An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents.
OBJECTIVE
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.
Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, 1501 San Pablo Street, Los Angeles, CA 90089, USA.
Yaoming
Y
Wang
Zhenggang
Z
Zhang
Nienwen
N
Chow
Thomas P
TP
Davis
John H
JH
Griffin
Michael
M
Chopp
Berislav V
BV
Zlokovic
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy*; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000473:pathology; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006454:Hemoglobins / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D020766:Intracranial Embolism / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009460:Neurologic Examination; D011486:Protein C / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006454:Hemoglobins; D011486:Protein C; D010959:Tissue Plasminogen Activator