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 15 U/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.

Mercurio, D., Piotti, A., Valente, A., Oggioni, M., Ponstein, Y., Van Amersfoort, E., et al. (2021). Plasma-derived and recombinant C1 esterase inhibitor: Binding profiles and neuroprotective properties in brain ischemia/reperfusion injury. BRAIN BEHAVIOR AND IMMUNITY, 93(March 2021), 299-311 [10.1016/j.bbi.2021.01.002].

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

Valente A.;
2021

Abstract

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 15 U/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.
Articolo in rivista - Articolo scientifico
C1 inhibitor; Complement system; Mannose-binding lectin; Stroke;
English
11-gen-2021
2021
93
March 2021
299
311
open
Mercurio, D., Piotti, A., Valente, A., Oggioni, M., Ponstein, Y., Van Amersfoort, E., et al. (2021). Plasma-derived and recombinant C1 esterase inhibitor: Binding profiles and neuroprotective properties in brain ischemia/reperfusion injury. BRAIN BEHAVIOR AND IMMUNITY, 93(March 2021), 299-311 [10.1016/j.bbi.2021.01.002].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/325006
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