The powerful neuroprotective action of C1-inhibitor on brain ischemia-reperfusion injury does not require C1q.
C1-inhibitor (C1-INH) is a major regulator of the complement classical pathway. Besides this action, it may also inhibit other related inflammatory systems. We have studied the effect of C1-INH in C57BL/6 mice with focal transient brain ischemia induced by 30 minutes of occlusion of the middle cerebral artery. C1-INH induced a dose-dependent reduction of ischemic volume that, with the dose of 15 U/mouse, reached 10.8% of the volume of saline-treated mice. Four days after ischemia the treated mice had significantly lower general and focal neurological deficit scores. Fluoro-Jade staining, a marker for neuronal degeneration, showed that C1-INH-treated mice had a lower number of degenerating cells. Leukocyte infiltration, as assessed by CD45 immunostaining, was also markedly decreased. We then investigated the response to ischemia in C1q(-/-) mice. There was a slight, nonsignificant decrease in infarct volume in C1q(-/-) mice (reduction to 72.3%) compared to wild types. Administration of C1-INH to these mice was still able to reduce the ischemic volume to 31.4%. The study shows that C1-INH has a strong neuroprotective effect on brain ischemia/reperfusion injury and that its action is independent from C1q-mediated activation of classical pathway.
De Simoni
Maria Grazia
MG
Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute for Pharmacological Research, Milan, Italy. desimoni@marionegri.it
Rossi
Emanuela
E
Storini
Claudio
C
Pizzimenti
Simone
S
Echart
Cinara
C
Bergamaschini
Luigi
L
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology; D003174:Complement C1 Inactivator Proteins / Q000494:pharmacology*; D015922:Complement C1q; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D005456:Fluorescent Dyes / Q000494:pharmacology; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009930:Organic Chemicals; D010477:Perfusion; D010641:Phenotype; D015427:Reperfusion Injury; D013997:Time Factors
D003174:Complement C1 Inactivator Proteins; D005452:Fluoresceins; D005456:Fluorescent Dyes; D009930:Organic Chemicals; C435731:fluoro jade; D015922:Complement C1q; D017493:Leukocyte Common Antigens