An Activated Protein C Analog With Reduced Anticoagulant Activity Extends the Therapeutic Window of Tissue Plasminogen Activator for Ischemic Stroke in Rodents

• Published in: Stroke (1970) Vol. 43; no. 9; pp. 2444 - 2449
• Main Authors: YAOMING WANG, ZHENGGANG ZHANG, CHOW, Nienwen, DAVIS, Thomas P, GRIFFIN, John H, CHOPP, Michael, ZLOKOVIC, Berislav V
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.09.2012
• Subjects: Animals; Anticoagulants - therapeutic use; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Brain - pathology; Brain Ischemia - drug therapy; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - pathology; Fibrinolytic Agents - adverse effects; Fibrinolytic Agents - therapeutic use; Hemoglobins - metabolism; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - pathology; Intracranial Embolism - drug therapy; Intracranial Embolism - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Neurologic Examination; Neurology; Pharmacology. Drug treatments; Protein C - analogs & derivatives; Protein C - therapeutic use; Rats; Rats, Wistar; Stroke - drug therapy; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - therapeutic use; Vascular diseases and vascular malformations of the nervous system; Cerebral infarction; Stroke; Nervous system diseases; Serine endopeptidases; Enzyme; proteases; Cardiovascular disease; Anticoagulant; t-Plasminogen activator; Cerebral disorder; Vascular disease; Peptidases; Treatment; Animal; neuroprotection; Central nervous system disease; Brain ischemia; thrombolytic therapy; Hydrolases; Cerebrovascular disease; Protein C (activated); ischemic stroke
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.112.658997

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. 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. 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. 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.