Xenon is an inhibitor of tissue-plasminogen activator: adverse and beneficial effects in a rat model of thromboembolic stroke.

Abstract

Preclinical evidence in rodents has proven that xenon may be a very promising neuroprotective agent for treating acute ischemic stroke. This has led to the general thinking that clinical trials with xenon could be initiated in acute stroke patients in a next future. However, an unappreciated physicochemical property of xenon has been that this gas also binds to the active site of a series of serine proteases. Because the active site of serine proteases is structurally conserved, we have hypothesized and investigated whether xenon may alter the catalytic efficiency of tissue-type plasminogen activator (tPA), a serine protease that is the only approved therapy for acute ischemic stroke today. Here, using molecular modeling and in vitro and in vivo studies, we show (1) xenon is a tPA inhibitor; (2) intraischemic xenon dose dependently inhibits tPA-induced thrombolysis and subsequent reduction of ischemic brain damage; (3) postischemic xenon virtually suppresses ischemic brain damage and tPA-induced brain hemorrhages and disruption of the blood-brain barrier. Taken together, these data indicate (1) xenon should not be administered before or together with tPA therapy; (2) xenon could be a golden standard for treating acute ischemic stroke if given after tPA-induced reperfusion, with both unique neuroprotective and antiproteolytic (anti-hemorrhaging) properties.

• Authors: Hélène N David, Benoît Haelewyn, Jean-Jacques Risso, Nathalie Colloc'h, Jacques H Abraini
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 30 Issue 4 Pg. 718-28 (Apr 2010) ISSN: 1559-7016 [Electronic] United States
• PMID: 20087367 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibrinolytic Agents
• Neuroprotective Agents
• Xenon
• Serine Proteases
• Tissue Plasminogen Activator
• Fibrinolysin

Topics

• Animals
• Brain Ischemia (drug therapy, pathology)
• Catalytic Domain
• Cerebral Hemorrhage (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Fibrinolysin (chemistry, metabolism)
• Fibrinolytic Agents (chemistry, therapeutic use)
• Humans
• Infarction, Middle Cerebral Artery
• Male
• Models, Molecular
• Neuroprotective Agents (therapeutic use)
• Protein Conformation
• Rats
• Rats, Sprague-Dawley
• Serine Proteases (chemistry, metabolism)
• Stroke (drug therapy, pathology)
• Tissue Plasminogen Activator (antagonists & inhibitors, chemistry, therapeutic use)
• Xenon (therapeutic use)