Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia

Franca Orsini, Pia Villa, Sara Parrella, Rosalia Zangari, Elisa R. Zanier, Raffaella Gesuete, Matteo Stravalaci, Stefano Fumagalli, Roberta Ottria, José J. Reina, Alessandra Paladini, Edoardo Micotti, Renato Ribeiro-Viana, Javier Rojo, Vasile I. Pavlov, Gregory L. Stahl, Anna Bernardi, Marco Gobbi, Maria Grazia De Simoni

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Backround-: 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.

Original languageEnglish
Pages (from-to)1484-1494
Number of pages11
JournalCirculation
Volume126
Issue number12
DOIs
Publication statusPublished - Sep 18 2012

Fingerprint

Mannose-Binding Lectin
Brain Ischemia
Brain Injuries
Therapeutics
Mannose-Binding Lectin Complement Pathway
Ischemia
Middle Cerebral Artery Infarction
Wounds and Injuries
Serine Proteases

Keywords

  • cerebral ischemia
  • complement system
  • endothelium
  • inflammation
  • stroke

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia. / Orsini, Franca; Villa, Pia; Parrella, Sara; Zangari, Rosalia; Zanier, Elisa R.; Gesuete, Raffaella; Stravalaci, Matteo; Fumagalli, Stefano; Ottria, Roberta; Reina, José J.; Paladini, Alessandra; Micotti, Edoardo; Ribeiro-Viana, Renato; Rojo, Javier; Pavlov, Vasile I.; Stahl, Gregory L.; Bernardi, Anna; Gobbi, Marco; De Simoni, Maria Grazia.

In: Circulation, Vol. 126, No. 12, 18.09.2012, p. 1484-1494.

Research output: Contribution to journalArticle

Orsini, F, Villa, P, Parrella, S, Zangari, R, Zanier, ER, Gesuete, R, Stravalaci, M, Fumagalli, S, Ottria, R, Reina, JJ, Paladini, A, Micotti, E, Ribeiro-Viana, R, Rojo, J, Pavlov, VI, Stahl, GL, Bernardi, A, Gobbi, M & De Simoni, MG 2012, 'Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia', Circulation, vol. 126, no. 12, pp. 1484-1494. https://doi.org/10.1161/CIRCULATIONAHA.112.103051
Orsini, Franca ; Villa, Pia ; Parrella, Sara ; Zangari, Rosalia ; Zanier, Elisa R. ; Gesuete, Raffaella ; Stravalaci, Matteo ; Fumagalli, Stefano ; Ottria, Roberta ; Reina, José J. ; Paladini, Alessandra ; Micotti, Edoardo ; Ribeiro-Viana, Renato ; Rojo, Javier ; Pavlov, Vasile I. ; Stahl, Gregory L. ; Bernardi, Anna ; Gobbi, Marco ; De Simoni, Maria Grazia. / Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia. In: Circulation. 2012 ; Vol. 126, No. 12. pp. 1484-1494.
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AU - Zanier, Elisa R.

AU - Gesuete, Raffaella

AU - Stravalaci, Matteo

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AU - Micotti, Edoardo

AU - Ribeiro-Viana, Renato

AU - Rojo, Javier

AU - Pavlov, Vasile I.

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AU - Gobbi, Marco

AU - De Simoni, Maria Grazia

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N2 - Backround-: 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.

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