Xenon is an inhibitor of tissue-plasminogen activator: adverse and beneficial effects in a rat model of thromboembolic stroke.
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.
David
Hélène N
HN
NNOXe Pharmaceuticals, Quebec City, Quebec, Canada.
Haelewyn
Benoît
B
Risso
Jean-Jacques
JJ
Colloc'h
Nathalie
N
Abraini
Jacques H
JH
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D020134:Catalytic Domain; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000737:chemistry / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D057057:Serine Proteases / Q000737:chemistry / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000627:therapeutic use; D014978:Xenon / Q000627:therapeutic use*
D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D014978:Xenon; D057057:Serine Proteases; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin