Annals of Neurology
Volume 9999 Issue 999A, Page NA
Published Online: 11 May 2009
Received: 12 November 2008; Revised: 9 April 2009; Accepted: 17 April 2009
Abstract
Objective.
C1-inhibitor(C1-INH) is an endogenous inhibitor of complement and kinin systems. We have explored the efficacy and the therapeutic window of the recently available recombinant human (rh)C1-INH on ischemic brain injury and investigated its mechanism of action in comparison with that of plasma-derived (pd)C1-INH.
Methods.
rhC1-INH was administered intravenously to C57Bl/6 mice undergoing transient or permanent ischemia and its protective effects were evaluated by measuring infarct volume and neurodegeneration. The binding profiles of rhC1-INH and pdC1-INH were assessed in vitro using surface plasmon resonance. Their localization in the ischemic brain tissue was determined by immunohistochemistry and confocal analysis. The functional consequences of rhC1-INH and pdC1-INH administration on complement activation were analysed by ELISA on plasma samples.
Results.
rhC1-INH markedly reduced cerebral damage when administered up to 18h after transient ischemia and up to 6h after permanent ischemia, thus showing a surprisingly wide therapeutic window. In vitro rhC1-INH bound mannose binding lectin (MBL), a key protein in the lectin complement pathway, with high affinity, whereas pdC1-INH, which has a different glycosylation pattern, did not. In the ischemic brain rhC1-INH was confined to cerebral vessels where it colocalized with MBL, while pdC1-INH diffused into the brain parenchyma. In addition rhC1-INH was more active than pdC1-INH in inhibiting MBL-induced complement activation.
Interpretation.
rhC1-INH showed a surprisingly wider time-window of efficacy compared to the corresponding plasmatic protein. We propose that the superiority of rhC1-INH is due to its selective binding to MBL, which emerged as a novel target for stroke treatment. Ann Neurol 2009.