Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia

Background and Purpose-Reperfusion brain injury after cerebral ischemia is associated with a developing inflammatory response at the site of infarctio n. Proteasome inhibitors block nuclear factor-kappa B activation and provid e antiinflammatory effects in several animal models of peripheral inflammat ion. We tested the novel proteasome inhibitor PS519 in a rat model of trans ient focal ischemia to establish its pharmacodynamics as a neuroprotection treatment and related effects on leukocyte infiltration. Methods-Rats were subjected to 2 hours of focal cerebral ischemia by means of the filament method of middle cerebral artery occlusion (MCAo). After ei ther 22 or 70 hours of reperfusion, infarct size was measured and neurologi cal function, electroencephalographic (EEG) activity, and/or neutrophil and macrophage infiltration was quantified. PS519 was administered in a single intravenous bolus at 2 hours after MCAo. In addition, the therapeutic wind ow for PS519 was estimated by delaying treatment for 4 or 6 hours after MCA o. Results-Dose-response analysis of infarct volume at 24 hours revealed that PS519 neuroprotection approached 60%, and clinical evaluations showed signi ficant improvements in neurological function and EEG activity. Neutrophil i nfiltration at 24 hours was also significantly decreased in cortical and st riatal infarcted tissue of PSS519-treated rats. Delaying the PS519 treatmen t up to 4 hours continued to result in significant neuroprotection. In the 72-hour injury model, infarction was reduced 40% by PS519, and significant improvements in neurological function and EEG recovery were again measured. Considerable reductions in both neutrophil and macrophage infiltration wer e evident. Conclusions-PS519 mitigates infarction and improves neurological recovery i n brain-injured rats, an effect in part caused by a reduction in the leukoc yte inflammatory response.