ABSTRACT
Title
Mannose binding lectin, a new target for stroke therapy
Authors
F. Orsini1, P. Villa1,4, S. Parrella1, E. R. Zanier1, M. Stravalaci1, R. Ottria2, J. Reina2, A. Bernardi2, M. Gobbi1 and M. G. De Simoni1
1Dept. Neuroscience, Mario Negri Inst.; 2Dept. Molecular Biochemistry and Pharmacology, Mario Negri Inst.; 3Dept Organic and Industrial Chemistry,University of Milan; 4CNR, Inst. Neuroscience, Milan, Italy.
1Dept. Neuroscience, Mario Negri Inst.; 2Dept. Molecular Biochemistry and Pharmacology, Mario Negri Inst.; 3Dept Organic and Industrial Chemistry,University of Milan; 4CNR, Inst. Neuroscience, Milan, Italy.
Abstract
Methods. The activation of lectin pathway after ischemia was analyzed by measuring circulating functional MBL/MASP-2 complexes by ELISA. MBL-A/MBL-C presence on cerebral vessels was assessed by immunostaining and confocal microscopy. Transient (mice) or permanent (mice and rats) focal ischemia was induced in C57Bl/6 (WT) or MBL-/- mice or in SD rats and neurological deficits and infarct volumes were evaluated 48h later. The affinity of mannosilated molecules to MBL were measured by surface plasmon resonance (SPR). The molecule showing the highest affinity to MBL was administered intravenously to ischemic mice.
Results.Cerebral ischemia led to a significant increase in the number of functional MBL/MASP-2 complexes and induced the deposition of both MBL-A and MBL-C on cerebral endothelial wall. MBL-/- mice showed a significantly lower susceptibility to transient and permanent ischemia (reduction of ischemic volume 28% and 41%, respectively compared to WT). Anti-MBL antibody was able toinduce a significant reduction of neurological deficits and ischemic volumewhen given to rats up to 18h after injury. Similarly, Polyman2, a dendrimeric molecule exposing multiple copies of synthetic mannoside and binding MBL with aKD=2.3±0.7μM, induced a significant protection from ischemic injury with a wide therapeutic window.
Conclusions. The lectin pathway is activated by ischemic injury. The resultsobtained in MBL-/- mice, in rats treated with anti-MBL antibody and in WT mice treated with a MBL-binding molecule indicate that the inhibition of this protein leads to neuroprotection with a wide therapeutic window. Our findings indicate that MBL inhibition represents a novel therapeutic target for stroke.
1) Gesuete R, Storini C, Fantin A, Stravalaci M, Zanier ER, Orsini F, Vietsch H, Mannesse ML, Ziere B, Gobbi M, De Simoni MG. RECOMBINANT C1-INHIBITOR IN BRAIN ISCHEMIC INJURY. Ann Neurol. 2009 Sep;66(3):332-42.
Results.Cerebral ischemia led to a significant increase in the number of functional MBL/MASP-2 complexes and induced the deposition of both MBL-A and MBL-C on cerebral endothelial wall. MBL-/- mice showed a significantly lower susceptibility to transient and permanent ischemia (reduction of ischemic volume 28% and 41%, respectively compared to WT). Anti-MBL antibody was able toinduce a significant reduction of neurological deficits and ischemic volumewhen given to rats up to 18h after injury. Similarly, Polyman2, a dendrimeric molecule exposing multiple copies of synthetic mannoside and binding MBL with aKD=2.3±0.7μM, induced a significant protection from ischemic injury with a wide therapeutic window.
Conclusions. The lectin pathway is activated by ischemic injury. The resultsobtained in MBL-/- mice, in rats treated with anti-MBL antibody and in WT mice treated with a MBL-binding molecule indicate that the inhibition of this protein leads to neuroprotection with a wide therapeutic window. Our findings indicate that MBL inhibition represents a novel therapeutic target for stroke.
1) Gesuete R, Storini C, Fantin A, Stravalaci M, Zanier ER, Orsini F, Vietsch H, Mannesse ML, Ziere B, Gobbi M, De Simoni MG. RECOMBINANT C1-INHIBITOR IN BRAIN ISCHEMIC INJURY. Ann Neurol. 2009 Sep;66(3):332-42.