The Neuroprotective Effect of Genetic Mannose-binding Lectin Deficiency is not Sustained in the Sub-acute Phase of Stroke

Document Type

Article

Abstract

INTRODUCTION: 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.

Publication Date

12-1-2011

Publication Title

Translational stroke research

ISSN

1868-4483

Volume

2

Issue

4

First Page

588

Last Page

99

PubMed ID

22505955

Digital Object Identifier (DOI)

10.1007/s12975-011-0104-2

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