Potential conflict of interest: Helene Vietsch, M. L. Maurice Mannesse, and Bertjan Ziere are employees of Pharming Technologies B.V.
Recombinant C1 inhibitor in brain ischemic injury†
Version of Record online: 11 MAY 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 66, Issue 3, pages 332–342, September 2009
How to Cite
Gesuete, R., Storini, C., Fantin, A., Stravalaci, M., Zanier, E. R., Orsini, F., Vietsch, H., Mannesse, M. L. M., Ziere, B., Gobbi, M. and De Simoni, M.-G. (2009), Recombinant C1 inhibitor in brain ischemic injury. Ann Neurol., 66: 332–342. doi: 10.1002/ana.21740
- Issue online: 1 OCT 2009
- Version of Record online: 11 MAY 2009
- Accepted manuscript online: 11 MAY 2009 12:00AM EST
- Manuscript Accepted: 17 APR 2009
- Manuscript Revised: 9 APR 2009
- Manuscript Received: 12 NOV 2008
- Pharming Technologies B.V.
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 human recombinant (rh) C1-INH on ischemic brain injury and investigated its mechanism of action in comparison with that of plasma-derived (pd) C1-INH.
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 analyzed by enzyme-linked immunosorbent assay on plasma samples.
rhC1-INH markedly reduced cerebral damage when administered up to 18 hours after transient ischemia and up to 6 hours 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, whereas pdC1-INH diffused into the brain parenchyma. In addition, rhC1-INH was more active than pdC1-INH in inhibiting MBL-induced complement activation.
rhC1-INH showed a surprisingly wider time window of efficacy compared with 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;66:332–342