title: Demonstration of therapeutic window of Cerebrolysin in embolic stroke: A prospective, randomized, blinded, and placebo-controlled study.
abstract: Background and aims In an effort to characterize the effects of Cerebrolysin for treatment of stroke that are essential for successful clinical translation, we have demonstrated that Cerebrolysin dose dependently enhanced neurological functional recovery in experimental stroke. Here, we conduct a prospective, randomized, placebo-controlled, blinded study to examine the therapeutic window of Cerebrolysin treatment of rats subjected to embolic stroke. Methods Male Wistar rats age 3-4 months (n = 100) were subjected to embolic middle cerebral artery occlusion. Animals were randomized to receive saline or Cerebrolysin daily for 10 consecutive days starting 4, 24, 48, and 72 h after middle cerebral artery occlusion. Neurological outcome was measured weekly with a battery of behavioral tests (adhesive removal test, modified neurological severity score (mNSS), and foot-fault test). Global test was employed to assess Cerebrolysin effect on neurological recovery with estimation of mean difference between Cerebrolysin and control-treated groups and its 95% confidence interval in the intent-to-treat population, where a negative value of the mean difference and 95% confidence interval < 0 indicated a significant treatment effect. All rats were sacrificed 28 days after middle cerebral artery occlusion and infarct volume was measured. Results Cerebrolysin treatment initiated within 48 h after middle cerebral artery occlusion onset significantly improved functional outcome; mean differences and 95% confidence interval were -11.6 (-17.7, -5.4) at 4 h, -7.1 (-13.5, -0.8) at 24 h, -8.4 (-14.2, -8.6) at 48 h, and -4.9 (-11.4, 1.5) at 72 h. There were no differences on infarct volume and mortality rate among groups. Conclusions With a clinically relevant rigorous experimental design, our data demonstrate that Cerebrolysin treatment effectively improves stroke recovery when administered up to 48 h after middle cerebral artery occlusion.
authors.affiliation: 1 Department of Neurology, Oakland University, Rochester, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 1 Department of Neurology, Oakland University, Rochester, USA.|2 Department of Physics, Oakland University, Rochester, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: 3 Department of Biostatistics and Research Epidemiology, Oakland University, Rochester, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.affiliation: 3 Department of Biostatistics and Research Epidemiology, Oakland University, Rochester, USA.
authors.forename: Talan
authors.initials: T
authors.lastname: Zhang
authors.affiliation: 1 Department of Neurology, Oakland University, Rochester, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: 4 EVER Pharma GmbH, Unterach, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.affiliation: 4 EVER Pharma GmbH, Unterach, Austria.
authors.forename: Hemma
authors.initials: H
authors.lastname: Brandstaetter
authors.affiliation: 4 EVER Pharma GmbH, Unterach, Austria.
authors.forename: Edith
authors.initials: E
authors.lastname: Doppler
authors.affiliation: 4 EVER Pharma GmbH, Unterach, Austria.
authors.forename: Dieter
authors.initials: D
authors.lastname: Meier
authors.affiliation: 5 Department of Pharmacology, Henry Ford Hospital, Detroit, USA.
authors.forename: Pardeep
authors.initials: P
authors.lastname: Pabla
authors.affiliation: 1 Department of Neurology, Oakland University, Rochester, USA.
authors.forename: Zheng G
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D004311:Double-Blind Method; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000209:etiology; D020767:Intracranial Thrombosis / Q000150:complications*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents
keywords: Cerebrolysin; brain infarction; embolic stroke; ischemic stroke; middle cerebral artery occlusion; neurological outcome; recovery; therapeutic window; treatment