C1-inhibitor protects against brain ischemia-reperfusion injury via inhibition of cell recruitment and inflammation.
Previous studies demonstrated that C1-inhibitor (C1-INH), a complement and contact-kinin systems inhibitor, is neuroprotective in cerebral ischemia. To investigate the mechanism of this action, we evaluated the expression of neurodegeneration and inflammation-related factors in mice subjected to 2-h ischemia and 2 or 46 h reperfusion. C1-INH significantly dampened the mRNA expression of the adhesion molecules P-selectin and ICAM-1 induced by the ischemic insult. It significantly decreased the pro-inflammatory cytokine (TNF alpha, IL-18) and increased the protective cytokine (IL-6, IL-10) gene expression. C1-INH treatment prevented the decrease of NFH gene, a marker of cellular integrity and counteracted the increase of pro-caspase 3, an apoptosis index. Furthermore, C1-INH markedly inhibited the activation and/or recruitment of microglia/macrophage, as shown by immunohistochemistry. In conclusion, C1-INH exerts an anti-inflammatory and anti-apoptotic action on ischemia-reperfusion injury. Our present and past data support a major effect of C1-INH on cell recruitment from the vasculature to the ischemic site.
Storini
Claudio
C
Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute, via Eritrea, 62, 20157 Milan, Italy.
Rossi
Emanuela
E
Marrella
Veronica
V
Distaso
Maria
M
Veerhuis
Robert
R
Vergani
Carlo
C
Bergamaschini
Luigi
L
De Simoni
Maria-Grazia
MG
D000818:Animals; D002545:Brain Ischemia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002464:Cell Migration Inhibition; D003174:Complement C1 Inactivator Proteins / Q000502:physiology / Q000627:therapeutic use*; D050718:Complement C1 Inhibitor Protein; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology; D018836:Inflammation Mediators / Q000502:physiology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
D015815:Cell Adhesion Molecules; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D016207:Cytokines; D018836:Inflammation Mediators; D018696:Neuroprotective Agents