Pharmacological inhibition of mannose-binding lectin ameliorates neurobehavioral dysfunction following experimental traumatic brain injury

J Cereb Blood Flow Metab. 2017 Mar;37(3):938-950. doi: 10.1177/0271678X16647397. Epub 2016 Jul 20.

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.

Keywords: Inflammation; behavior (rodent); brain recovery; brain trauma; mannose-binding lectin inhibitor; neuroregeneration.

MeSH terms

  • Animals
  • Brain Injuries, Traumatic / drug therapy*
  • Dendrimers / administration & dosage
  • Dendrimers / therapeutic use*
  • Disease Models, Animal
  • Glycosides / administration & dosage
  • Glycosides / therapeutic use*
  • Ligands
  • Male
  • Mannose / metabolism
  • Mannose-Binding Lectin / antagonists & inhibitors*
  • Mannose-Binding Lectin / genetics
  • Mice
  • Mice, Knockout
  • Neurogenesis / drug effects
  • Protein Binding / drug effects
  • Recovery of Function / drug effects
  • Sensorimotor Cortex / drug effects

Substances

  • Dendrimers
  • Glycosides
  • Ligands
  • Mannose-Binding Lectin
  • Mbl2 protein, mouse
  • glycodendrimer 13.3
  • Mannose