Randomized controlled trial of Cerebrolysin’s effects on long-term histological outcomes and functional recovery in rats with moderate closed head injury

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  • 1 Departments of Neurosurgery,
  • 2 Neurology, and
  • 4 Public Health Sciences, Henry Ford Hospital, Detroit; and
  • 3 Department of Physics, Oakland University, Rochester, Michigan
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OBJECTIVE

The authors previously demonstrated that Cerebrolysin is effective for treatment of mild closed head injury (CHI) when administered 4 hours after injury. The aim of this study was to determine Cerebrolysin’s effects on functional and histological outcomes in rats subjected to moderate CHI.

METHODS

In this randomized, blinded, and vehicle-controlled preclinical trial, male adult Wistar rats subjected to moderate CHI received either Cerebrolysin treatment at a dose of 2.5 ml/kg (n = 13) or vehicle (saline, n = 13) intraperitoneally administered daily for 10 days, starting at 4 hours after injury. Animals were subjected to cognitive and sensorimotor functional tests at multiple time points, and they were killed 3 months after injury. The brains were processed for analyses of neuronal cell loss, amyloid precursor protein, axonal damage, and neurogenesis.

RESULTS

Compared with rats treated with vehicle (saline), rats treated with Cerebrolysin had significantly increased numbers of neuroblasts and newborn mature neurons in the dentate gyrus (DG) and attenuated amyloid precursor protein accumulation and axonal damage in various brain regions, as well as decreased neuronal loss in the DG and cornu ammonis 3 (CA3) region of the hippocampus (p < 0.05). Global testing using generalized estimating equations showed a significant beneficial effect of Cerebrolysin treatment on sensorimotor functional outcomes from 1 day to 3 months after injury compared to that of saline treatment (p < 0.05). Compared with vehicle-treated rats, Cerebrolysin-treated rats showed significantly and robustly improved long-term (up to 3 months) cognitive functional recovery, as measured by social interaction, Morris water maze, novel object recognition, and odor recognition tests. In the Cerebrolysin-treated rats there were significant correlations between multiple histological outcomes and functional recovery evident 3 months after moderate CHI, as indicated by Pearson partial correlation analyses.

CONCLUSIONS

The authors’ findings demonstrate that Cerebrolysin treatment significantly improves long-term functional and histological outcomes in rats with moderate CHI, with functional outcomes significantly correlated with histological indices of neuroplasticity and neuroprotection. These data indicate that Cerebrolysin may be useful for the treatment of moderate CHI.

ABBREVIATIONS AD = Alzheimer’s disease; APP = amyloid precursor protein; BrdU = bromodeoxyuridine; BSA = bovine serum albumin; CA = cornu ammonis; CC = corpus callosum; CHI = closed head injury; CT = cortex; DCX = doublecortin; DG = dentate gyrus; IP = intraperitoneal/intraperitoneally; mNSS = modified neurological severity score; MWM = Morris water maze; NeuN = neuronal nuclei; NOR = novel object recognition; PBS = phosphate-buffered saline; pNfH = phosphorylated neurofilament heavy subunit; TBI = traumatic brain injury.

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Contributor Notes

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

INCLUDE WHEN CITING Published online September 6, 2019; DOI: 10.3171/2019.6.JNS191027.

Disclosures This work was funded by EVER Neuro Pharma GmbH.

The authors disclose receipt of the following financial support for the research, authorship, and/or publication of this article. Dr. Chopp received travel support and honoraria from EVER Neuro Pharma GmbH for presenting data at scientific meetings. EVER Neuro Pharma GmbH also provided financial support to Dr. Chopp for travel to meetings supported by EVER Neuro Pharma GmbH. Dr. Mei Lu and Ms. Talan Zhang received some salary support provided by EVER Neuro Pharma GmbH for statistical analyses. Drs. Yanlu Zhang and Ye Xiong had a percentage of salary support provided from a nonrestricted research contract with EVER Neuro Pharma GmbH.

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