Affiliation:
1. From the Zilkha Neurogenetic Institute (Y.W. and B.V.Z.), Keck School of Medicine, University of Southern California, Los Angeles, CA; Center for Neurodegenerative and Vascular Brain Disorders (Y.W. and B.V.Z.), University of Rochester Medical Center, Rochester, NY; Department of Neurology (Z.Z. and M.C.), Henry Ford Health Sciences Center, Detroit, MI; ZZ Biotech Research Laboratory (N.C.), Rochester, NY; Department of Medical Pharmacology (T.P.D.), Blood–Brain Barrier Research Laboratory, College...
Abstract
Background and Purpose—
Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, tPA has a brief therapeutic window. Its side effects include intracerebral bleeding and neurotoxicity. Therefore, a combination therapy with tPA and agents that can extend the therapeutic window of tPA and/or counteract its side effects are warranted. Here, we studied whether 3K3A-APC, a neuroprotective analog of activated protein C with reduced anticoagulant activity, can enhance the therapeutic effects of tPA in models of ischemic stroke in rodents.
Methods—
Human recombinant tPA (10 mg/kg), alone or in combination with human recombinant 3K3A-APC (2 mg/kg), was administered intravenously 4 hours after proximal or distal transient middle cerebral artery occlusion in mice and embolic stroke in rats. The 3K3A-APC was additionally administered for 3 to 4 consecutive days after stroke. The neuropathological and neurological analyses were performed at 1 to 7 days after stroke.
Results—
In all models, tPA alone had no effects on the infarct volume or behavior (ie, neurological score, foot-fault, forelimb asymmetry, adhesive removal) compared with vehicle. The tPA and 3K3A-APC combination therapy reduced the infarct volume 24 hours and 7 days after proximal or distal transient middle cerebral artery occlusion in mice and 7 days after embolic stroke in rats by 65%, 63%, and 52%, respectively, significantly (
P
<0.05) improved behavior and eliminated tPA-induced intracerebral microhemorrhages.
Conclusions—
The 3K3A-APC extends the therapeutic window of tPA for ischemic stroke in rodents. Therefore, this combination therapy also should be considered for treating stroke in humans.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Advanced and Specialised Nursing,Cardiology and Cardiovascular Medicine,Clinical Neurology
Cited by
64 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献