Prolonged therapeutic window associated with pharmacologic blockade of vascular adhesion protein-1 (VAP-1)-related post-ischemic leukocyte adhesion in diabetic, ovariectomized (OVX) female rats given chronic estrogen replacement

Abstract

Endothelial VAP-1 facilitates post-ischemic leukocyte adhesion and infiltration in cerebral venules (abstract-this meeting). Evidence suggests that this role of VAP-1 relates, in part, to its function as an amine oxidase and the formation of H2O2 and aldehydes. In the present study, we examined whether treatment with a specific inhibitor of the enzymatic function of VAP-1 (LJP-1207) was capable of reducing the neuropathology accompanying transient forebrain ischemia (TFI). We used a model associated with a high level of post-ischemic leukocyte adhesion and infiltration—diabetic (6–8 wks post-streptozotocin) OVX female rats given 1 week of estrogen replacement therapy (ERT). The rats were allowed to recover over 3 days following 20 min TFI. We compared rats treated, either at the onset or at 6 h reperfusion, with saline or LJP-1207 (30 mg/kg iv). Neurologic function was scored each day over the 3-day reperfusion period. The daily scores could range from 0 (no dysfunction) to 18 (severe dysfunction). In controls (n=10), the 3-day score was 13 2; while in the VAP-1-inhibited rats, the scores were 2 1 (LJP-1207 treatment @0 h reperfusion [n=7]) and 6 1 (LJP-1207 treatment at 6 h reperfusion [n=5]) (see figure 1). Both treatment groups were statistically different from control. Findings from our laboratory have shown that leukocyte infiltration, in diabetic OVX females given ERT, commences at >6 h reperfusion (Stroke 35: 1974–8, 2004), and that this transformation is largely prevented by LJP-1207 (abstract-this meeting). These findings, therefore, indicate that VAP-1-mediated post-TFI leukocyte adhesion/infiltration, in diabetic OVX females given chronic ERT, contributes substantially to neuropathology. One intriguing implication of these findings is that preventing leukocyte infiltration may provide a substantial measure of neuroprotection. This could explain the finding of LJP-1207 having at least a 6-hour therapeutic window, in this model.