Post-ischemic vascular adhesion protein-1 inhibition provides neuroprotection in a rat temporary middle cerebral artery occlusion model

J Neurochem. 2012 Nov;123 Suppl 2(Suppl 2):116-24. doi: 10.1111/j.1471-4159.2012.07950.x.

Abstract

We examined the neuroprotective efficacy associated with post-ischemic vascular adhesion protein-1 (VAP-1) blockade in rats subjected to transient (1 h) middle cerebral artery occlusion (MCAo). We compared saline-treated control rats to rats treated with a highly selective VAP-1 inhibitor, LJP-1586 [Z-3-fluoro-2-(4-methoxybenzyl) allylamine hydrochloride]. Initial intraperitoneal LJP-1586 (or saline control) treatments were delayed until 6 h or 12 h reperfusion. At 72-h reperfusion, LJP-1586-treated rats displayed 51% and 33% smaller infarct volumes, relative to their controls, in the 6- and 12-h treatment groups, respectively. However, only in the 6-h treatment group was the infarct volume reduction significant (p < 0.05). On the other hand, we observed significantly improved neurologic functions in both 6- and 12-h treatment groups, versus their matched controls (p < 0.05). Also, the effect of 6-h LJP-1586 treatment on post-ischemic leukocyte trafficking in pial venules overlying the ischemic cortex was evaluated using intravital microscopy. These experiments revealed that: 1) LJP-1586 did not affect intravascular leukocyte (largely neutrophil) adhesion, at least out to 12-h reperfusion; and 2) the onset of neutrophil extravasation, which occurred between 6-8-h reperfusion in control rats, was prevented by LJP-1586-treatment. In conclusion, in rats subjected to transient MCAo, selective VAP-1 pharmacologic blockade provided neuroprotection, with a prolonged therapeutic window of 6-12-h reperfusion.

Publication types

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

MeSH terms

  • Allylamine / administration & dosage
  • Allylamine / analogs & derivatives*
  • Amine Oxidase (Copper-Containing) / antagonists & inhibitors
  • Amine Oxidase (Copper-Containing) / metabolism*
  • Animals
  • Brain Infarction / etiology*
  • Brain Infarction / prevention & control*
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / metabolism*
  • Cell Movement / drug effects
  • Cerebrovascular Circulation / drug effects
  • Disease Models, Animal
  • Infarction, Middle Cerebral Artery / complications*
  • Laser-Doppler Flowmetry
  • Leukocytes / drug effects
  • Leukocytes / physiology
  • Male
  • Microscopy, Confocal
  • Nervous System Diseases / etiology
  • Nervous System Diseases / prevention & control
  • Neuroprotective Agents / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Statistics, Nonparametric

Substances

  • 3-fluoro-2-(4-methoxybenzyl)allylamine
  • Cell Adhesion Molecules
  • Neuroprotective Agents
  • Allylamine
  • Amine Oxidase (Copper-Containing)
  • vascular adhesion protein-1, rat