Post-ischemic vascular adhesion protein-1 inhibition provides neuroprotection in a rat temporary middle cerebral artery occlusion model.
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.
Neuroanesthesia Research Laboratory, University of Illinois, Chicago, Illinois, USA.
Jittiya
J
Watcharotayangul
Lizhen
L
Mao
Haoliang
H
Xu
Francesco
F
Vetri
Verna L
VL
Baughman
Chanannait
C
Paisansathan
Dale A
DA
Pelligrino
D000499:Allylamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D020520:Brain Infarction / Q000209:etiology* / Q000517:prevention & control*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D017078:Laser-Doppler Flowmetry; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D018613:Microscopy, Confocal; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018709:Statistics, Nonparametric
C526615:3-fluoro-2-(4-methoxybenzyl)allylamine; D015815:Cell Adhesion Molecules; D018696:Neuroprotective Agents; D000499:Allylamine; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat