title: High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats.
abstract: OBJECTIVE
  Recent studies demonstrated anticoagulatory, antiinflammatory, antiapoptotic, and neuroprotective properties of activated protein C (APC) in rodent models of acute neurodegenerative diseases, suggesting APC as promising broad acting therapeutic agent. Unfortunately, continuous infusion of recombinant human APC (rhAPC) failed to improve brain damage following cardiac arrest in rats. The present study was designed to investigate the neuroprotective effect after global cerebral ischemia (GI) with an optimized infusion protocol.
  
  
  METHODS
  Rats were subjected to bilateral clip occlusion of the common carotid arteries (BCAO) and controlled hemorrhagic hypotension to 40 mm Hg for 14 min and a subsequent 5h-infusion of rhAPC (2mg/kg bolus+6 mg/kg/h continuous IV) or vehicle (0.9% NaCl). The dosage was calculated to maintain plasma hAPC activity at 150%. Cerebral inflammation, apoptosis and neuronal survival was determined at day 10.
  
  
  RESULTS
  rhAPC infusion did not influence cortical cerebral perfusion during reperfusion and failed to reduce neuronal cell loss, microglia activation, and caspase 3 activity.
  
  
  CONCLUSIONS
  Even an optimized rhAPC infusion protocol designed to maintain a high level of APC plasma activity failed to improve the sequels following GI. Despite positive reports about protective effects of APC following, e.g., ischemic stroke, the present study supports the notion that infusion of APC during the early reperfusion phase does not result in sustained neuroprotection and fails to improve outcome after global cerebral ischemia.
authors.affiliation: Department of Anesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Brückner
authors.forename: Irina
authors.initials: I
authors.lastname: Lasarzik
authors.forename: Antje
authors.initials: A
authors.lastname: Jahn-Eimermacher
authors.forename: Dirk
authors.initials: D
authors.lastname: Peetz
authors.forename: Christian
authors.initials: C
authors.lastname: Werner
authors.forename: Kristin
authors.initials: K
authors.lastname: Engelhard
authors.forename: Serge C
authors.initials: SC
authors.lastname: Thal
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death; D006801:Humans; D007262:Infusions, Intravenous; D011486:Protein C / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D011486:Protein C; D011994:Recombinant Proteins
keywords: APC; Activated protein C; BCAO; Coagulation; Drotrecogin alfa; Global cerebral ischemia; Inflammation; MAP; Neuroprotection; activated protein C; bilateral occlusion of the common carotid arteries; mean arterial blood pressure; recombinant human APC; rhAPC