Vascular adhesion protein-1 inhibition provides antiinflammatory protection after an intracerebral hemorrhagic stroke in mice

J Cereb Blood Flow Metab. 2011 Mar;31(3):881-93. doi: 10.1038/jcbfm.2010.167. Epub 2010 Sep 29.

Abstract

The systemic immune response has a vital role in propagating the damage of an intracerebral hemorrhage (ICH). Vascular adhesion protein-1 (VAP-1), a semicarbazide (SCZ)-sensitive-amine-oxidase, was found in previous studies to have a role in migration of immune cells. In this study, we hypothesize that VAP-1 inhibition may decrease brain injury by attenuating the transmigration of immune cells to the injury site, and by doing so, reduce cerebral edema and improve neurobehavioral function in mice. Two VAP-1 inhibitors, LJP1586 and SCZ were given 1 hour after ICH induction by either collagenase or autologous blood injection. The VAP-1 siRNA, a VAP-1 gene silencer, and human recombinant AOC3 protein, a VAP-1 analogue, were delivered by intracerebroventricular injection. Postassessment included neurobehavioral testing, brain edema measurement, quantification of neutrophil infiltration and microglia/macrophage activation, and measurement of intercellular adhesion molecule-1 (ICAM-1), P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) expression 24 hours after ICH. We found that LJP1586 and SCZ reduced brain edema and neurobehavioral deficits 24 hours after ICH induction. These two drugs were also found to decrease levels of ICAM-1, MCP-1, TNF-α, and inhibit neutrophilic infiltration and microglia/macrophage activation. We conclude that VAP-1 inhibition provided antiinflammation effect by reducing adhesion molecule expression and immune cell infiltration after ICH.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allylamine / administration & dosage
  • Allylamine / analogs & derivatives*
  • Allylamine / antagonists & inhibitors
  • Amine Oxidase (Copper-Containing) / administration & dosage
  • Amine Oxidase (Copper-Containing) / antagonists & inhibitors*
  • Amine Oxidase (Copper-Containing) / genetics
  • Animals
  • Behavior, Animal / drug effects
  • Brain Edema / pathology
  • Cell Adhesion Molecules / administration & dosage
  • Cell Adhesion Molecules / antagonists & inhibitors*
  • Cell Adhesion Molecules / genetics
  • Chemokine CCL2 / metabolism
  • Down-Regulation
  • Gene Silencing
  • Humans
  • Inflammation / etiology*
  • Inflammation / prevention & control*
  • Injections, Intraperitoneal
  • Injections, Intraventricular
  • Intercellular Adhesion Molecule-1 / metabolism
  • Intracranial Hemorrhages / complications*
  • Intracranial Hemorrhages / pathology
  • Intracranial Hemorrhages / physiopathology
  • Intracranial Hemorrhages / psychology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Nervous System / drug effects
  • Nervous System / physiopathology
  • Neutrophil Infiltration / drug effects
  • RNA, Small Interfering / administration & dosage
  • Recombinant Proteins / administration & dosage
  • Semicarbazides / administration & dosage
  • Stroke / complications*
  • Stroke / etiology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 3-fluoro-2-(4-methoxybenzyl)allylamine
  • Cell Adhesion Molecules
  • Chemokine CCL2
  • RNA, Small Interfering
  • Recombinant Proteins
  • Semicarbazides
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • carbamylhydrazine
  • Allylamine
  • AOC3 protein, human
  • Amine Oxidase (Copper-Containing)
  • semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse