Targeting Mannose-Binding Lectin Confers Long-Lasting Protection With a Surprisingly Wide Therapeutic Window in Cerebral IschemiaClinical Perspective

Targeting Mannose-Binding Lectin Confers Long-Lasting Protection With a Surprisingly Wide Therapeutic Window in Cerebral IschemiaClinical Perspective

• Original Article
  
  
  • Stroke
  
  
  
  

Targeting Mannose-Binding Lectin Confers Long-Lasting Protection With a Surprisingly Wide Therapeutic Window in Cerebral Ischemia

1. Franca Orsini, BD;


2. Pia Villa, BD;


3. Sara Parrella, BD;


4. Rosalia Zangari, BD;


5. Elisa R. Zanier, MD;


6. Raffaella Gesuete, PhD;


7. Matteo Stravalaci, BD;


8. Stefano Fumagalli, BD;


9. Roberta Ottria, PhD;


10. José J. Reina, PhD;


11. Alessandra Paladini, BD;


12. Edoardo Micotti, PhD;


13. Renato Ribeiro-Viana, BD;


14. Javier Rojo, PhD;


15. Vasile I. Pavlov, MD;


16. Gregory L. Stahl, PhD;


17. Anna Bernardi, PhD;


18. Marco Gobbi, PhD;


19. Maria-Grazia De Simoni, PhD

+ Author Affiliations

1. 
   From the Neuroscience Department (F.O., P.V., S.P., R.Z., E.R.Z., R.G., S.F., A.P., E.M., M.G.D.S.); Molecular Biochemistry and Pharmacology Department (M.S., M.G.), Mario Negri Institute, Milan; Department of Chemistry, University of Milan (R.O., J.J.R., A.B.); CNR Neuroscience Institute, Milan (P.V.); University of Siena, Siena, Italy (R.Z.); Instituto de Investigaciones Químicas (IIQ), CSIC - University of Seville, Seville, Spain (R.R.-V., J.R.); and Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA (V.I.P., G.L.S.); present address: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR (R.G.).
   
   

1. Correspondence to Maria-Grazia De Simoni, PhD, Head of the Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute, Via G. La Masa 19, 20156 Milano, Italy. E-mail desimoni@marionegri.it

Abstract

Background—The involvement of the complement system in brain injury has been scarcely investigated. Here, we document the pivotal role of mannose-binding lectin (MBL), one of the recognition molecules of the lectin complement pathway, in brain ischemic injury.

Methods and Results—Focal cerebral ischemia was induced in mice (by permanent or transient middle cerebral artery occlusion) and rats (by 3-vessel occlusion). We first observed that MBL is deposited on ischemic vessels up to 48 hours after injury and that functional MBL/MBL-associated serine protease 2 complexes are increased. Next, we demonstrated that (1) MBL^−/− mice are protected from both transient and permanent ischemic injury; (2) Polyman2, the newly synthesized mannosylated molecule selected for its binding to MBL, improves neurological deficits and infarct volume when given up to 24 hours after ischemia in mice; (3) anti-MBL-A antibody improves neurological deficits and infarct volume when given up to 18 hours after ischemia, as assessed after 28 days in rats.

Conclusions—Our data show an important role for MBL in the pathogenesis of brain ischemic injury and provide a strong support to the concept that MBL inhibition may be a relevant therapeutic target in humans, one with a wide therapeutic window of application.

Key Words:

• cerebral ischemia


• endothelium


• inflammation


• stroke


• complement system

• Received March 6, 2012.


• Accepted July 31, 2012.

• © 2012 American Heart Association, Inc.

Clinical Perspective