Vascular adhesion protein-1 (VAP-1), also called semicarbazide-sensitive amine oxidase (SSAO), is reported to play an important role in the adhesion and endothelial transmigration of multiple leukocyte subsets (i.e., neutrophils, monocytes, lymphocytes) in peripheral vascular beds. Our laboratory recently reported that pharmacologic blockade of VAP-1/SSAO, during the reperfusion period following transient forebrain ischemia (TFI), prevented neutrophil infiltration into the brain, and was associated with a 6h post-ischemic therapeutic window in animals where heightened neutrophil diapedesis (which begins at ~6h reperfusion) had been documented. These results strongly suggested that post-TFI neutrophil infiltration and neuropathology were linked. However, the rats used in that study (diabetic, estrogen-treated ovariectomized females) are known to exhibit an exaggerated post-ischemic neutrophil infiltration response and, therefore, such findings may not necessarily be taken to suggest a beneficial role for VAP-1/SSAO inhibition over a wide spectrum of rodent models of ischemia/reperfusion. In the present project, we will examine the effect of a highly- selective inhibitor of VAP-1/SSAO, LJP-1586. Treatments will be initiated at 0-24h reperfusion in adult male rats subjected to 1h MCAo (intraluminal suture) and 1-14 days recovery. The proposal is guided by two Specific Aims designed to test the following hypotheses: (1) VAP-1/SSAO blockade will provide long-term neuroprotection (i.e., reduced infarct volumes;improved neurobehavioral function) with extended therapeutic windows that may, in part, be linked to diminished expression/activation of selected adhesion molecules. (2) The neuroprotection will largely involve interference with non- neutrophil leukocyte subsets. Experiments will involve selective depletion of neutrophils (anti-PMNL antibody) and monocytes (liposome-encapsulated clodronate), coupled with analysis of post-MCAo intracerebral expression of neutrophils, hematogenous monocytes, and T-lymphocytes using immunohistochemistry and FACS analyses. Preliminary evidence supports both hypotheses, suggesting a restricted role for neutrophils, but favoring a significant contribution from non-neutrophil subsets (i.e., mononuclear leukocytes) in the neuropathology accompanying temporary MCAo. Published evidence that mononuclear leukocytes do not display increased intracerebral adhesion and transmigration until many hours (even days) following the appearance of neutrophils may account for the long therapeutic windows (6-12h) we have observed in these early experiments (based upon results using 2 different, but selective, VAP- 1/SSAO blockers). The characterization of a validated pharmacologic approach that affects multiple leukocyte subsets, but with limited off-target actions, has substantial translational implications, since it may prove to be efficacious over a wide range of clinical stroke and ischemic presentations.
Post-ischemic brain inflammation can play a major role in the cerebral neuropathology that occurs following stroke. One potentially key player in that inflammatory attack is the leukocyte. These blood-derived cells may enter the brain after a stroke and release neurotoxic agents. The failure of anti-leukocyte strategies in clinical trials to date may, in part, relate to the presence of multiple leukocyte subsets and redundancy in the pathways responsible for their passage into the brain. The present project utilizes a selective pharmacologic approach that targets a novel protein which appears to be important in the trafficking of all leukocyte subsets and, therefore, may prove to have wide-ranging clinical efficacy.
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