title: Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats.
abstract: OBJECTIVE
  3K3A-activated protein C (APC) protects young, healthy male rodents after ischemic stroke. 3K3A-APC is currently under development as a neuroprotectant for acute ischemic stroke in humans. Stroke Therapy Academic Industry Roundtable recommends that after initial studies in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions. Here, we studied the effects of delayed 3KA-APC therapy alone and with tissue-type plasminogen activator (tPA) in aged female mice and spontaneously hypertensive rats.
  
  
  METHODS
  We used Stroke Therapy Academic Industry Roundtable recommendations for ensuring good scientific inquiry. Murine recombinant 3K3A-APC (0.2 mg/kg) alone or with recombinant tPA (10 mg/kg) was given intravenously 4 hours after transient middle cerebral artery occlusion in aged female mice and rats and after embolic stroke in spontaneously hypertensive rat. 3K3A-APC was additionally administered within 3 to 7 days after stroke. The neuropathological analysis and neurological scores, foot-fault, forelimb asymmetry, and adhesive removal tests were performed within 7 and 28 days of stroke.
  
  
  RESULTS
  In all models, tPA alone had no effects on the infarct volume or behavior. 3K3A-APC alone or with tPA reduced the infarct volume 7 days after the middle cerebral artery occlusion in aged female mice and embolic stroke in spontaneously hypertensive rat by 62% to 66% and 50% to 53%, respectively, significantly improved (P<0.05) behavior, and eliminated tPA-induced intracerebral microhemorrhages. In aged female mice, 3K3A-APC was protective within 4 weeks of stroke.
  
  
  CONCLUSIONS
  3K3A-APC protects from ischemic stroke and extends the therapeutic window of tPA in aged female mice and in spontaneously hypertensive rat with a comorbid condition.
authors.affiliation: From the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA (Y.W., Z.Z., B.V.Z.); ZZ Biotech Research Laboratory, Rochester, NY (N.C.); Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA (P.S.R., P.D.L.); and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (J.H.G.).
authors.forename: Yaoming
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Nienwen
authors.initials: N
authors.lastname: Chow
authors.forename: Padmesh S
authors.initials: PS
authors.lastname: Rajput
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Lyden
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D004347:Drug Interactions; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011486:Protein C / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D011486:Protein C; D010959:Tissue Plasminogen Activator
keywords: neuroprotectant; protein C; rats, spontaneously hypertensive; stroke