Plasma-derived and recombinant C1 esterase inhibitor: Binding profiles and neuroprotective properties in brain ischemia/reperfusion injury

Mercurio, Domenico; Piotti, Arianna; Valente, Alessia; Oggioni, Marco; Ponstein, Yolanda; Amersfoort, Edwin van; Gobbi, Marco; Fumagalli, Stefano; Simoni, Maria-Grazia De

doi:10.1016/j.bbi.2021.01.002

Cited by 12 publications

(10 citation statements)

References 41 publications

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“…Finally, minor differences in the glycosylation of the C1-INH-protein could be of importance. An IRI study in mice found plasma-derived C1-INH, as we have used in the present study, inferior to recombinant human C1-INH (24). On the other hand, half-life of a recombinant human C1-Inhibitor produced in rabbits with a distinctive glycosylation (Ruconest, Pharming) had a shorter half-life in pigs than humans (14).…”

Section: Discussionmentioning

confidence: 51%

A Novel Porcine Model of Ischemia-Reperfusion Injury After Cross-Clamping the Thoracic Aorta Revealed Substantial Cardiopulmonary, Thromboinflammatory and Biochemical Changes Without Effect of C1-Inhibitor Treatment

et al. 2022

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Ischemic injury worsens upon return of blood and innate immunity including the complement system play a central role in ischemia-reperfusion injury (IRI) as in thoracic aortic surgery. Complement component1 inhibitor (C1-INH) has been shown to reduce IRI and is a broad-acting plasma cascade inhibitor. We established a new porcine model of IRI by cross-clamping the thoracic aorta and evaluated the global changes occurring in organ function, systemic inflammatory response and organ damage with or without treatment with C1-INH-concentrate. Twenty-four piglets (8.8-11.1 kg) underwent 45 minutes clamping of the thoracic aorta at the Th8 level. Upfront 12 piglets received human saline and 12 received C1-INH (250 IU/kg) intravenously. Three sham animals received thoracic opening without clamping. Reperfusion lasted 5 hours. We studied ten cardiorespiratory markers, three hematologic markers, eleven inflammatory markers, and twelve organ damage markers over the whole experimental period. Postmortem tissue homogenates from seven organs were examined for inflammatory markers and analysed by two-way repeated-measures ANOVA, area under the curve or unpaired t-tests. By excluding sham and combining treated and untreated animals, the markers reflected a uniform, broad and severe organ dysfunction. The mean and range fold change from before cross-clamp onset to maximum change for the different groups of markers were: cardiorespiratory 1.4 (0.2-3.7), hematologic 1.9 (1.2-2.7), plasma inflammatory 19.5 (1.4-176) and plasma organ damage 2.9 (1.1-8.6). Treatment with C1-INH had only a marginal effect on the IRI-induced changes, reaching statistical significance only for the plasma complement activation product TCC (p=0.0083) and IL-4 (p=0.022) and INF-α (p=0.016) in the colon tissue. In conclusion, the present novel model of porcine global IRI is forceful with regards to central markers and could generally be applicable for pathophysiological studies. C1-INH treatment had no significant effect, but the model allows for future testing of other drugs attenuating IRI globally.

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Section: Discussionmentioning

confidence: 51%

A Novel Porcine Model of Ischemia-Reperfusion Injury After Cross-Clamping the Thoracic Aorta Revealed Substantial Cardiopulmonary, Thromboinflammatory and Biochemical Changes Without Effect of C1-Inhibitor Treatment

et al. 2022

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“…Recently, a number of studies confirmed the neuroprotection role of C1-INH that supports our results. For example, Mercurio et al indicated that recombinant human C1-INH exhibited stronger neuroprotective effects than the corresponding plasma-derived protein after experimental ischemia/reperfusion injury in the brain [ 44 ]. Earlier studies found that C1-INH was produced in normal brain, whereas in Alzheimer disease (AD), C1-INH was significantly responsive to abnormal neuronal processes, such as dystrophic neurites and neuropil threads [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

A large-scale polygenic risk score analysis identified candidate proteins associated with anxiety, depression and neuroticism

et al. 2022

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Psychiatric disorders and neuroticism are closely associated with central nervous system, whose proper functioning depends on efficient protein renewal. This study aims to systematically analyze the association between anxiety / depression / neuroticism and each of the 439 proteins. 47,536 pQTLs of 439 proteins in brain, plasma and cerebrospinal fluid (CSF) were collected from recent genome-wide association study. Polygenic risk scores (PRS) of the 439 proteins were then calculated using the UK Biobank cohort, including 120,729 subjects of neuroticism, 255,354 subjects of anxiety and 316,513 subjects of depression. Pearson correlation analyses were performed to evaluate the correlation between each protein and each of the mental traits by using calculated PRSs as the instrumental variables of protein. In general population, six correlations were identified in plasma and CSF such as plasma protease C1 inhibitor (C1-INH) with neuroticism score (r = − 0.011, P = 2.56 × 10− 9) in plasma, C1-INH with neuroticism score (r = -0.010, P = 3.09 × 10− 8) in CSF, and ERBB1 with self-reported depression (r = − 0.012, P = 4.65 × 10− 5) in CSF. C1-INH and ERBB1 may induce neuroticism and depression by affecting brain function and synaptic development. Gender subgroup analyses found that BST1 was correlated with neuroticism score in male CSF (r = − 0.011, P = 1.80 × 10− 5), while CNTN2 was correlated with depression score in female brain (r = − 0.013, P = 6.43 × 10− 4). BST1 and CNTN2 may be involved in nervous system metabolism and brain health. Six common candidate proteins were associated with all three traits (P < 0.05) and were confirmed in relevant proteomic studies, such as C1-INH in plasma, CNTN2 and MSP in the brain. Our results provide novel clues for revealing the roles of proteins in the development of anxiety, depression and neuroticism.

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“…Namely, during the intra-ischemic period, we applied a clinical assessment score as described previously by centre IRFMN. 17 These inclusion criteria do not require specific tools to be applied and therefore could be easy to implement in a multicentric trial. Animals were judged ischemic, and included in the trial if presenting !3 of the following deficits during the intra-ischemic period:…”

Section: Inclusion and Exclusion Criteriamentioning

confidence: 99%

Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke

Valente

Mariani

Seminara

et al. 2023

J Cereb Blood Flow Metab

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Multicentre preclinical randomized controlled trials (pRCTs) are a valuable tool to improve experimental stroke research, but are challenging and therefore underused. A common challenge regards the standardization of procedures across centres. We here present the harmonization phase for the quantification of sensorimotor deficits by composite neuroscore, which was the primary outcome of two multicentre pRCTs assessing remote ischemic conditioning in rodent models of ischemic stroke. Ischemic stroke was induced by middle cerebral artery occlusion for 30, 45 or 60 min in mice and 50, 75 or 100 min in rats, allowing sufficient variability. Eleven animals per species were video recorded during neurobehavioural tasks and evaluated with neuroscore by eight independent raters, remotely and blindly. We aimed at reaching an intraclass correlation coefficient (ICC) ≥0.60 as satisfactory interrater agreement. After a first remote training we obtained ICC = 0.50 for mice and ICC = 0.49 for rats. Errors were identified in animal handling and test execution. After a second remote training, we reached the target interrater agreement for mice (ICC = 0.64) and rats (ICC = 0.69). In conclusion, a multi-step, online harmonization phase proved to be feasible, easy to implement and highly effective to align each centre’s behavioral evaluations before project’s interventional phase.

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Plasma-derived and recombinant C1 esterase inhibitor: Binding profiles and neuroprotective properties in brain ischemia/reperfusion injury

Cited by 12 publications

References 41 publications

A Novel Porcine Model of Ischemia-Reperfusion Injury After Cross-Clamping the Thoracic Aorta Revealed Substantial Cardiopulmonary, Thromboinflammatory and Biochemical Changes Without Effect of C1-Inhibitor Treatment

A Novel Porcine Model of Ischemia-Reperfusion Injury After Cross-Clamping the Thoracic Aorta Revealed Substantial Cardiopulmonary, Thromboinflammatory and Biochemical Changes Without Effect of C1-Inhibitor Treatment

A large-scale polygenic risk score analysis identified candidate proteins associated with anxiety, depression and neuroticism

Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke

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