Vascular Adhesion Protein-1 Plays an Important Role in Postischemic Inflammation and Neuropathology in Diabetic, Estrogen-Treated Ovariectomized Female Rats Subjected to Transient Forebrain Ischemia

Abstract

Endothelial vascular adhesion protein-1 (VAP-1) facilitates leukocyte adhesion and infiltration. This relates partly to the function of VAP-1 as a semicarbazide-sensitive amine oxidase (SSAO). We examined the effects of VAP-1/SSAO inhibition [via LJP-1207 (NЈ-(2-phenyl-allyl)-hydrazine hydrochloride)] on pial venular leukocyte adhesion and infiltration (at 2-10 h of reperfusion) and neuropathology (at 72 h of reperfusion) after transient forebrain ischemia (TFI). A model associated with increased postischemic inflammation was used-i.e., diabetic ovariectomized (OVX) female rats given chronic estrogen replacement therapy (ERT). We compared rats treated, either at the onset or at 6 h of reperfusion, with saline or LJP-1207. Additional rats, rendered neutropenic 24 h before TFI, were studied. In saline-treated controls, intravascular accumulation of adherent leukocytes gradually increased, reaching 15 to 20% of the venular area, at which point neutrophil infiltration commenced (at ϳ6 h). In the rats given LJP-1207 at the onset of reperfusion, limited neutrophil adhesion (ϳ5% maximum) and no infiltration were observed. These results generally paralleled those in neutropenic rats. In rats treated at 6 h of reperfusion, the pattern of neutrophil adhesion was similar to that of the saline-treated group up to 6 h, but further infiltration was essentially prevented. Neurologic outcomes and histopathology were similar to one another in the LJP-1207-treated and neutropenic groups and significantly improved over those in saline-treated controls. Thus, VAP-1-mediated post-TFI leukocyte adhesion/infiltration in diabetic OVX females given chronic ERT contributes substantially to neuropathology. One implication is that specifically preventing leukocyte infiltration provides a substantial measure of neuroprotection. This could explain the finding of LJP-1207 having at least a 6-h therapeutic window in this model.

Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice

“…These data imply that the cytotoxic or suppressor T cells may rely more on the Ab-defined epitope of VAP-1 than the SSAO activity of VAP-1 in the accumulation process. The sequential use of both functional modalities (the Ab-defined epitope and the SSAO activity) of VAP-1 has been shown to be important in interactions between endothelial cells and lymphocytes or granulocytes (8)(9)(10)(11)(13)(14)(15)(16)(17)(18)(19)(20). Inhibition of the catalytic SSAO activity of VAP-1 through using SZE5302 effectively retarded Gr-1 +…”

“…The anti-VAP-1 Abs inhibit leukocyte-endothelial interactions in several in vitro and in vivo models (8)(9)(10)(11)(12)(13)(14). The small-molecule SSAO inhibitors also effectively attenuate inflammation by diminishing leukocyte rolling, firm adhesion, and transmigration through multiple types of endothelial cells (9,13,(15)(16)(17)(18)(19)(20). Notably, the anti-VAP-1 Abs do not inhibit the enzymatic activity of VAP-1, and the enzyme inhibitors do not alter the mAb-defined surface epitopes of VAP-1 (8,15).…”

Neurogenesis and Inflammation after Ischemic Stroke: What is Known and Where We Go from Here

“…The pharmacologic agent LJP-1586, and its predecessor LJP-1207, are highly selective vascular adhesion protein-1 inhibitors and prevent neutrophil transmigration into the brain parenchyma. Furthermore, when these drugs are given to rodents subjected to transient forebrain ischemia 102 or transient middle cerebral artery occlusion 10 6 to 12 hours after reperfusion, there is a profound antiinflammatory action, which is linked to neuroprotection. 10,102 These studies, and others currently in preclinical development may identify clinical targets for antiinflammatory therapeutic options.…”

Plasma VAP-1/SSAO Activity Predicts Intracranial Hemorrhages and Adverse Neurological Outcome After Tissue Plasminogen Activator Treatment in Stroke

“…Although this is the first study showing the benefits of VAP-1/SSAO inhibition in tPA-treated animals subjected to an embolic ischemic episode, a previous study showed that rats treated only with an SSAO inhibitor significantly improved after a transient forebrain ischemia. 25 We observed a peak plasma VAP-1/SSAO activity in rats after 2 hours post-tPA treatment, suggesting that the circulating form of this enzyme could be implicated in the inflammatory response to cerebral ischemic-reperfusion damage. In our experimental model, owing to the low rate of HT, we were unable to evaluate this parameter.…”