Nanodelivery of Cerebrolysin and Rearing in Enriched Environment Induce Neuroprotective Effects in a Preclinical Rat Model of Parkinson's Disease.

Rearing in enriched environment (EE) improves the recuperation in animal models of Parkinson's disease (PD). Administration of TiO2-nanowired cerebrolysin (CBL) could represent an additional strategy to protect or repair the nigrostriatal system. This study aims to explore morphofunctional and biochemical changes in a preclinical stage of PD testing the synergistic efficiency of combining both strategies, housing in EE, and nanodelivery of CBL. Sprague-Dawley male rats receiving intrastriatally 6-hydroxydopamine after a short evolution time were segregated into CBL group (rats receiving nanowired CBL), EE group (rats housed in EE), CBL + EE group (rats housed in EE and receiving nanowired CBL), and control group (rats without additional treatment). Prodromic stage and treatment effects were characterized by the presence of motor symptoms (amphetamine-induced rotational behavior test). Tyrosine hydroxylase (TH) immunohistochemistry and Western blot (p-Akt/Akt and p-ERK/ERK 1/2 as survival markers and caspase-3 as apoptotic marker) were performed in striatum and SN. A decrease in motor symptoms was shown by rats receiving CBL. EE monitoring cages revealed that rats from CBL + EE group showed more significant number of laps in the wheel than EE group. In SN, CBL + EE group also presented the highest neuronal density. Moreover, p-Akt/Akt and p-ERK/ERK 1/2 ratio was significant higher and caspase-3 expression was lower in CBL + EE group. In conclusion, the combination of CBL and EE provided evidence of neuoprotective-neurorestorative mechanisms by which this combined strategy promoted morphofunctional improvement by activation of survival pathways after dopamine depletion in a preclinical model of PD.

Efficacy and safety of Cerebrolysin treatment in early recovery after acute ischemic stroke: a randomized, placebo-controlled, double-blinded, multicenter clinical trial.

Background and Purpose : The aim of this study was to evaluate the efficacy, safety, and tolerability of cerebrolysin in the early recovery phase after acute ischemic stroke. Methods. This prospective, randomized, double-blinded, placebo-controlled, multicenter, parallel-group study enrolled a total of 100 patients within 18 h after the onset of stroke. The patients were treated with Cerebrolysin (30 mL over seven days followed by 10 mL until day 30) or placebo once daily over a period of four weeks. Efficacy was primarily assessed by the NIH Stroke Scale at day 30, and additional parameters included the modified Rankin Scale, the Clinical Global Impression, the Patient Global Satisfaction (PGS) and the Mini Mental State Examination (MMSE). Nonparametric statistical procedures employing the Wilcoxon-Mann-Whitney test were used for data analysis. Safety and tolerability were assessed by adverse events, vital signs, and laboratory parameters. Results.The estimated effect size on the change from baseline in the NIH Stroke Scale on day 30 indicated a medium to large superiority of cerebrolysin compared to placebo (Mann-Whitney [MW] 0.66; 95% confidence interval [CI] 0.55-0.78, P=0.005). Similar effect sizes were reported for the modified Ranking Scale (MW 0.65; 95% CI 0.54-0.76; P=0.010) and the Clinical Global Impression (MW 0.70; 95% CI 0.55-0.85; P=0.006). Effect sizes in the MMSE and PGS did not reach statistical significance. No significant group differences were seen in any of the safety parameters. Conclusions. Cerebrolysin was effective, safe, and well tolerated in the early recovery phase after acute ischemic stroke and significantly improved neurological and global function outcomes compared to placebo.

Long-term treatment of aged Long Evans rats with a dietary supplement containing neuroprotective peptides (N-PEP-12) to prevent brain aging: effects of three months daily treatment by oral gavage.

Aging is associated with morphological and functional changes in the brain, resulting in the deterioration of cognitive performance. Growth factors like BDNF are suggested to be involved in the regulation of age-related processes in the brain. A novel dietary supplement produced from purified nerve cell proteins, N-PEP-12, has shown to share properties with naturally occurring peptide growth factors by stimulating neurite outgrowth and beneficial effects on neuronal survival and protection against metabolic stress in cell cultures. The current study investigates the effects of long-term intake on age-dependent memory decline by assessing cognitive performance and synaptic density. All the experiments were performed in aged Long Evans rats randomly assigned to saline or N-PEP-12 once daily by gavage over a period of three months. Behavioral tests were performed in the Morris Water Maze after one, two and three months of treatment. Histological examinations were performed in the hippocampal formation and in the entorhinal cortex by measuring the synaptic density. This study shows that the oral intake of N-PEP-12 has beneficial effects on the cognitive performance of aged animals and that these effects go along with an increase in the synaptic density. Thus, N-PEP-12 may help maintain memory and learning performance during the aging process.

Combination treatment in Alzheimer's disease: results of a randomized, controlled trial with cerebrolysin and donepezil.

Treatment with neurotrophic agents might enhance and/or prolong the effects of cholinesterase inhibitors (ChEIs) in Alzheimer's disease (AD). We compared the safety and efficacy of the neurotrophic compound Cerebrolysin (10 ml; n=64), donepezil (10 mg; n=66) and a combination of both treatments (n=67) in mild-to-moderate (mini-mental state examination-MMSE score 12-25) probable AD patients enrolled in a randomized, double-blind trial. Primary endpoints were global outcome (Clinician's Interview-Based Impression of Change plus caregiver input; CIBIC+) and cognition (change from baseline in AD Assessment Scale-cognitive subscale+; ADAS-cog+) at week 28. Changes in functioning (AD Cooperative Study-Activities of Daily Living scale, ADCS-ADL) and behaviour (Neuropsychiatric Inventory, NPI) were secondary endpoints. Treatment effects in cognitive, functional and behavioral domains showed no significant group differences; whereas improvements in global outcome favored Cerebrolysin and the combination therapy. Cognitive performance improved in all treatment groups (mean±SD for Cerebrolysin: -1.7±7.5; donepezil: -1.2±6.1; combination: -2.3±6.0) with best scores in the combined therapy group at all study visits. Cerebrolysin was as effective as donepezil, and the combination of neurotrophic (Cerebrolysin) and cholinergic (donepezil) treatment was safe in mild-to-moderate AD. The convenience of exploring long-term synergistic effects of this combined therapy is suggested.

Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimer's disease: results of a randomized, double-blind, controlled trial investigating three dosages of Cerebrolysin.

BACKGROUND: cerebrolysin is a neuropeptide preparation mimicking the effects of neurotrophic factors. This subgroup analysis assessed safety and efficacy of Cerebrolysin in patients with moderate to moderately severe Alzheimer's disease (AD) (ITT data set: N = 133; MMSE: 14-20) included in a dose-finding study (ITT data set: N = 51; MMSE: 14-25). Results of the mild AD subgroup (ITT data set: N = 118; MMSE: 21-25) are also presented. METHODS: patients with AD received 100 ml IV infusions of Cerebrolysin (10, 30 or 60 ml diluted in saline; N = 32, 34 and 35, respectively) or placebo (saline; N = 32) over twelve weeks (5 days per week for 4 weeks and 2 days per week for another 8 weeks). Primary efficacy criteria ADAS-cog+ (Alzheimer's Disease Assessment Scale Cognitive Subpart Modified) and CIBIC+ (Clinical Interview-based Impression of Change with Caregiver Input) were assessed 24 weeks after baseline. RESULTS: at week 24, Cerebrolysin improved the global clinical function significantly with all three dosages and induced significant improvements in cognition, initiation of activities of daily living (ADL) and neuropsychiatric symptoms at 10-, 30- and 60-ml doses, respectively. Treatment effects on total ADL and other secondary parameters (MMSE, Trail-making test) were not significant. Cerebrolysin was safe and well tolerated. CONCLUSIONS: these results demonstrate the efficacy of Cerebrolysin in moderate to moderately severe AD, showing dose-specific effects similar to those reported for patients with mild to moderate AD. The benefits of Cerebrolysin in advanced AD need to be confirmed in larger trials.

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.

[The effect of cerebrolysin in dosage 50 ml on the volume of lesion in ischemic stroke].

The purpose of this randomized, double-blind, placebo-controlled study was to assess safety and efficacy of cerebrolysin used in dosage 50 ml in acute ischemic stroke. Forty-seven patients with ischemic stroke, aged 45-85 years, who were admitted to a clinical unit within the first 12 h after stroke onset were included in the study. A quantitative time-related MRI analysis of the dynamics of neurological deficit revealed the more rapid decrease of stroke volume to the 28th day in the group treated with cerebrolysin (45.4% versus 43.6% in the placebo-group (p < 0.05)). No side-effects of treatment with cerebrolysin was found. The results of this prospective, randomized, placebo-controlled study suggest the positive effect of cerebrolysin on the dynamics of volume lesion in patients with ischemic stroke.

A double-blind, placebo-controlled, randomized trial to evaluate the safety and efficacy of Cerebrolysin in patients with acute ischaemic stroke in Asia--CASTA.

Cerebrolysin has exhibited neuroprotective as well as neurotrophic properties in various animal models of cerebral ischaemia and has shown clinical efficacy and good safety in several small controlled clinical studies in ischaemic stroke. Therefore, a large double-blind placebo-controlled randomized clinical trial was launched in Asia to prove the validity of this treatment strategy. In the more than 50 participating centres patients with acute ischemic hemispheric stroke are randomized within 12 hours of symptoms onset to treatment (30 ml Cerebrolysin diluted in physiologic saline) or placebo (saline) given as intravenous infusion once daily added to standard care for 10 days. The patients are followed with regular visits for 90 days. Efficacy is evaluated on day 90 by three outcome scales - modified Rankin Scale, Barthel Index and NIH Stroke Scale - combined to single global directional test. Additionally, adverse events are documented to prove safety. In this study a total of 1060 patients will be included and analysis of data will be completed in 2010. If positive, this trial will add an effective strategy to the treatment of acute ischaemic stroke.

A 24-week, double-blind, placebo-controlled study of three dosages of Cerebrolysin in patients with mild to moderate Alzheimer's disease.

Cerebrolysin (Cere) is a compound with neurotrophic activity shown to be effective in Alzheimer's disease in earlier trials. The efficacy and safety of three dosages of Cere were investigated in this randomized, double-blind, placebo-controlled, study. Two hundred and seventy-nine patients were enrolled (69 Cere 10 ml; 70 Cere 30 ml; 71 Cere 60 ml and 69 placebo). Patients received iv infusions of 10, 30, 60 ml Cere or placebo 5 days/week for the first 4 weeks and thereafter, two iv infusions per week for 8 weeks. Effects on cognition and clinical global impressions were evaluated 4, 12 and 24 weeks after the beginning of the infusions using the CIBIC+ and the modified Alzheimer's Disease Assessment Scale (ADAS)-cog. At week 24, significant improvement of cognitive performance on the ADAS-cog (P=0.038) and global function (CIBIC+; P>0.001) was observed for the 10 ml dose. The 30 and 60 ml doses showed significant improvement of the global outcome but failed to show significant improvement of cognition. The results are consistent with a reversed U-shaped dose-response relationship for Cere. The percentage of patients reporting adverse events was similar across all study groups. Cere treatment was well tolerated and led to significant, dose-dependent improvement of cognition and global clinical impression.

Neuroprotection of cerebrolysin in tissue culture models of brain ischemia: post lesion application indicates a wide therapeutic window.

All attempts to reduce neuronal damage after acute brain ischemia by the use of neuroprotective compounds have failed to prove efficacy in clinical trials so far. One of the main reasons might be the relatively narrow time window for intervention. In this study 2 different tissue culture models of ischemia, excitotoxic lesion by the use of glutamate and oxygen-glucose deprivation (OGD), were used to investigate the effects of delayed application of Cerebrolysin (Cere) on neuronal survival. This drug consists of low molecular weight peptides with neuroprotective and neurotrophic properties similar to naturally occurring growth factors. After both types of lesion, acute as well as delayed treatment with Cere resulted in a dose dependent and significant rescue of neurons. In the model of excitotoxic cell death significant drug effects were found even when the treatment started with a delay of 96 hours after addition of glutamate. In the OGD model pronounced effects were found after 48 hours delay of treatment, and even after 72 hours a small but significant rescue of neurons was detected. The neuroprotective effects of a single addition of Cerebrolysin to the culture medium resulted in significant protection until end of the experiments which was up to 2 weeks after the initial lesion. A shift of the efficacious dosages from low to high concentrations indicates that most likely active compounds are used up, indicating that multiple dosing might even increase the effect size. In conclusion the results indicate that Cere displays a relatively wide therapeutic time window which might be explained by a combination of acute neuroprotective properties and neurotrophic efficacy.

A peptide preparation protects cells in organotypic brain slices against cell death after glutamate intoxication.

Cerebrolysin has been shown to have neurotrophic and neuroprotective potential similar to NGF or BDNF. In the present study organotypic brain slices were utilized to determine the neuroprotective effects of Cerebrolysin, in a glutamate lesion paradigm mimicking a key event in ischemia. The study focused on the effects of Cerebrolysin on both necrotic and apoptotic cell death. Two specific DNA intercalating dyes were used to distinguish the type of cell death. The drug effect was evaluated both microscopically and quantitatively before, 24 hours after and then again 8 days after the lesion. Cerebrolysin was added either before and after the lesion or after the lesion only. The most pronounced effect was seen with the drug added both prior to and after the glutamate lesioning. A treatment after the lesion only also counteracted necrosis and apoptosis. The results render the drug relevant for treating acute as well as chronic neurodegenerative diseases.

Neuropeptide dietary supplement N-PEP-12 enhances cognitive function and activates brain bioelectrical activity in healthy elderly subjects.

N-PEP-12 is a dietary supplement consisting of neuropeptides and amino acids. In animal experiments, the compound has been shown to enhance cognitive function and reduce neurodegenerative events associated with aging. In this study, we investigated the effects of a single oral dose of N-PEP-12 (180 mg) on brain bioelectrical activity and cognitive performance in healthy elderly subjects. N-PEP-12 induced a significant (p < 0.05) increase in relative alpha-activity power 6 h after administration. This enhancement was accompanied by a generalized decrease in slow Delta-activity. Significant improvement in memory performance subtests was also seen 6 h after N-PEP-12 administration in some but not in all tests. Taken together, these data suggest that N-PEP-12 might be a reliable dietary supplement to be investigated for improving and, perhaps, maintaining brain function among healthy older adults.

N-PEP-12--a novel peptide compound that protects cortical neurons in culture against different age and disease associated lesions.

The neuroprotective potency of N-PEP-12, a novel, proprietary compound consisting of biopeptides and amino acids was investigated. Lesion models have been applied in neuronal cultures of embryonic chicken cortex, pre-treated with N-PEP-12 from the first day onwards. On day 8 in vitro neurons were lesioned and cell viability was measured 24 and 48 hours later. To simulate acute brain ischemia, cytotoxic hypoxia was induced by sodium cyanide or by iodoacetate and excitotoxicity by L-glutamate. Ionomycin for up to 48 hours induced calcium overload. The cytoskeleton was disrupted by addition of colchicine. N-PEP-12 shows dose-dependent neuroprotection in all different models. The effect size depends on the recovery time but also on the extent of the lesion. In cases of mild to moderate lesion pronounced dose-dependent effects could be demonstrated. This indicates that chronic exposure to N-PEP-12 is able to prevent neuronal cell death associated to conditions occurring during normal aging and neurological disorders like ischemic stroke, hypoxia, brain trauma, or AD.

Amelioration of the cerebrovascular amyloidosis in a transgenic model of Alzheimer's disease with the neurotrophic compound cerebrolysin.

Increased production and reduced clearance of amyloid beta (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). We have recently shown that the neurotrophic peptide mixture Cerebrolysin (Cbl) has the ability of improving synaptic functioning and reducing amyloid deposition in a transgenic (tg) animal model of Alzheimer's disease (AD). Since in AD, potentially toxic Abeta aggregates accumulate not only around neurons but also in the blood vessels, then it is important to investigate whether bioactive compounds such as Cbl might have the capacity to ameliorate the age-related cerebral amyloid angiopathy (CAA) in tg models. To this end, tg mice expressing mutant human amyloid precursor protein (APP) under the Thy1 promoter were treated with Cbl or saline alone starting at 7 or 12 months of age for a total of three months. Neuropathological analysis with an antibody against Abeta showed that Cbl decreased amyloid deposition around the blood vessels in a time dependent manner. These effects were accompanied by a reduction in perivascular microgliosis and astrogliosis and increased expression of markers of vascular fitness such as CD31 and ZO-1. No lymphocytic infiltration was observed associated with Abeta in the vessels. Consistent with these findings, ultrastructural analysis showed that while in tg mice treated with saline alone there was an abundant accumulation of amyloid fibers in the vascular wall accompanied by thickening of the basal membrane and endothelial cell damage, in Cbl-treated mice there was considerable reduction in the subcellular alterations of endothelial and smooth muscle cells with preservation of basal membranes and intercellular junctions. Taken together, these results suggest that Cbl treatment might have beneficial effects in patients with cognitive impairment due to cerebrovascular amyloidosis by reducing Abeta accumulation and promoting the preservation of the cerebrovasculature.

Neuroprotective treatment with cerebrolysin in patients with acute stroke: a randomised controlled trial.

BACKGROUND AND PURPOSE: Cerebrolysin is a compound with neurotrophic and neuroprotective activity. It is produced by enzymatic breakdown of purified brain proteins and consists of low molecular weight peptides and amino acids. Cellular and animal models of cerebral ischaemia have shown that it is a potent neuroprotective agent. We explored the safety and preliminary outcome of Cerebrolysin treatment in patients with acute stroke. METHODS: Randomised, placebo-controlled, parallel group trial. Patients with acute stroke were randomised within 24 h of stroke onset to IV therapy with placebo or Cerebrolysin 50 mL/day for 21 days. Both groups received concomitant treatment with ASA 250 mg/day PO and pentoxifylline 300 mg/day IV. Clinical examinations were performed on days 1, 3, 7, 21 and 90 post baseline. Outcome measures were the Canadian Neurological Scale, the Barthel Index, the Clinical Global Impressions, the Mini-Mental State Examination, and the Syndrome Short Test. Treatment emergent adverse events, lab tests, and vital signs were recorded to assess the safety of Cerebrolysin. RESULTS: 146 patients were enrolled in two groups: 78 Cerebrolysin and 68 placebo. At baseline, no significant group differences were observed. Patients in the Cerebrolysin group had no significant improvement in the CNS score, the Barthel Index and the Clinical Global Impressions when compared to the placebo group. A significant improvement of cognitive function of the patients on Cerebrolysin was observed in the Syndrome Short Test when compared to the placebo group. Cerebrolysin was well tolerated and safe. Adverse events occurred with a similar frequency in both groups. CONCLUSION: The results demonstrate that neurotrophic treatment with Cerebrolysin is safe and well tolerated by patients with acute stroke. The findings, despite the small sample size, also indicate a potential treatment effect of Cerebrolysin in acute stroke. Larger studies, however, are needed to confirm and extend these findings.

The neuroprotective effects of Cerebrolysin in a transgenic model of Alzheimer's disease are associated with improved behavioral performance.

Cerebrolysin is a peptide mixture with neurotrophic effects that might have the ability of both reducing amyloid burden and improving synaptic plasticity in Alzheimer's disease (AD). In order to determine if Cerebrolysin is capable of ameliorating the neurodegenerative and behavioral alterations associated with amyloid beta (A beta) production; transgenic (tg) mice expressing mutant human amyloid precursor protein (APP) under the Thy1 promoter were treated with Cerebrolysin or saline alone starting at 3 or 6 months of age for a total of three months. Animals were then tested behaviorally (at 6 and 9 months of age respectively) in the water maze and then analyzed neuropathologically for amyloid burden, synaptic density, astrogliosis and apoptosis. Performance analysis in the water maze showed that in the younger tg mice cohort, Cerebrolysin treatment significantly ameliorated the performance deficits. In the older cohort, there was a trend toward improved performance in the learning curve. Neuropathological examination showed that in both age/treatment groups, Cerebrolysin promoted synaptic regeneration, and reduced the proportion of neurons displaying DNA fragmentation by the (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method. Moreover, Cerebrolysin treatment reduced A beta burden by 43% in the young group and by 27% in the older group. Taken together, these results suggest that Cerebrolysin treatment might have beneficial effects in patients with cognitive impairment by reducing A beta accumulation and promoting the preservation of synaptic terminals.

Sustained improvement of cognition and global function in patients with moderately severe Alzheimer's disease: a double-blind, placebo-controlled study with the neurotrophic agent Cerebrolysin.

BACKGROUND: In a recent study, Cerebrolysin (Cere), a compound with neurotrophic activity, has been shown to be effective in the treatment of mild to moderate Alzheimer's disease (AD). A subgroup analysis of this double-blind, placebo-controlled study was performed to assess the effects of Cere in cases with more advanced forms of AD. PATIENTS AND METHODS: Patients received infusions of 30 ml Cere or placebo five days/week for four weeks. This treatment was repeated after a two-months therapy-free interval. Effects on cognition, global function, behavioural symptoms and activities of daily living were evaluated 4, 12, 16, and 28 weeks after the beginning of the infusions. 109 patients with MMSE scores <20 were included in this analysis. RESULTS: The responder rate of the Cere group was 65% on the CGI, compared to 24.5% in the placebo group (p < 0.004). In the ADAS-cog, a score difference of 4.1 points in favour of Cere was observed (p < 0.0001). Notably, improvements were largely maintained in the Cere group up to the week 28 visit. CONCLUSION: The data clearly demonstrate the efficacy of Cere treatment in moderate to severe forms of AD with sustained treatment effects on cognition and global function even after discontinuation of treatment.

Improved global function and activities of daily living in patients with AD: a placebo-controlled clinical study with the neurotrophic agent Cerebrolysin.

BACKGROUND: Cerebrolysin (Cere) is a peptidergic, neurotrophic drug which has been shown to improve cognitive performance and global function of Alzheimer's disease (AD) patients in earlier trials. In this study, we have attempted to replicate this findings with particular emphasis on functional improvement of the patients. PATIENTS AND METHODS: Patients received infusions of 30 ml Cere or placebo five days/week for six consecutive weeks. Patients had to have a diagnosis of AD and a MMSE score of 14-25 inclusive. Effects on cognition, global function, and activities of daily living were evaluated 3, 6, and 18 weeks after the beginning of the infusions. RESULTS: Significant improvement of cognitive function, clinical global impression and activities of daily living were seen after the end of the therapy. The effects were most pronounced in the DAD score, a measure for the capability to perform activities of daily living. Interestingly, and in line with the findings of earlier studies, the treatment effect of Cere was maintained after cessation of treatment up to the week 18 assessment. CONCLUSION: The data confirm the findings of earlier trials and clearly demonstrates that Cere leads to functional improvement of patients with AD. The sustained treatment effect of Cere after withdrawal has been confirmed.

Effects of Cerebrolysin on amyloid-beta deposition in a transgenic model of Alzheimer's disease.

We investigated the potential mechanisms through which Cerebrolysin, a neuroprotective noothropic agent, might affect Alzheimer's disease pathology. Transgenic (tg) mice expressing mutant human (h) amyloid precursor protein 751 (APP751) cDNA under the Thy-1 promoter (mThy1-hAPP751) were treated for four weeks with this compound and analyzed by confocal microscopy to asses its effects on amyloid plaque formation and neurodegeneration. In this model, amyloid plaques in the brain are found much earlier (beginning at 3 months) than in other tg models. Quantitative computer-aided analysis with anti-amyloid-beta protein (A beta) antibodies, revealed that Cerebrolysin significantly reduced the amyloid burden in the frontal cortex of 5-month-old mice. Furthermore, Cerebrolysin treatment reduced the levels of A beta(1-42). This was accompanied by amelioration of the synaptic alterations in the frontal cortex of mThy1-hAPP751 tg mice. In conclusion, the present study supports the possibility that Cerebrolysin might have neuroprotective effects by decreasing the production of A beta(1-42) and reducing amyloid deposition.

Cerebrolysin in Alzheimer's disease: a randomized, double-blind, placebo-controlled trial with a neurotrophic agent.

UNLABELLED: Cerebrolysin (Cere) is a compound with neurotrophic activity. It has been shown to be effective in the treatment of Alzheimer's disease (AD) in earlier trials. In this multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients were injected intravenously with placebo or 30 mL Cere five days per week for four weeks. Effects on cognition and global function were evaluated with the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinicians Interview-based Impression of Change with Caregiver Input scale (CIBIC+) 4, 12, 24 weeks after the beginning of the injections. 192 patients were enrolled, 95 were randomized to placebo, and 97 to Cere. At baseline, there was a significant difference between groups for age, age of onset of dementia, and the number of patients with hallucinations. At week 12 there was a significant difference on the CIBIC+ (p = 0.033) in favor of Cere. The number of CIBIC+ responders (score < or = 4), was significantly higher (p = 0.007), with 68 (76%) in the Cere group and 51 (57%) in the placebo group. Trends were noted in the Disability Assessment in Dementia scale and the Cornell Depression Scale. Adverse events were recorded in 73% of placebo and 64% of Cere patients. Most common adverse events were headaches, dizziness, weight loss and anxiety. CONCLUSIONS: Cere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatment.