title: Preclinical evaluation of the neuroprotective effect of soluble complement receptor type 1 in a nonhuman primate model of reperfused stroke.
abstract: OBJECTIVE
  Postischemic cerebral inflammatory injury has been extensively investigated in an effort to develop effective neuroprotective agents. The complement cascade has emerged as an important contributor to postischemic neuronal injury. Soluble complement receptor Type 1 (sCR1), a potent inhibitor of complement activation, has been shown to reduce infarct volume and improve functional outcome after murine stroke. Given numerous high-profile failures to translate promising antiinflammatory strategies from the laboratory to the clinic and given the known species-specificity of the complement cascade, the authors sought to evaluate the neuroprotective effect of sCR1 in a nonhuman primate model of stroke.
  
  
  METHODS
  A total of 48 adult male baboons (Papio anubis) were randomly assigned to receive 15 mg/kg of sCR1 or vehicle. The animals were subjected to 75 minutes of middle cerebral artery occlusion/reperfusion. Perioperative blood samples were analyzed for total complement activity by using a CH50 assay. Infarct volume and neurological scores were assessed at the time the animals were killed, and immunohistochemistry was used to determine cerebral drug penetration and C1q deposition. An interim futility analysis led to termination of the trial after study of 12 animals. Total serum complement activity was significantly depressed in the sCR1-treated animals compared with the controls. Immunostaining also demonstrated sCR1 deposition in the ischemic hemispheres of treated animals. Despite these findings, there were no significant differences in infarct volume or neurological score between the sCR1--and vehicle-treated cohorts.
  
  
  CONCLUSIONS
  A preischemic bolus infusion of sCR1, the most effective means of administration in mice, was not neuroprotective in a primate model. This study illustrates the utility of a translational primate model of stroke in the assessment of promising antiischemic agents prior to implementation of large-scale clinical trials.
authors.affiliation: Department of Neurological Surgery, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mocco
authors.forename: William J
authors.initials: WJ
authors.lastname: Mack
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ducruet
authors.forename: Ryan G
authors.initials: RG
authors.lastname: King
authors.forename: Michael E
authors.initials: ME
authors.lastname: Sughrue
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Coon
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: Robert R
authors.initials: RR
authors.lastname: Sciacca
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Henry C
authors.initials: HC
authors.lastname: Marsh
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D015922:Complement C1q / Q000032:analysis; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007124:Immunoenzyme Techniques; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology* / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D048530:Papio anubis; D017463:Receptors, Complement 3b / Q000008:administration & dosage*; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D017463:Receptors, Complement 3b; D015922:Complement C1q