title: Pharmacologic blockade of vascular adhesion protein-1 lessens neurologic dysfunction in rats subjected to subarachnoid hemorrhage.
abstract: Aneurysmal subarachnoid hemorrhage (SAH) is a potentially devastating clinical problem. Despite advances in the diagnosis and treatment of SAH, outcome remains unfavorable. An increased inflammatory state, one that is characterized by enhanced leukocyte trafficking has been reported to contribute to neuronal injury in association with multiple brain insults, including hemorrhagic and ischemic stroke. This study was designed to investigate, in rats, the neuropathologic consequences of heightened leukocyte trafficking following SAH, induced via endovascular perforation of the anterior cerebral artery. Experiments focused on the initial 48 h post-SAH and sought to establish whether blockade of vascular adhesion protein-1 (VAP-1), with LJP-1586, was able to provide dose-dependent neuroprotection. Treatment with LJP-1586 was initiated at 6h post-SAH. An intravital microscopy and closed cranial window system, that permitted examination of temporal patterns of rhodamine-6G-labeled leukocyte adhesion/extravasation, was used. Effects of LJP-1586 on neurologic outcomes and leukocyte trafficking at 24 h and 48 h post-SAH were examined. In VAP-1-inhibited vs control rats, results revealed a significant attenuation in leukocyte trafficking at both 24 h and 48 h after SAH, along with an improvement in neurologic outcome. In conclusion, our findings support the involvement of an amplified inflammatory state, characterized by enhanced leukocyte trafficking, during the first 48 h after SAH. VAP-1 blockade yielded neuroprotection that was associated with an attenuation of leukocyte trafficking and improved neurologic outcome.
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W. Taylor Street, M/C 515, Chicago, IL 60612, USA.
authors.forename: Hao-Liang
authors.initials: HL
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W. Taylor Street, M/C 515, Chicago, IL 60612, USA.
authors.forename: Maggie
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Department of Neurology and Rehabilitation, University of Illinois at Chicago, 912 S Wood Street, Chicago, IL 60612-7330, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Testai
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W. Taylor Street, M/C 515, Chicago, IL 60612, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetri
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W. Taylor Street, M/C 515, Chicago, IL 60612, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Barabanova
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W. Taylor Street, M/C 515, Chicago, IL 60612, USA.
authors.forename: Dale A
authors.initials: DA
authors.lastname: Pelligrino
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, 1740 W. Taylor Street, M/C 515, Chicago, IL 60612, USA. Electronic address: oon@uic.edu.
authors.forename: Chanannait
authors.initials: C
authors.lastname: Paisansathan
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000473:pathology; D013997:Time Factors
chemical_list: C526615:3-fluoro-2-(4-methoxybenzyl)allylamine; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D000499:Allylamine; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat
keywords: Hemorrhagic stroke; Leukocyte trafficking; Neuroinflammation; Rhodamine-6G; Subarachnoid hemorrhage