Cerebrolysin reduces blood‐cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat

Sharma, Hari Shanker; Zimmermann-Meinzingen, Sibilla; Johanson, Conrad E.

doi:10.1111/j.1749-6632.2009.05329.x

Cited by 82 publications

(50 citation statements)

References 37 publications

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“…29 A previous study demonstrated that early intervention with Cerebrolysin reduces the BBB permeability and diminishes brain edema and other brain pathology, which contributes to recovery of sensorimotor function after TBI induced by a stab cerebral injury. 56 In the present study, Cerebrolysin treatment significantly increased the percentage of FITC-dextran-perfused vessels in the brain cortex, indicating that Cerebrolysin enhances the microvascular patency of the brain after CHI. This beneficial effect of Cerebrolysin may result from a combined action of multiple neurotrophic factors, such as CNTF, IGF-1, and GDNF.…”

Section: Discussionmentioning

confidence: 59%

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Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Zhang¹,

Chopp

Meng³

et al. 2013

JNS

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Object Cerebrolysin is a unique peptide preparation that mimics the action of neurotrophic factors. This study was designed to investigate the effects of acute treatment of experimental closed head injury (CHI) in rats with Cerebrolysin on neurological function. Methods Adult male Wistar rats (n = 60) were subjected to impact acceleration–induced CHI. Closed head injured rats received intraperitoneal injection of saline (n = 30) or Cerebrolysin (2.5 ml/kg, n = 30) starting 1 hour postinjury and administered once daily until they were killed (2 or 14 days after CHI). To evaluate functional outcome, the modified neurological severity score (mNSS), foot fault, adhesive removal, and Morris water maze (MWM) tests were performed. Animals were killed on Day 14 (n = 20) after injury, and their brains were removed and processed for measurement of neuronal cells, axonal damage, apoptosis, and neuroblasts. The remaining rats (n = 40) were killed 2 days postinjury to evaluate cerebral microvascular patency by fluorescein isothiocyanate (FITC)–dextran perfusion (n = 16) and to measure the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase–9 (MMP-9) by using real-time reverse transcriptase-polymerase chain reaction (RT-PCR, n = 8) and by immunohistochemical analysis (n = 16). Results At 14 days post-CHI, the Cerebrolysin treatment group exhibited significant improvements in functional outcomes (the adhesive removal, mNSS, foot-fault, and MWM tests), and significantly more neurons and neuroblasts were present in the dentate gyrus (DG) (p < 0.05) compared with the saline-treated group (p < 0.05). At 2 days post-CHI, the Cerebrolysin group exhibited a significantly higher percentage of phosphorylated neurofilament H (pNF-H)–positive staining area in the striatum (p < 0.05), a significant increase in the percentage of FITC-dextran perfused vessels in the brain cortex (p < 0.05), a significant increase in the number of VEGF-positive cells (p < 0.05), and a significant reduction in the MMP-9 staining area (p < 0.05) compared with the saline-treated group. There was no significant difference in mRNA levels of MMP-9 and VEGF in the hippocampus and cortex 48 hours postinjury between Cerebrolysin- and saline-treated rats that sustained CHI. Conclusions Acute Cerebrolysin treatment improves functional recovery in rats after CHI. Cerebrolysin is neuroprotective for CHI (increased neurons in the dentate gyrus and the CA3 regions of the hippocampus and increased neuroblasts in the dentate gyrus) and may preserve axonal integrity in the striatum (significantly increased percentage of pNF-H–positive tissue in the striatum). Reduction of MMP-9 and elevation of VEGF likely contribute to enhancement of vascular patency and integrity as well as neuronal survival induced by Cerebrolysin. These promising results suggest that Cerebrolysin may be a useful treatment in improving the recovery of patients with CHI.

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Section: Discussionmentioning

confidence: 59%

“…Until now, only one preclinical study investigated the effects of acute Cerebrolysin treatment in a stab injury model of TBI in rats. 56 Closed head injury is the leading cause of death and disability in young patients in industrialized countries. 54 However, the efficacy of Cerebrolysin treatment for CHI has not been investigated.…”

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confidence: 99%

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Zhang¹,

Chopp

Meng³

et al. 2013

JNS

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“…[17][18][19][20] Cerebrolysin has been shown to be safe and well-tolerated in clinical trials. 18,21,22 Cerebrolysin has important pharmacological actions that are relevant to its beneficial clinical effects, eg, promotion of synaptic regeneration, 23 improvement of neuronal survival, 24 protection of blood-brain barrier and blood-cerebrospinal fluid barrier, 25,26 and promotion of neural progenitor cell migration and neurogenesis. 27 Cerebrolysin given before spinal cord injury in rats reduced spinal cord water content, leakage of plasma proteins, and the number of injured neurons.…”

Section: Introductionmentioning

confidence: 99%

Cerebrolysin protects against rotenone-induced oxidative stress and neurodegeneration

Abdel-Salam¹,

Mohammed²,

Youness³

et al. 2014

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Abstract:We investigated the effect of cerebrolysin, a peptide mixture used for promoting memory and recovery from cerebral stroke, on the development of oxidative stress and nigrostriatal cell injury induced by rotenone administration in rats. Rotenone 1.5 mg/kg was given subcutaneously three times weekly either alone or in combination with cerebrolysin at 21.5, 43, or 86 mg/kg. Rats were euthanized 14 days after starting the rotenone injection. Lipid peroxidation (malondialdehyde), reduced glutathione (GSH), nitric oxide (nitrite) concentrations, paraoxonase 1 (PON1), and acetylcholinesterase (AChE) activities -as well as the monocyte chemoattractant protein-1 (MCP-1) and the antiapoptotic protein Bcl-2 -were measured in the brain. Histopathology, tyrosine hydroxylase, inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and cleaved caspase-3 immunohistochemistry were also performed. Rotenone caused a significantly elevated oxidative stress and proinflammatory response in the different brain regions. Malondialdehyde and nitric oxide concentrations were significantly increased, while GSH markedly decreased in the cerebral cortex, striatum, hippocampus, and in the rest of the brain. PON1 and AChE activities significantly decreased with respect to the control levels after rotenone application. Striatal Bcl-2 was significantly decreased while MCP-1 increased following rotenone injection. Rotenone caused prominent iNOS, TNF-α, and caspase-3 immunostaining in the striatum and resulted in markedly decreased tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum. Cerebrolysin coadministered with rotenone decreased lipid peroxidation, increased GSH, and inhibited the elevation of nitric oxide induced by rotenone. Cerebrolysin also decreased the rotenone-induced decline in the PON1 and AChE activities and the rotenone-mediated changes in the striatal Bcl-2 and MCP-1 levels. The drug reduced iNOs, TNF-α, and caspase 3 expressions and increased the tyrosine hydroxylase immunoreactivity in the striatum. Cerebrolysin markedly prevented the development of neuronal damage in the cortex and striatum. These data suggest that cerebrolysin may have potential therapeutic effect in Parkinson's disease.

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“…Cerebrolysin is a mixture of neurotrophic factors and peptides that could act in the brain to attenuate oxidative or cellular stress [22,23]. The reduction in oxidative stress in TBI mediated by cerebrolysin appears to be one of the most important effects of the drug in terms of inducing neuroprotection [8].…”

Section: Discussionmentioning

confidence: 99%

Cerebrolysin Attenuates Astrocyte Activation Following Repetitive Mild Traumatic Brain Injury: Implications for Chronic Traumatic Encephalopathy

강현배¹,

김기훈

김현중³

et al. 2013

Journal of Life Science

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Chronic traumatic encephalopathy (CTE), which is common in athletes, is a progressive neurodegenerative disease and a long-term consequence of repetitive closed head injuries. CTE is regarded as a chronic brain syndrome due to the effects of repetitive traumatic brain injury (TBI). Because neurotrophic factors are neuroprotective in models of brain and spinal cord injuries, we examined the effects of cerebrolysin, a mixture of various neurotrophic factors, on brain pathology in a mouse model of repetitive mild TBI (rmTBI), which is a good model of CTE. Five groups were created and treated as follows: groups 1 and 2: rmTBI for 4 weeks following cerebrolysin injection for 4 weeks; groups 3 and 4: rmTBI for 8 weeks with or without cerebrolysin injection for 4 weeks; group 5: control. We found that p-tau expression was increased in the pyramidal layer of the cortex and hippocampus, particularly the CA3 region, but not in the CA1 region and the dentate gyrus (DG). Intra-tail vein administration of cerebrolysin (10 ml of 1 mg/ml) after/during rmTBI treatment reduced p-tau expression in both the cortex and hippocampus. Histological analysis revealed mild astrocyte activation (increased expression of glial fibrillary acidic protein (GFAP)) but not microglia activation (ionized calcium binding adaptor molecule 1 (iba-1) expression) and peripheral macrophage infiltration (CD45). Additionally, administration of cerebrolysin after rmTBI resulted in reduced astrocyte activation. These observations in rmTBI demonstrated that cerebrolysin treatment reduces phosphorylation of tau and astrocyte activation, attenuates brain pathology, and mitigates function deficits in TBI. Taken together, our observations suggest that cerebrolysin has potential therapeutic value in CTE.

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Cerebrolysin reduces blood‐cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat

Cited by 82 publications

References 37 publications

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Improvement in functional recovery with administration of Cerebrolysin after experimental closed head injury

Cerebrolysin protects against rotenone-induced oxidative stress and neurodegeneration

Cerebrolysin Attenuates Astrocyte Activation Following Repetitive Mild Traumatic Brain Injury: Implications for Chronic Traumatic Encephalopathy

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