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 (N′-(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 ∼6 h). In the rats given LJP-1207 at the onset of reperfusion, limited neutrophil adhesion (∼5% 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.
Footnotes
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This work was supported by National Institutes of Health Grants DK65629 and HL52594.
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ABBREVIATIONS: OVX, ovariectomized; VAP-1, vascular adhesion protein-1; SSAO, semicarbazide-sensitive amine oxidase; TFI, transient forebrain ischemia; LJP-1207, N′-(2-phenyl-allyl)-hydrazine hydrochloride; STZ, streptozotocin; E2, 17β-estradiol; CBF, cerebral blood flow; PMNL, polymorphonuclear leukocyte; MPO, myeloperoxidase; FJ, Fluoro-Jade B; MAO, monoamine oxidase; COX, cyclooxygenase.
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doi:10.1124/jpet.105.096958.
- Received October 12, 2005.
- Accepted December 6, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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