title: VAP-1 blockade prevents subarachnoid hemorrhage-associated cerebrovascular dilating dysfunction via repression of a neutrophil recruitment-related mechanism.
abstract: Our previous findings indicated that in rats subjected to subarachnoid hemorrhage (SAH), suppression of post-SAH neuroinflammation via vascular adhesion protein-1 (VAP-1) blockade provides significant neuroprotection. We and others have reported that neuroinflammation contributes to cerebral microvascular impairment. Thus, in the present study, we tested the hypotheses that: (1) treatment with LJP-1586, a selective VAP-1 blocker, prevents SAH-associated pial arteriolar dilating dysfunction; and (2) the vasculoprotective effect of LJP-1586 arises from inhibiting SAH-elicited neutrophil recruitment. We utilized an endovascular perforation model of SAH. Rats subjected to SAH were either treated with LJP-1586 or rendered neutropenic via anti-neutrophil-antibody treatment. Findings from these groups were compared to their respective control groups. At 48 h post-SAH, rats were evaluated for neurobehavioral function, pial venular leukocyte trafficking, and pial arteriolar reactivity to topically-applied acetylcholine (ACh) and S-nitroso-N-acetyl penicillamine (SNAP). Pial arteriolar responses decreased at 48 h post-SAH. However, in the presence of LJP-1586, those responses were significantly preserved. Neutrophil-depletion yielded a substantial suppression of SAH-associated leukocyte adhesion and infiltration. This was accompanied by a significant preservation of pial arteriolar dilating function, suggesting a direct link between neutrophil recruitment and the loss of cerebral microvascular reactivity. Moreover, neutrophil depletion also was associated with significant protection of neurobehavioral function. The present findings suggest that attenuating SAH-linked elevation in neutrophil trafficking will protect against the development of microvascular dysfunction and subsequent neurological impairment.
authors: Neuroanesthesia Research Laboratory, Department of Anesthesiology, University of Illinois-Chicago, Chicago, IL, United States. Electronic address: hlxu@uic.edu.
authors: Haoliang
authors: H
authors: Xu
authors: Department of Neurology and Rehabilitation, University of Illinois-Chicago, Chicago, IL, United States.
authors: Fernando D
authors: FD
authors: Testai
authors: Department of Pathology, University of Illinois-Chicago, Chicago, IL, United States.
authors: Tibor
authors: T
authors: Valyi-Nagy
authors: Department of Psychiatry, University of Illinois-Chicago, Chicago, IL, United States.
authors: Mani
authors: M
authors: N Pavuluri
authors: Neuroanesthesia Research Laboratory, Department of Anesthesiology, University of Illinois-Chicago, Chicago, IL, United States.
authors: Fengguo
authors: F
authors: Zhai
authors: Neuroanesthesia Research Laboratory, Department of Anesthesiology, University of Illinois-Chicago, Chicago, IL, United States.
authors: Danop
authors: D
authors: Nanegrungsunk
authors: Neuroanesthesia Research Laboratory, Department of Anesthesiology, University of Illinois-Chicago, Chicago, IL, United States.
authors: Chanannait
authors: C
authors: Paisansathan
authors: Neuroanesthesia Research Laboratory, Department of Anesthesiology, University of Illinois-Chicago, Chicago, IL, United States.
authors: Dale A
authors: DA
authors: Pelligrino
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000499:Allylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004195:Disease Models, Animal; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D014699:Venules / Q000187:drug effects / Q000503:physiopathology
chemical_list: C526615:3-fluoro-2-(4-methoxybenzyl)allylamine; D002317:Cardiovascular Agents; D015815:Cell Adhesion Molecules; D018679:Cholinergic Agonists; D020030:Nitric Oxide Donors; D000499:Allylamine; D026423:S-Nitroso-N-Acetylpenicillamine; D006631:Amine Oxidase (Copper-Containing); C510433:vascular adhesion protein-1, rat; D000109:Acetylcholine
keywords: Cerebral vascular function; Leukocyte adhesion; Neuroinflammation; Neurological outcome; Stroke