DOI: 10.1161/01.str.31.7.1686. Proteasome Inhibitor PS519 Reduces Infarction and Attenuates Leukocyte Infiltration in a Rat Model of Focal Cerebral Ischemia

Proteasome Inhibitor PS519 Reduces Infarction and Attenuates Leukocyte Infiltration in a Rat Model of Focal Cerebral Ischemia

10.1161/01.str.31.7.1686

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Stroke (276)

Abstract

Background and Purpose—Reperfusion brain injury after cerebral ischemia is associated with a developing inflammatory response at the site of infarction. Proteasome inhibitors block nuclear factor-κB activation and provide anti-inflammatory effects in several animal models of peripheral inflammation. We tested the novel proteasome inhibitor PS519 in a rat model of transient 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 either 22 or 70 hours of reperfusion, infarct size was measured and neurological 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 window for PS519 was estimated by delaying treatment for 4 or 6 hours after MCAo.Results—Dose-response analysis of infarct volume at 24 hours revealed that PS519 neuroprotection approached 60%, and clinical evaluations showed significant improvements in neurological function and EEG activity. Neutrophil infiltration at 24 hours was also significantly decreased in cortical and striatal infarcted tissue of PS519-treated rats. Delaying the PS519 treatment 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 were evident.Conclusions—PS519 mitigates infarction and improves neurological recovery in brain-injured rats, an effect in part caused by a reduction in the leukocyte inflammatory response.

Bibliography

Phillips, J. B., Williams, A. J., Adams, J., Elliott, P. J., & Tortella, F. C. (2000). Proteasome Inhibitor PS519 Reduces Infarction and Attenuates Leukocyte Infiltration in a Rat Model of Focal Cerebral Ischemia. Stroke, 31(7), 1686â1693.

Authors 5

James B. Phillips (first)
Anthony J. Williams (additional)
Julian Adams (additional)
Peter J. Elliott (additional)
Frank C. Tortella (additional)

References 41 Referenced 141

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Dates

Type	When
Created	14 years, 2 months ago (June 17, 2011, 4:10 p.m.)
Deposited	5 months, 2 weeks ago (March 6, 2025, 3:01 a.m.)
Indexed	2 months, 2 weeks ago (June 7, 2025, 7:23 a.m.)
Issued	25 years, 1 month ago (July 1, 2000)
Published	25 years, 1 month ago (July 1, 2000)
Published Print	25 years, 1 month ago (July 1, 2000)

Funders 0

None

BibTeX

@article{Phillips_2000, title={Proteasome Inhibitor PS519 Reduces Infarction and Attenuates Leukocyte Infiltration in a Rat Model of Focal Cerebral Ischemia}, volume={31}, ISSN={1524-4628}, url={http://dx.doi.org/10.1161/01.str.31.7.1686}, DOI={10.1161/01.str.31.7.1686}, number={7}, journal={Stroke}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Phillips, James B. and Williams, Anthony J. and Adams, Julian and Elliott, Peter J. and Tortella, Frank C.}, year={2000}, month=jul, pages={1686–1693} }

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  "abstract": "<jats:p><jats:italic>Background and Purpose</jats:italic>\u2014Reperfusion brain injury after cerebral ischemia is associated with a developing inflammatory response at the site of infarction. Proteasome inhibitors block nuclear factor-\u03baB activation and provide anti-inflammatory effects in several animal models of peripheral inflammation. We tested the novel proteasome inhibitor PS519 in a rat model of transient focal ischemia to establish its pharmacodynamics as a neuroprotection treatment and related effects on leukocyte infiltration.</jats:p><jats:p><jats:italic>Methods</jats:italic>\u2014Rats were subjected to 2 hours of focal cerebral ischemia by means of the filament method of middle cerebral artery occlusion (MCAo). After either 22 or 70 hours of reperfusion, infarct size was measured and neurological 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 window for PS519 was estimated by delaying treatment for 4 or 6 hours after MCAo.</jats:p><jats:p><jats:italic>Results</jats:italic>\u2014Dose-response analysis of infarct volume at 24 hours revealed that PS519 neuroprotection approached 60%, and clinical evaluations showed significant improvements in neurological function and EEG activity. Neutrophil infiltration at 24 hours was also significantly decreased in cortical and striatal infarcted tissue of PS519-treated rats. Delaying the PS519 treatment 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 were evident.</jats:p><jats:p><jats:italic>Conclusions</jats:italic>\u2014PS519 mitigates infarction and improves neurological recovery in brain-injured rats, an effect in part caused by a reduction in the leukocyte inflammatory response.</jats:p>",
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