Prospective, randomized, blinded, and placebo-controlled study of Cerebrolysin dose-response effects on long-term functional outcomes in a rat model of mild traumatic brain injury

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OBJECTIVE

Cerebrolysin is a neuropeptide preparation that mimics the properties of neurotrophic factors and has had beneficial effects in the treatment of neurodegenerative diseases, stroke, and traumatic brain injury (TBI). To further evaluate treatment schemes, the authors assessed the dose-response of Cerebrolysin on functional improvement in a rat model of mild TBI (mTBI).

METHODS

This dose-response study was a prospective, randomized, blinded, and placebo-controlled preclinical experiment. Male Wistar adult rats, subjected to mTBI induced by a closed head impact, were treated randomly with 0 (saline as placebo), 0.8, 2.5, or 7.5 ml/kg of Cerebrolysin 4 hours after mTBI and daily for a total of 10 consecutive days. A battery of cognitive and sensorimotor functional tests was performed over 90 days.

RESULTS

The primary outcome was functional improvement over the 90 days; animal weight and death were the secondary and safety outcomes, respectively. A significant (p < 0.001) dose effect of Cerebrolysin on cognitive recovery 3 months after injury was found. Cerebrolysin at a dose of ≥ 0.8 ml/kg significantly (p < 0.001) improved cognitive outcome. The higher dose (7.5 ml/kg) resulted in significantly better cognitive recovery than the lowest doses (0.8 ml/kg) but not relative to the 2.5-ml/kg dose. Cerebrolysin at a dose of 2.5 or 7.5 ml/kg also caused different onset times of significant improvement in sensorimotor function. No differences in body weight or mortality rate among the groups were found.

CONCLUSIONS

This preclinical randomized, placebo-controlled, and blinded study with a clinically relevant treatment scheme revealed that Cerebrolysin at doses of 0.8–7.5 ml/kg, administered 4 hours after mTBI and then once daily for a total of 10 consecutive days, improved functional outcomes 3 months after injury. A dose of 2.5 ml/kg is likely an optimal dose for the treatment of experimental mTBI.

ABBREVIATIONS mNSS = modified neurological severity score; mTBI = mild TBI; MWM = Morris water maze; NOR = novel object recognition; RCT = randomized controlled trial; TBI = traumatic brain injury.

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Article Information

Correspondence Ye Xiong: Henry Ford Health System, Detroit, MI. yxiong1@hfhs.org.

INCLUDE WHEN CITING Published online January 5, 2018; DOI: 10.3171/2017.6.JNS171007.

Disclosures Drs. Winter and Brandstätter are employees of Clinical Research and Pharmacology, EVER Neuro Pharma GmbH (Unterach, Austria), which did not participate in the animal studies, data collection, or data analyses. All the authors designed the study together, and EVER Neuro reviewed the report and manuscript without interfering with the conclusions that were drawn. This work was supported by EVER Pharma GmbH.

© AANS, except where prohibited by US copyright law.

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Figures

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    Effects of Cerebrolysin on spatial learning performance in the MWM test 3 months after mTBI. A: mTBI did not affect the swim speed of injured rats compared with sham-surgery-group rats. There was no significant difference in the swim speed of Cerebrolysin-treated rats compared with saline-treated rats. B: Cerebrolysin treatment significantly improved spatial learning performance compared with that of the vehicle group at 3 months after mTBI. C: Cerebrolysin treatment significantly reduced the time to reach the hidden platform in the MWM compared with that of the saline group at 3 months after mTBI. *p < 0.05 versus vehicle (saline). Data represent means (± SD); n = 12 rats per group. Figure is available in color online only.

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    Effects of Cerebrolysin on NOR memory 1 (A) and 3 (B) months after mTBI. Control rats spent significantly more time exploring the novel object than the familiar object. Rats with mTBI treated with vehicle showed impaired NOR memory 1 and 3 months after injury, whereas rats with mTBI treated with Cerebrolysin showed significantly improved NOR memory compared with the vehicle group 1 (A) and 3 (B) months after mTBI. *p < 0.05 versus vehicle. Data represent means (± SD); n = 12 rats per group. Figure is available in color online only.

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    Effects of Cerebrolysin on social interaction measured by the 3-chamber test 1 (A) and 3 (B) months after mTBI. Control rats spent significantly more time exploring the novel rat than the familiar rat. Rats with mTBI treated with vehicle spent equivalent times exploring the novel rat and the familiar rat 1 and 3 months after injury. Cerebrolysin treatment significantly improved social interaction compared with saline treatment 1 (A) and 3 (B) months after mTBI. *p < 0.05 versus vehicle. Data represent means (± SD); n = 12 rats per group. Figure is available in color online only.

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    Effects of Cerebrolysin on sensorimotor functional outcomes measured by the foot-fault (A) and adhesive-removal (B) tests and the mNSS (C). A: Cerebrolysin treatment at 2.5 ml/kg significantly reduced the frequency of foot faults from day 1 to 7 after mTBI compared with vehicle treatment. B: Cerebrolysin treatment at doses of 2.5 and 7.5 ml/kg resulted in significantly reduced adhesive-removal times compared with vehicle treatment. C: Cerebrolysin did not significantly lower the mNSSs compared with vehicle treatment. *p < 0.05 versus vehicle. Data represent means (± SD); n = 12 rats per group. Figure is available in color online only.

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    Effects of mTBI and Cerebrolysin on body weight. We found no significant difference in the body weight of rats with mTBI treated with vehicle or Cerebrolysin compared with control rats. Data represent means (± SD); n = 12 rats per group. Figure is available in color online only.

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