Received for publication October 13, 2005.
Revised December 6, 2005.
Accepted for publication December 6, 2005.

Vascular adhesion protein-1 plays an important role in post-ischemic 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, in part, 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) on pial venular leukocyte adhesion and infiltration (at 2-10h reperfusion) and neuropathology (at 72h reperfusion) following transient forebrain ischemia (TFI). A model associated with a high level of post-ischemic 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 6h reperfusion, with saline or LJP-1207. Additional rats, rendered neutropenic 24h prior to TFI, were studied. In controls, intravascular accumulation of adherent leukocytes gradually increased, reaching 15-20% of the venular area, at which point neutrophil infiltration commenced (at ~6h). In the rats given LJP-1207 at the onset of reperfusion, limited neutrophil adhesion (~5% maximum), and no infiltration, was observed. These results generally paralleled those in neutropenic rats. In rats treated at 6h reperfusion, the pattern of neutrophil adhesion was similar to that of the control group up to 6h, 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 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-hour therapeutic window, in this model.

Key words: Fluoro-Jade, cerebral ischemia, leukocyte infiltration, neutropenia, semicarbazide-sensitive amine oxidase, streptozotocin

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