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

AbstractWe 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.