Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure.

BACKGROUND: Alzheimer's Disease (AD) and Fronto temporal lobar dementia (FTLD) are common causes of dementia in the aging population for which limited therapeutical options are available. These disorders are associated with Tau accumulation. We have previously shown that Cerebrolysin™ (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the behavioral deficits and neuropathological alterations in amyloid precursor protein (APP) transgenic (tg) mouse model of AD by reducing hyper-phosphorylated Tau. CBL has been tested in clinical trials for AD, however it's potential beneficial effects in FTLD are unknown. For this purpose we sought to investigate the effects of CBL in a tg model of tauopathy. Accordingly, double tg mice expressing mutant Tau under the mThy-1 promoter and GSK3ß (to enhance Tau phosphorylation) were treated with CBL and evaluated neuropathologically. RESULTS: Compared to single Tau tg mice the Tau/GSK3ß double tg model displayed elevated levels of Tau phosphorylation and neurodegeneration in the hippocampus. CBL treatment reduced the levels of Tau phosphorylation in the dentate gyrus and the degeneration of pyramidal neurons in the temporal cortex and hippocampus of the Tau/GSK3ß double tg mice. Interestingly, the Tau/GSK3ß double tg mice also displayed elevated levels of Dynamin-related protein-1 (Drp-1), a protein that hydrolyzes GTP and is required for mitochondrial division. Ultrastructural analysis of the mitochondria in the Tau/GSK3ß double tg mice demonstrated increased numbers and fragmentation of mitochondria in comparison to non-tg mice. CBL treatment normalized levels of Drp-1 and restored mitochondrial structure. CONCLUSIONS: These results suggest that the ability of CBL to ameliorate neurodegenerative pathology in the tauopathy model may involve reducing accumulation of hyper-phosphorylated Tau and reducing alterations in mitochondrial biogenesis associated with Tau.

Regional comparison of the neurogenic effects of CNTF-derived peptides and cerebrolysin in AßPP transgenic mice.

Adult neurogenesis, the production of new neurons in certain brain regions, is known to decrease with age and the loss of neurogenic potential has been implicated in Alzheimer's disease (AD), a leading cause of dementia in the elderly. Cerebrolysin (CBL) has been shown to increase neurogenesis in models of stroke and AD. CBL is composed of small peptides with activity similar to neurotrophic factors including ciliary neurotrophic factor (CNTF), which may mediate its neurogenic effects. This study compares the effects of CBL and two peptides with corresponding to an active region of CNTF (Peptide 6 and 6A) across neurogenic brain regions in amyloid-ß protein precursor (AßPP) transgenic (tg) mice. Both CBL and Peptides 6 and 6A were able to increase the numbers of neuroblasts (DCX+ cells) and BrdU+ cells in a regionally specific manner across the subventricular zone, olfactory bulb, and hippocampus. The increased generation of new cells and cell survival in animals treated with Peptides 6 and 6A was accompanied by an increase in PCNA+ cells. In contrast, AßPP tg mice treated with CBL displayed reduced levels of TUNEL staining, while levels of PCNA were unaltered. Collectively these results demonstrate that while CBL and Peptides 6 and 6A all potentiate neurogenesis in the AßPP tg mice, their relative modes of action may differ with CBL associated with reduced apoptosis and Peptides 6 and 6A working by augmenting cell proliferation. These results are consistent with a potential therapeutic relevance for Peptides 6 and 6A in AD and other disorders characterized by neurogenic deficits.

Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer's disease.

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the loss of neurotrophic factors, and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity. Cerebrolysin, a peptide mixture with neurotrophic-like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice overexpressing the amyloid precursor protein (APP). However, it is unclear how long-lasting the beneficial effects of Cerebrolysin are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption. The objective of the present study was to investigate the consequences of interrupting Cerebrolysin treatment (washout effect) 3 and 6 months after the completion of a 3-month treatment period in APP tg mice. We demonstrate that, in APP tg mice, Cerebrolysin-induced amelioration of memory deficits in the water maze and reduction of neurodegenerative pathology persist for 3 months after treatment interruption; however, these effects dissipate 6 months following treatment termination. Immunohistochemical analysis demonstrated that the decrease in neocortical and hippocampal amyloid plaque load observed in Cerebrolysin-treated APP tg mice immediately after treatment was no longer apparent at 3 months after treatment interruption, indicating that the beneficial effects of Cerebrolysin at this time point were independent of its effect on amyloid-ß deposition. In conclusion, the results demonstrate that the effects of Cerebrolysin persist for a significant period of time following treatment termination and suggest that this prolonged effect may involve the neurotrophic factor-like activity of Cerebrolysin.

Cerebrolysin in vascular dementia: improvement of clinical outcome in a randomized, double-blind, placebo-controlled multicenter trial.

No drug to treat vascular dementia (VaD) has yet been approved by the American or European authorities, leaving a large population of patients without effective therapy. Cerebrolysin has a long record of safety and might be efficacious in this condition. We conducted a large, multicenter, double-blind, placebo-controlled study in 242 patients meeting the criteria for VaD. The primary endpoint was the combined outcome of cognition (based on Alzheimer's Disease Assessment Scale Cognitive Subpart, Extended Version [ADAS-cog+] score) and overall clinical functioning (based on Clinician's Interview-Based Impression of Change plus Caregiver Input [CIBIC+] score) assessed after 24 weeks of treatment. Intravenous Cerebrolysin 20 mL was administered once daily over the course of 2 treatment cycles as add-on therapy to basic treatment with acetylsalicylic acid. The addition of Cerebrolysin was associated with significant improvement in both primary parameters. At week 24, ADAS-cog+ score improved by 10.6 points in the Cerebrolysin group, compared with 4.4 points in the placebo group (least squares mean difference, -6.17; P < .0001 vs placebo). CIBIC+ showed a mean improvement of 2.84 in the treatment arm and 3.68 in the placebo arm, a treatment difference of 0.84 (P < .0001 vs placebo). These findings were confirmed by responder analyses demonstrating higher rates in the Cerebrolysin group (ADAS-cog+ improvement of ≥4 points from baseline, 82.1% vs 52.2%; CIBIC+ score of <4 at week 24, 75.3% vs 37.4%; combined response in ADAS-cog+ and CIBIC+, 67.5% vs 27.0%). For Cerebrolysin, the odds ratio for achieving a favorable CIBIC+ response was 5.08 (P < .05), and that for achieving a favorable combined response was 5.63 (P < .05). Our data indicate that the addition of Cerebrolysin significantly improved clinical outcome, and that the benefits persisted for at least 24 weeks. Cerebrolysin was safe and well tolerated.

Efficacy and safety of Cerebrolysin in patients with hemorrhagic stroke.

UNLABELLED: The purpose of the study was to investigate the efficacy and safety of Cerebrolysin in patients with hemorrhagic stroke. The primary objective of this trial was to assess the clinical efficacy and safety of a 10-days course of therapy with a daily administration of Cerebrolysin (50 mL i.v. per day). The trial had to demonstrate that Cerebrolysin treatment is safe in hemorrhagic stroke. METHODS: The study was performed as a prospective, randomized, double blind, placebo-controlled, parallel group study with 2 treatment groups. Efficacy measures were the Unified Neurological Stroke Scale, Barthel Index, and Syndrome Short Test. The duration of the trial was of 21 days for each patient. Out of 100 randomized patients, a total of 96 (96%) completed the study. RESULTS: Overall, no statistically significant group effects were observed based on single average comparisons at the individual visits. It could be shown that the treatment of hemorrhagic stroke with Cerebrolysin is safe and well tolerated. CONCLUSION: In the changes of UNSS, BI and SST from baseline to day 21, the group differences are not statistically significant; however, the use of Cerebrolysin in hemorrhagic stroke is safe and well tolerated and studies with a larger sample size may provide statistical evidence of Cerebrolysin's efficacy in patients with hemorrhagic stroke.

Persistence of the effects of Cerebrolysin on cognition and qEEG slowing in vascular dementia patients: results of a 3-month extension study.

The maintenance of the effects of Cerebrolysin, a peptidergic compound with neurotrophic activity, on cognitive performance and qEEG activity was investigated through a 12-week, open-label extension of a 4-week, randomised, placebo-controlled pilot study. Thirty-three out of 41 patients with mild-to-moderate severe probable vascular dementia (VaD) according to NINDS-AIREN participating in the double-blind phase of the study were also assessed at the follow-up visit at week 16. Patients received i.v. infusions of Cerebrolysin (10 or 30 mL) or placebo (saline) 5 days/week for 4 weeks. Neuropsychological evaluations and qEEG recordings were done at baseline, week 4 and week 16. The mean change in score from baseline in the ADAS-cog+ and the slow-to-fast qEEG power ratio (PR), used as an index of qEEG slowing, were the two primary endpoints. Correlations between changes in cognition and qEEG induced by the treatment were also assessed. At the week 16 follow-up visit, Cerebrolysin improved (p<0.05) cognitive performance at the 10-mL and 30-mL doses and reduced qEEG slowing significantly (p<0.05) at the 30-mL dose with respect to the placebo. In addition, a significant (p<0.05) positive correlation between the change from the baseline qEEG PR and ADAS-cog+ variables was observed at week 16. These results indicate a persistence of the beneficial effects of Cerebrolysin on cognition and qEEG activity in VaD patients for at least 12 weeks after treatment cessation, and they suggest the potential utility of qEEG parameters as biomarkers for VaD clinical trials.

Acute drug prescribing to children on chronic antiepilepsy therapy and the potential for adverse drug interactions in primary care.

AIMS: To investigate the extent of acute coprescribing in primary care to children on chronic antiepileptic therapy, which could give rise to potentially harmful drug-drug interactions. DESIGN: Acute coprescribing to children on chronic antiepileptic drug therapy in primary care was assessed in 178 324 children aged 0-17 years for the year 1 November 1999 to 31 October 2000. Computerized prescribing data were retrieved from 161 representative general practices in Scotland. SETTING: One hundred and sixty-one general practices throughout Scotland. RESULTS: During the study year 723 (0.41%) children chronically prescribed antiepileptic therapy were identified. Fourteen antiepileptic agents were prescribed, with carbamazepine, sodium valproate and lamotrigine accounting for 80% of the total. During the year children on chronic antiepileptic therapy were prescribed 4895 acute coprescriptions for 269 different medicines. The average number of acute coprescriptions for non-epileptic drug therapy were eight, 11, six, and six for the 0-1, 2-4, 5-11, and 12-17-year-olds, respectively. Of these acute coprescriptions 72 (1.5%) prescribed to 22 (3.0%) children were identified as a potential source of clinically serious interactions. The age-adjusted prevalence rates for potentially serious coprescribing were 86, 26, 22, and 33/1000 children chronically prescribed antiepileptic therapy in the 0-1, 2-4, 5-11, and 12-17-year-old age groups, respectively. The drugs most commonly coprescribed which could give rise to such interactions were antacids, erythromycin, ciprofloxacin, theophylline and the low-dose oral contraceptive. For 10 (45.5%0 of the 20 children identified at risk of a potentially clinically serious adverse drug interaction, the acute coprescription was prescribed off label because of age or specific contraindication/warning. CONCLUSIONS: In primary care, 3.0% of children on chronic antiepileptic therapy are coprescribed therapeutic agents, which could give rise to clinically serious drug-drug interactions.