title: Pharmacological inhibition of mannose-binding lectin ameliorates neurobehavioral dysfunction following experimental traumatic brain injury.
abstract: Mannose-binding lectin is present in the contusion area of traumatic brain-injured patients and in that of traumatic brain-injured mice, where mannose-binding lectin-C exceeds mannose-binding lectin-A. The reduced susceptibility to traumatic brain injury of mannose-binding lectin double knock-out mice (mannose-binding lectin-/-) when compared to wild type mice suggests that mannose-binding lectin may be a therapeutic target following traumatic brain injury. Here, we evaluated the effects of a multivalent glycomimetic mannose-binding lectin ligand, Polyman9, following traumatic brain injury in mice. In vitro surface plasmon resonance assay indicated that Polyman9 dose-dependently inhibits the binding to immobilized mannose residues of plasma mannose-binding lectin-C selectively over that of mannose-binding lectin-A. Male C57Bl/6 mice underwent sham/controlled cortical impact traumatic brain injury and intravenous treatment with Polyman9/saline. Ex-vivo surface plasmon resonance studies confirmed that Polyman9 effectively reduces the binding of plasma mannose-binding lectin-C to immobilized mannose residues. In vivo studies up to four weeks post injury, showed that Polyman9 induces significant improvement in sensorimotor deficits (by neuroscore and beam walk), promotes neurogenesis (73% increase in doublecortin immunoreactivity), and astrogliosis (28% increase in glial fibrillary acid protein). Polyman9 administration in brain-injured mannose-binding lectin-/-mice had no effect on post-traumatic brain-injured functional deficits, suggestive of the specificity of its neuroprotective effects. The neurobehavioral efficacy of Polyman9 implicates mannose-binding lectin-C as a novel therapeutic target for traumatic brain injury.
authors.affiliation: 1 IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.|2 Department of Anesthesia and Critical Care Medicine, Fondazione IRCCS Ca'Granda - Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Daiana
authors.initials: D
authors.lastname: De Blasio
authors.affiliation: 1 IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.|2 Department of Anesthesia and Critical Care Medicine, Fondazione IRCCS Ca'Granda - Ospedale Maggiore Policlinico, Milano, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fumagalli
authors.affiliation: 3 Department of Anesthesia and Critical Care Medicine, Neurosurgical Intensive Care Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Longhi
authors.affiliation: 1 IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Orsini
authors.affiliation: 4 Department of Chemistry, Università degli Studi di Milano, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Palmioli
authors.affiliation: 1 IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Stravalaci
authors.affiliation: 1 IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Vegliante
authors.affiliation: 1 IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Elisa R
authors.initials: ER
authors.lastname: Zanier
authors.affiliation: 4 Department of Chemistry, Università degli Studi di Milano, Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bernardi
authors.affiliation: 1 IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: 1 IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: De Simoni
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy*; D050091:Dendrimers / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006027:Glycosides / Q000008:administration & dosage / Q000627:therapeutic use*; D008024:Ligands; D008297:Male; D008358:Mannose / Q000378:metabolism; D037601:Mannose-Binding Lectin / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects; D066191:Sensorimotor Cortex / Q000187:drug effects
chemical_list: D050091:Dendrimers; D006027:Glycosides; D008024:Ligands; D037601:Mannose-Binding Lectin; C445639:Mbl2 protein, mouse; C000621955:glycodendrimer 13.3; D008358:Mannose
keywords: Inflammation; behavior (rodent); brain recovery; brain trauma; mannose-binding lectin inhibitor; neuroregeneration