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Tytuł pozycji:

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

Tytuł :
Plasma-derived and recombinant C1 esterase inhibitor: Binding profiles and neuroprotective properties in brain ischemia/reperfusion injury.
Autorzy :
Mercurio D; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Neuroscience, Milan, Italy.
Piotti A; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Biochemistry and Molecular Pharmacology, Milan, Italy.
Valente A; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Neuroscience, Milan, Italy.
Oggioni M; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Neuroscience, Milan, Italy.
Ponstein Y; Pharming Technologies B.V., Leiden, The Netherlands.
Van Amersfoort E; Pharming Technologies B.V., Leiden, The Netherlands.
Gobbi M; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Biochemistry and Molecular Pharmacology, Milan, Italy.
Fumagalli S; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Neuroscience, Milan, Italy. Electronic address: .
De Simoni MG; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Neuroscience, Milan, Italy.
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Źródło :
Brain, behavior, and immunity [Brain Behav Immun] 2021 Mar; Vol. 93, pp. 299-311. Date of Electronic Publication: 2021 Jan 11.
Typ publikacji :
Journal Article
Język :
English
Imprint Name(s) :
Publication: <2000- > : Amsterdam : Elsevier
Original Publication: San Diego : Academic Press, [c1987-
Contributed Indexing :
Keywords: C1 inhibitor; Complement system; Mannose-binding lectin; Stroke
Entry Date(s) :
Date Created: 20210114 Latest Revision: 20210319
Update Code :
20210319
DOI :
10.1016/j.bbi.2021.01.002
PMID :
33444732
Czasopismo naukowe
C1 esterase inhibitor (C1INH) is known to exert its inhibitory effect by binding to several target proteases of the contact and complement systems. One of C1INH's targets comprise mannose-binding lectin (MBL), a critical player in post-stroke pathophysiology. We therefore explored the effects of recombinant human (rh) and plasma derived (pd) C1INH in C57BL/6J mice subjected to transient occlusion of the middle cerebral artery (tMCAo), receiving 15U/mouse of pd or rhC1INH intravenously, at reperfusion. We analyzed the compounds' (i)neuroprotective effects, (ii) plasma presence, (iii)effects on circulating and brain MBL, (iv)time course of endothelial deposition, and (v) effects on the formation of active complement products. rhC1INH-treated mice had neuroprotective effects, including reduced behavioral deficits and neuronal loss, associated with decreased MBL brain deposition and decreased formation of complement C4b active fragments. In contrast, pdC1INH did not show these neuroprotective effects despite its longer plasma residence time. We also analyzed the response to tMCAo in C1INH-deficient mice, observing a poorer ischemic outcome compared to the wild type mice, which could be partially prevented by rhC1INH administration. In conclusion, we show that rhC1INH exhibits stronger neuroprotective effects than the corresponding plasma-derived protein after experimental ischemia/reperfusion injury in the brain, placing it as a promising drug for stroke. Differential effects are likely related to more effective MBL inhibition which further confirms it as a useful pharmacological target for stroke.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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