Cerebrolysin (Cbl) shows neurotrophic and neuroprotective properties while donepezil (Dnp) is a potent acetylcholinesterase (AChE) inhibitor, both drugs are prescribed for Alzheimer's disease (AD) treatment. Previous studies have shown that the Dnp and Cbl administered separately, modify dendritic morphology of neurons in the prefrontal cortex and hippocampus in senile rodents. Since the deficit of neurotrophic factor activity is implicated in the degeneration of cholinergic neurons of basal forebrain, a combination therapy of Dnp and Cbl has been tested recently in Alzheimer's patients. However, the plastic changes that may underlie this combined treatment have not yet been explored. We present here the effect of the combined administration of Cbl and Dnp on dendritic morphology in brain regions related to learning and memory in aged mice. The Golgi-Cox staining protocol and Sholl analysis were used for studying dendritic changes. Cbl and Dnp were administrated daily for 2 months to 9-months-old mice. Locomotor activity was assessed, as well as the dendritic morphology of neurons in several limbic regions was analyzed. Results showed that Cbl and Dnp induced an increase in locomotor activity without synergistic effect. The Cbl or Dnp treatment modified the dendritic morphology of neurons from prefrontal cortex (PFC), dorsal hippocampus (DH), dentate gyrus (DG), and the shell of nucleus accumbens (NAcc). These changes show an increase in the total dendritic length and spine density, resulting in an improvement of dendritic arborization. Prominently, a synergistic effect of Cbl and Dnp was observed on branching order and total dendritic length of pyramidal neurons from PFC. These results suggest that Dnp and Cbl may induce plastic changes in a manner independent of each other, but could enhance their effect in target cells from PFC.

Combined administration of cerebrolysin and donepezil induces plastic changes in prefrontal cortex in aged mice.

https://journals.sagepub.com/doi/pdf/10.1177/0963689717714105

Impact of Traumatic Brain Injury on Dopaminergic Transmission.

Traumatic brain injury (TBI) is a leading cause of death and disability for which there is currently no effective drug therapy available. Because drugs targeting a single TBI pathological pathway have failed to show clinical efficacy to date, pleiotropic agents with effects on multiple mechanisms of secondary brain damage could represent an effective option to improve brain recovery and clinical outcome in TBI patients. In this multicenter retrospective study, we investigated severity-related efficacy and safety of the add-on therapy with two concentrations (20 ml/day or 30 ml/day) of Cerebrolysin (EVER Neuro Pharma, Austria) in TBI patients. Adjunctive treatment with Cerrebrolysin started within 48 hours after TBI and clinical outcomes were ranked according to the Glasgow Outcome Scale and the Modified Rankin Disability Score at 10 and 30 days post-TBI. Analyses of efficacy were performed separately for subgroups of patients with mild, moderate or severe TBI according to Glasgow Coma Scale scores at admission. Compared to standard medical care alone (control group), both doses of Cerebrolysin were associated with improved clinical outcome scores at 10 days post-TBI in mild patients and at 10 and 30 days in moderate and severe cases. A dose-dependent effect of Cerebrolysin on TBI recovery was supported by the dose-related differences and the significant correlations with treatment duration observed for outcome measures. The safety and tolerability of Cerebrolysin in TBI patients was very good. In conclusion, the results of this large retrospective study revealed that early Cerebrolysin treatment is safe and is associated to improved TBI outcome.

A retrospective, multi-center cohort study evaluating the severity- related effects of cerebrolysin treatment on clinical outcomes in traumatic brain injury.

Background Traumatic brain injury (TBI) remains a main public health problem being associated with high mortality and morbidity. The functional outcome of TBI remains unfavorable despite several surgical and medical therapies. Cerebrolysin is a neuropeptide with potential neuroregenerative entities. Objective The aim of the current systematic review and meta-analysis was to investigate the effects of cerebrolysin on functional outcome in patients with moderate and severe TBI. Data sources Online databases used included Medline, Scopus, EMBASE, Google Scholar, Web of Science, and Cochrane Library. Study eligibility criteria All the relevant studies with randomized clinical trial and cohort design evaluating the effects of intravenous cerebrolysin vs placebo on functional outcome of patients with TBI within the English literature up to October 2018 were included. Study appraisal and synthesis methods The articles were reviewed by two independent authors and the data were extracted to a data sheet. I2 and Cochran's Q-statistics were used to assess heterogeneity. Based on the presence of significant heterogeneity across included studies, data were pooled using random-effects model with Dersimonian-Laird method and presented as standardized mean differences (SMDs) and corresponding 95% CI. Results Five articles (5,685 participants) were included in the current meta-analysis. The overall pooled findings using random-effects models among patients with TBI indicated that intravenous administration of cerebrolysin significantly increased Glasgow Outcome Scale score (SMD =0.30; 95% CI: 0.18 to 0.42; P<0.001; I2: 87.8%) and decreased modified Rankin Scale score (SMD =-0.29; 95% CI: -0.42 to 0.16; P=0.05; I2: 89.6%). Limitations The results are mainly based on cohort studies and there is a lack of clinical trials in the literature. There is also heterogeneity among the studies regarding the dosage and duration of administration and the measurement of functional outcome. Conclusion The results of the current study revealed that intravenous administration of cerebrolysin is associated with improved functional outcome in patients with TBI measured by the Glasgow Outcome Scale and the modified Rankin Scale scores.

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Effects of cerebrolysin on functional outcome of patients with traumatic brain injury: a systematic review and meta-analysis.

The objective of this trial was to evaluate the efficacy and safety of Cerebrolysin in treating patients after moderate to severe traumatic brain injury (TBI) as an adjunct to standard care protocols. The trial was designed to investigate the clinical effects of Cerebrolysin in the acute (neuroprotective) stage and during early and long-term recovery as part of a neurorestorative strategy. The study was a phase IIIb/IV single-center, prospective, randomized, double-blind, placebo-controlled clinical trial. Eligible patients with a Glasgow Coma Score (GCS) between 7 and 12 received study medication (50 ml of Cerebrolysin or physiological saline solution per day for 10 days, followed by two additional treatment cycles with 10 ml per day for 10 days) in addition to standard care. We tested ensembles of efficacy criteria for 90, 30, and 10 days after TBI with a priori ordered hypotheses using a multivariate, directional test, to reflect the global status of patients after TBI. The study enrolled 142 patients, of which 139 underwent formal analysis (mean age = 47.4, mean admission GCS = 10.4, and mean Baseline Prognostic Risk Score = 2.6). The primary endpoint, a multidimensional ensemble of 13 outcome scales, indicated a “small-to-medium”–sized effect in favor of Cerebrolysin, statistically significant at day 90 (MWcombined = 0.59, 95% CI 0.52 to 0.66, P = 0.0119). Safety and tolerability observations were comparable between treatment groups. Our trial confirms previous beneficial effects of the multimodal, biological agent Cerebrolysin for overall outcome after moderate to severe TBI, as measured by a multidimensional approach. Study findings must be appraised and aggregated in conjunction with existing literature, as to improve the overall level of insight regarding therapeutic options for TBI patients. The widely used pharmacologic intervention may benefit from a large-scale observational study to map its use and to establish comparative effectiveness in real-world clinical settings.

Efficacy and safety of cerebrolysin in neurorecovery after moderate-severe traumatic brain injury: results from the CAPTAIN II trial

Background: Discovery of neurotrophic factors–emblematic: the nerve growth factor (NGF)–resulted in better approaching central nervous system (CNS) lesions. Recently, another crucial property has been unveiled: their rather unique pleiotropic effect. Cerebrolysin is a peptide mixture that penetrates the blood–brain barrier in significant amounts and mimics the effects of NGF.

Methods: Comparative analysis: Cerebrolysin treated (10 ml x 2/ day, i.v. x 3 weeks) vs. non–treated, in patients (all received aside, a rather equivalent complementary, pharmacological and physical, therapy). Two lots of patients, admitted in our Physical and Rehabilitation (neural–muscular) Medical–PR(n–m)M–Clinic Division, during 2007–2009: 69 treated with Cerebrolysin (22 F, 47 M; Average: 59.333; Mean of age: 61.0 Years old; Standard deviation 16.583) and 70 controls (41 F, 29 M; A: 70.014; M.o.a.: 70.5 Y.o.; S.d.: 6.270) were studied. The total number of assessed items was 13: most contributive in relation with the score of Functional Independence Measure at discharge (d FIM), were: admission (a FIM), number of physical therapy days (PT), number of hospitalization days (H), age (A) and–relatively–days until the first knee functional extension (KE). Concomitantly, the main/ key, focused on neuro–motor rehabilitative outcomes, functional/analytical parameters, have been assessed regarding the speed in achieving their functional recovery.

Results: Concerning d FIM, there have not been objectified significant differences between the two lots (p=0.2453) but regarding key, focused on neuro–motor rehabilitative outcomes, functional/analytical parameters: KE (p=0.0007) and days until the first time recovery of the ability to walk between parallel bars (WPB–p=0.0000)–highly significant differences in favor of Cerebrolysin lot resulted.

Conclusion: Cerebrolysin administration, as neurorehabilitative outcomes, proved to hasten, statistically significant, especially the recovery of some critical, for standing and walking, parameters. Thus encouraged, we have now initiated a comprehensive national, 5 year retrospective, multi–centre – based on unitary data acquisition frame and mathematical apparatus–study, to evaluate the results of the treatment with Cerebrolysin in traumatic brain injuries (TBI).

D C Mardare

Papers

Neuroprotective and consequent neurorehabilitative clinical outcomes, in patients treated with the pleiotropic drug cerebrolysin