The Neuroprotective Effect of Genetic Mannose-Binding Lectin Deficiency Is Not Sustained in the Subacute Phase of Stroke

Andrew F. Ducruet, Sergey A. Sosunov, Brad E. Zacharia, Justin Gorski, Mason L. Yeh, Peter DeRosa, Gregory Cohen, Paul R. Gigante, E. Sander Connolly

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

The complement cascade is a critical mediator of the inflammatory response following cerebral ischemia. Recent work has demonstrated that genetic deficiency of mannose-binding lectin (MBL) ameliorates reperfusion injury and improves outcome in the acute phase of stroke. The present study sought to further delineate the pathogenic role of MBL in stroke and to examine whether the neuroprotection associated with MBL deficiency is sustained beyond the acute phase. We hypothesized that genetic MBL deficiency would suppress complement activation and ameliorate reperfusion injury in the acute phase, but that persistent inhibition of complement into the subacute phase would serve to abrogate this neuroprotective effect. The time course and localization of post-ischemic cerebral MBL and C3 deposition were characterized using both Western blot and immunohistochemistry. MBL-a/c null (MBL-KO) mice subjected to transient middle cerebral artery occlusion were then employed to investigate the histologic injury and functional outcome associated with genetic MBL deletion at both 24 h and 7 days. MBL-a/c rapidly deposit on ischemic endothelium and trigger downstream complement activation in the acute phase. Genetic deficiency of MBL abrogates C3 cleavage as well as the subacute accumulation of mononuclear cells in the ischemic region. Although MBL-KO mice demonstrate significantly improved outcome at 24 h, the neuroprotective effect associated with genetic MBL deletion is not sustained. Development of a successful anti-complement neuroprotective strategy will require carefully tailored inhibition coupled with a greater understanding of the functional effects of complement activation during later phases of stroke recovery.

Original languageEnglish (US)
Pages (from-to)588-599
Number of pages12
JournalTranslational Stroke Research
Volume2
Issue number4
DOIs
StatePublished - Dec 2011

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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