Vascular adhesion protein-1 inhibition provides antiinflammatory protection after an intracerebral hemorrhagic stroke in mice.
The systemic immune response has a vital role in propagating the damage of an intracerebral hemorrhage (ICH). Vascular adhesion protein-1 (VAP-1), a semicarbazide (SCZ)-sensitive-amine-oxidase, was found in previous studies to have a role in migration of immune cells. In this study, we hypothesize that VAP-1 inhibition may decrease brain injury by attenuating the transmigration of immune cells to the injury site, and by doing so, reduce cerebral edema and improve neurobehavioral function in mice. Two VAP-1 inhibitors, LJP1586 and SCZ were given 1 hour after ICH induction by either collagenase or autologous blood injection. The VAP-1 siRNA, a VAP-1 gene silencer, and human recombinant AOC3 protein, a VAP-1 analogue, were delivered by intracerebroventricular injection. Postassessment included neurobehavioral testing, brain edema measurement, quantification of neutrophil infiltration and microglia/macrophage activation, and measurement of intercellular adhesion molecule-1 (ICAM-1), P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) expression 24 hours after ICH. We found that LJP1586 and SCZ reduced brain edema and neurobehavioral deficits 24 hours after ICH induction. These two drugs were also found to decrease levels of ICAM-1, MCP-1, TNF-α, and inhibit neutrophilic infiltration and microglia/macrophage activation. We conclude that VAP-1 inhibition provided antiinflammation effect by reducing adhesion molecule expression and immune cell infiltration after ICH.
Ma
Qingyi
Q
Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California 92354, USA.
Manaenko
Anatol
A
Khatibi
Nikan H
NH
Chen
Wanqiu
W
Zhang
John H
JH
Tang
Jiping
J
D000499:Allylamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D006631:Amine Oxidase (Copper-Containing) / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics; D018932:Chemokine CCL2 / Q000378:metabolism; D015536:Down-Regulation; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020300:Intracranial Hemorrhages / Q000150:complications* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009420:Nervous System / Q000187:drug effects / Q000503:physiopathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage; D012663:Semicarbazides / Q000008:administration & dosage; D020521:Stroke / Q000150:complications* / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C526615:3-fluoro-2-(4-methoxybenzyl)allylamine; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D012663:Semicarbazides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C010059:carbamylhydrazine; D000499:Allylamine; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse