title: The Neuroprotective Effect of Genetic Mannose-binding Lectin Deficiency is not Sustained in the Sub-acute Phase of Stroke.
abstract: BACKGROUND
  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 sub-acute phase would serve to abrogate this neuroprotective effect.
  
  
  METHODS
  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(MCAO) were then employed to investigate the histologic injury and functional outcome associated with genetic MBL deletion at both 24 hours and 7 days.
  
  
  RESULTS
  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 sub-acute accumulation of mononuclear cells in the ischemic region. Although MBL-KO mice demonstrate significantly improved outcome at 24 hours, the neuroprotective effect associated with genetic MBL deletion is not sustained.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurological Surgery, Columbia University, New York, NY.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ducruet
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: Brad E
authors.initials: BE
authors.lastname: Zacharia
authors.forename: Justin
authors.initials: J
authors.lastname: Gorski
authors.forename: Mason L
authors.initials: ML
authors.lastname: Yeh
authors.forename: Peter
authors.initials: P
authors.lastname: Derosa
authors.forename: Gregory
authors.initials: G
authors.lastname: Cohen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gigante
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly