title: Cerebrolysin dose-dependently improves neurological outcome in rats after acute stroke: A prospective, randomized, blinded, and placebo-controlled study.
abstract: BACKGROUND
  Cerebrolysin is a mixture of neuropeptides and free amino acids that is clinically used for the treatment of stroke. To further standardize treatment schemes, we assessed the dose response of Cerebrolysin on sensorimotor outcome in a rat model of ischemic stroke.
  
  
  METHODS
  This study was a prospective, blinded, placebo-controlled, preclinical experiment. Male and female Wistar rats, subjected to embolic middle cerebral artery occlusion, were randomly treated with Cerebrolysin doses of 0.8, 2.5, 5.0, 7.5 ml/kg or placebo, 4 h after middle cerebral artery occlusion for a total of 10 consecutive days.
  
  
  RESULTS
  The primary outcome was neurologic improvement at day 28, lesion volume, mortality, and animal weight were secondary and safety outcomes, respectively. There was a significant (p < 0.001) dose effect of Cerebrolysin on neurological outcome. Cerebrolysin at a dose of ≥ 2.5 ml/kg significantly (p < 0.001) improved neurological outcome (Mean Estimate (95% CL): 0.8 ml/kg: 6.2 (-6.0/18.4), 2.5 ml/kg: -28.9 (-41.6/-16.2), 5.0 ml/kg: -33.4 (-45.0/-21.7), 7.5 ml/kg: -36.3 (-48.2/-24.4). Higher doses (≥ 2.5 ml/kg) resulted in better recovery; however, differences between effective doses were not significant. Treatment with 5 ml/kg reduced lesion volume (p = 0.016). No treatment gender interactions were found and there were no differences in death or weight loss.
  
  
  CONCLUSIONS
  Collectively, these data on Cerebrolysin efficacy demonstrate the feasibility of a preclinical study setup following a randomized, placebo-controlled, and blinded design with a clinical relevant treatment scheme. Cerebrolysin at doses of ≥ 2.5 ml/kg improved functional outcome and at a dose of 5 ml/kg reduced infarct volume.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: Department of Pharmacology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Talan
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Physics, Oakland University, Rochester, MI, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.affiliation: Department of Physics, Oakland University, Rochester, MI, USA.
authors.forename: Edith
authors.initials: E
authors.lastname: Doppler
authors.affiliation: Department of Physics, Oakland University, Rochester, MI, USA.
authors.forename: Dieter
authors.initials: D
authors.lastname: Meier
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chao
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Eapen
authors.affiliation: EVER Pharma GmbH, Oberburgau 3, Unterach, Austria.
authors.forename: Pardeep
authors.initials: P
authors.lastname: Pabla
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI, USA zhazh@neuro.hfh.edu.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Gang Zhang
mesh_terms: D000596:Amino Acids / Q000627:therapeutic use*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D056228:Feedback, Sensory / Q000187:drug effects*; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010919:Placebos; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy*
chemical_list: D000596:Amino Acids; D018696:Neuroprotective Agents; D010919:Placebos; C006952:cerebrolysin
keywords: Ischemic stroke; cerebral infarction; cerebrolysin; neurological outcome; recovery; treatment