Background and Purpose—: The aim of this trial was to investigate whether stroke patients who receive Cerebrolysin show improved motor function in the upper extremities at day 90 compared with patients who receive a placebo. Methods—: This study was a prospective, randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Patients were treated with Cerebrolysin (30 mL/d) or a placebo (saline) once daily for 21 days, beginning at 24 to 72 hours after stroke onset. The patients also participated in a standardized rehabilitation program for 21 days that was initiated within 72 hours after stroke onset. The primary end point was the Action Research Arm Test score on day 90. Results—: The nonparametric effect size on the Action Research Arm Test score on day 90 indicated a large superiority of Cerebrolysin compared with the placebo (Mann–Whitney estimator, 0.71; 95% confidence interval, 0.63–0.79; P <0.0001). The multivariate effect size on global status, as assessed using 12 different outcome scales, indicated a small-to-medium superiority of Cerebrolysin (Mann–Whitney estimator, 0.62; 95% confidence interval, 0.58–0.65; P <0.0001). The rate of premature discontinuation was <5% (3.8%). Cerebrolysin was safe and well tolerated. Conclusions—: Cerebrolysin had a beneficial effect on function and global outcome in early rehabilitation patients after stroke. Its safety was comparable with that of the placebo, suggesting a favorable benefit/risk ratio. Because this study was exploratory and had a relatively small sample size, the results should be confirmed in a large-scale, randomized clinical trial. Clinical Trial Registration—: URL: http://www.clinicaltrialsregister.eu . Unique identifier: 2007-000870-21.

The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age‐related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS‐related therapies for AD.

This meta-analysis combines the results of nine ischemic stroke trials, assessing efficacy of Cerebrolysin on global neurological improvement during early post-stroke period. Cerebrolysin is a parenterally administered neuropeptide preparation approved for treatment of stroke. All included studies had a prospective, randomized, double-blind, placebo-controlled design. The patients were treated with 30–50 ml Cerebrolysin once daily for 10–21 days, with treatment initiation within 72 h after onset of ischemic stroke. For five studies, original analysis data were available for meta-analysis (individual patient data analysis); for four studies, aggregate data were used. The combination by meta-analytic procedures was pre-planned and the methods of synthesis were pre-defined under blinded conditions. Search deadline for the present meta-analysis was December 31, 2016. The nonparametric Mann-Whitney (MW) effect size for National Institutes of Health Stroke Scale (NIHSS) on day 30 (or 21), combining the results of nine randomized, controlled trials by means of the robust Wei-Lachin pooling procedure (maximin-efficient robust test), indicated superiority of Cerebrolysin as compared with placebo (MW 0.60, P < 0.0001, N = 1879). The combined number needed to treat for clinically relevant changes in early NIHSS was 7.7 (95% CI 5.2 to 15.0). The additional full-scale ordinal analysis of modified Rankin Scale at day 90 in moderate to severe patients resulted in MW 0.61 with statistical significance in favor of Cerebrolysin (95% CI 0.52 to 0.69, P = 0.0118, N = 314). Safety aspects were comparable to placebo. Our meta-analysis confirms previous evidence that Cerebrolysin has a beneficial effect on early global neurological deficits in patients with acute ischemic stroke.

Aquaporin-4 (AQP4) is the most abundant water channel in the brain, and its inhibition before inducing focal ischemia, using the AQP4 inhibitor TGN-020, has been showed to reduce oedema in imaging studies. Here, we aimed to evaluate, for the first time, the histopathological effects of a single dose of TGN-020 administered after the occlusion of the medial cerebral artery (MCAO). On a rat model of non-reperfusion ischemia, we have assessed vascular densities, albumin extravasation, gliosis, and apoptosis at 3 and 7 days after MCAO. TGN-020 significantly reduced oedema, glial scar, albumin effusion, and apoptosis, at both 3 and 7 days after MCAO. The area of GFAP-positive gliotic rim decreased, and 3D fractal analysis of astrocytic processes revealed a less complex architecture, possibly indicating water accumulating in the cytoplasm. Evaluation of the blood vessels revealed thicker basement membranes colocalizing with exudated albumin in the treated animals, suggesting that inhibition of AQP4 blocks fluid flow towards the parenchyma in the paravascular drainage pathways of the interstitial fluid. These findings suggest that a single dose of an AQP4 inhibitor can reduce brain oedema, even if administered after the onset of ischemia, and AQP4 agonists/antagonists might be effective modulators of the paravascular drainage flow.

Background: Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration - implantation of viable cells as a therapeutical approach.Discussion: Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies.Summary: In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.

Background and purpose: Early pharmacological support for post‐stroke neurorehabilitation has seen an abundance of mixed results from clinical trials, leaving practitioners at a loss regarding the best options to improve patient outcomes. The objective of this evidence‐based guideline is to support clinical decision‐making of healthcare professionals involved in the recovery of stroke survivors.Methods: This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. PubMed, Cochrane Library and Embase were searched (from database inception to June 2018, inclusive) to identify studies on pharmacological interventions for stroke rehabilitation initiated in the first 7 days (inclusive) after stroke, which were delivered together with neurorehabilitation. A sensitivity analysis was conducted on identified interventions to address results from breaking studies (from end of search to February 2020).Results: Upon manually screening 17,969 unique database entries (of 57,001 original query results), interventions underwent meta‐analysis. Cerebrolysin (30 ml/day, intravenous, minimum 10 days) and citalopram (20 mg/day, oral) are recommended for clinical use for early neurorehabilitation after acute ischaemic stroke. The remaining interventions identified by our systematic search are not recommended for clinical use: amphetamine (5, 10 mg/day, oral), citalopram (10 mg/day, oral), dextroamphetamine (10 mg/day, oral), Di‐Huang‐Yi‐Zhi (2 × 18 g/day, oral), fluoxetine (20 mg/day, oral), lithium (2 × 300 mg/day, oral), MLC601(3 × 400 mg/day, oral), phosphodiesterase‐5 inhibitor PF‐03049423 (6 mg/day, oral). No recommendation ‘for’ or ‘against’ is provided for selegiline (5 mg/day, oral). Issues with safety and tolerability were identified for amphetamine, dextroamphetamine, fluoxetine and lithium.Conclusions: This guideline provides information for clinicians regarding existing pharmacological support in interventions for neurorecovery after acute ischaemic stroke. Updates to this material will potentially elucidate existing conundrums, improve current recommendations, and hopefully expand therapeutic options for stroke survivors.