotective agents after experimental HCA.

Cited by 3 publications

References 27 publications

Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage

Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage

Serum protein pattern during cow pregnancy: Acute‐phase proteins increase in the peripartum period

C1 inhibitor: molecular and clinical aspects

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