EVER Neuro Pharma (Austria)

Plasma neuronal-derived extracellular vesicles (NDEV) contain proteins of pathological, diagnostic, and therapeutic relevance. We investigated the associations of six plasma NDEV markers with Alzheimer's disease (AD) severity, cognition and functioning, and changes in these biomarkers after Cerebrolysin®, donepezil, and a combination therapy in AD. Plasma NDEV levels of Aβ42, total tau, P-T181-tau, P-S393-tau, neurogranin, and REST were determined in: 1) 116 mild to advanced AD patients and in 20 control subjects; 2) 110 AD patients treated with Cerebrolysin®, donepezil, or combination therapy in a randomized clinical trial (RCT). Samples for NDEV determinations were obtained at baseline in the NDEV study and at baseline and study endpoint in the RCT. Cognition and functioning were assessed at the same time points. NDEV levels of Aβ42, total tau, P-T181-tau, and P-S393-tau were higher and those of neurogranin and REST were lower in mild-to-moderate AD than in controls (p < 0.05 to p < 0.001). NDEV total tau, neurogranin, and REST increased with AD severity (p < 0.05 to p < 0.001). NDEV Aβ42 and P-T181-tau correlated negatively with serum BDNF (p < 0.05), and total-tau levels were associated to plasma TNF-α (p < 0.01) and cognitive impairment (p < 0.05). Combination therapy reduced NDEV Aβ42 with respect to monotherapies (p < 0.05); and NDEV total tau, P-T181-tau, and P-S396-tau were decreased in Cerebrolysin-treated patients compared to those on donepezil monotherapy (p < 0.05). The present results demonstrate the utility of NDEV determinations of pathologic and synaptic proteins as effective AD biomarkers, as markers of AD severity, and as potential tools for monitoring the effects of anti-AD drugs.

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic growth factor regulating vascular, endothelial/blood brain barrier, and neural functions that have been involved in the pathophysiology of Alzheimer's disease (AD). Here we report serum VEGF levels and its cognitive correlates in baseline conditions and after drug treatment in moderately-severe AD patients as a function of the ApoE genotype. Serum VEGF levels, cognitive and functional performance were evaluated in AD patients, MCI subjects and controls at baseline; as well as in AD patients treated with Cerebrolysin, donepezil, or a combination of both drugs in a 28-week RCT. VEGF levels were measured in serum samples by using specific ELISA kits for VEGF165. In moderately severe AD patients: 1) Baseline serum VEGF levels increased significantly in ApoE4 carriers, but not in non-carriers; 2) higher baseline VEGF values were related to better memory and language performance as evaluated with ADAS-cog+, but only in ApoE4 cases; 3) combined therapy with donepezil plus Cerebrolysin reduced the elevated levels of VEGF, and improved cognition and functioning as compared to donepezil alone; 4) elevated baseline levels of VEGF were significantly associated with drug-induced functional and cognitive improvements. Elevations in the baseline levels of VEGF observed in moderately severe AD patients bearing the ApoE4 were found to be associated with better cognitive performance as well as with improvements in cognition and functioning induced by drug treatment in advanced AD cases. These findings are suggesting that increases in endogenous VEGF represent a reactive neuroprotective response modulated by ApoE that could be reversed by effective treatment with a combined therapy in advanced AD. The present results are pointing to VEGF as a relevant target for AD pathology and therapy

Objective: to study cognitive functions and level of proteins of acute brain damage in a group of patients receiving Cerebrolysin, and in a comparison group in the pre- and postoperative period of coronary artery bypass graft surgery. Materials and methods. The open-label randomized comparative controlled parallel study included 60 men. The average age in the group of patients receiving the therapy with Cerebrolysin was 61.5 (57÷66) years, and was – 61 (56÷65) years ( р &gt; 0.05) in the comparison group. Results. Groups differed statistically significantly according to the left ventricular ejection fraction: 56 (48÷64) – in the group of comparison, 61 (59÷65) – in the group of patients receiving therapy with Cerebrolysin ( p &lt; 0.05). In the group of patients receiving Cerebrolysin, an increase in score according to MMSE ( р &lt; 0.01) was noted from 25 (24÷27) to 26.2 (24–28) points, and in the group without brain neuroprotection in the preoperative period a decrease in score according the Mini-Mental State Examination was revealed to be from 25.5 (25÷27) to 25 (23÷27) ( р &lt; 0.01). Clinical value of the level of protein S100ß as a biological indicator of postoperative cognitive dysfunction after cardiac surgery was ambiguous and required additional research. Conclusion. Brain neuroprotection with use of Cerebrolysin (authors’ schema) promoted not only maintenance but also improvement of cognitive functions and decreased the likelihood of complications in mental activity after coronary artery bypass graft surgery under conditions of artificial circulation and cold cardioplegia, particularly in patients with a high risk for their development.

Background:Aging is associated with some cognitive decline and enhanced risk of development of neurodegenerative diseases. It is assumed that altered metabolism and functions of neurotrophin systems may underlie these age-related functional and structural modifications. CerebrolysinTM (CBL) is a neuropeptide mixture with neurotrophic effects, which is widely used for the treatment of stroke and traumatic brain injury patients. It is also evident that CBL has an overall beneficial effect and a favorable benefit-risk ratio in patients with dementia. However, the effects of CBL on cognition and brain neurotrophin system in normal aging remain obscure.Objective:The aim of the present study was to examine the age-related modifications of endogenous neurotrophin systems in the brain of male Wistar rats and the effects of CBL on learning and memory as well as the levels neurotrophins and their receptors.Methods:Old (23–24 months) and young (2–3 months) male Wistar rats were used for the study. A half of animals were subjected to CBL course (2.5 ml/kg, 20 i.p. injections). Behavior of rats was studied using the open field test and simple water maze training. The contents of NGF and BDNF were studied using enzyme-linked immunosorbent assay; the expression of neurotrophin receptors was estimated by Western-blot analysis.Results:CBL treatment did not affect general status, age-related weight changes, general locomotor activity as well as general brain histology. In a water maze task, a minor effect of CBL was observed in old rats at the start of training and no effect on memory retention was found. Aging induced a decrease in neurotrophin receptors TrkA, TrkB, and p75NTR in the neocortex. CBL counteracted effects of aging on neocortical TrkA and p75NTR receptors and decreased expression of proNGF without influencing overall NGF levels. BDNF system was not significantly affected by CBL.Conclusion:The pro-neuroplastic “antiaging” effects of CBL in the neocortex of old animals were generally related to the NGF rather than the BDNF system.

Cerebrolysin, a mixture of neurotrophic peptides, enhances neurogenesis and improves neurological outcome in experimental neurodegenerative diseases and stroke. The Sonic hedgehog (Shh) signaling pathway stimulates neurogenesis after stroke. The present study tests whether the Shh pathway mediates cerebrolysin-induced neurogenesis and improves neurological outcome after stroke. Rats subjected to embolic stroke were treated with cerebrolysin with or without cyclopamine. Using neural progenitor cells derived from the subventricular zone of the lateral ventricle of adult rats, we found that cerebrolysin significantly increased neural progenitor cells proliferation and their differentiation into neurons and myelinating oligodendrocytes, which were associated with upregulation of Shh and its receptors patched and smoothened. Blockage of the Shh signaling pathway with a pharmacological smoothened inhibitor, cyclopamine, abolished cerebrolysin-induced in vitro neurogenesis and oligodendrogenesis. In the ischemic rats, treatment with cerebrolysin starting 24 hours after stroke significantly increased neural progenitor cell proliferation in the subventricular zone and enhanced neurogenesis, oligodendrogenesis, and axonal remodeling in the peri-infarct area. Moreover, profound neurological function improvements were observed in rats treated with cerebrolysin from week 3 to week 5 after stroke onset compared with vehicle-treated rats. However, in vivo inhibition of the Shh pathway with cyclopamine completely reversed the effects of cerebrolysin on neurorestoration and functional recovery. These results demonstrate that the Shh pathway mediates cerebrolysin-enhanced neurogenesis and white matter remodeling and improves functional recovery in rats after stroke.

Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75(NTR) immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons.

Studies were performed in three Russian centers (Moscow, St. Petersburg, Nizhnii Novgorod). The cohort consisted of 110 patients whose mental state corresponded to the concept of “mild cognitive impairment” (MCI). Patient status was assessed using widely accepted scales (MMSE, GDS, CDR, etc.) and a battery of neuropsychological tests. ApoE genotypes were also identified. Patients were divided into two comparable groups depending on treatment: 55 patients received cerebrolysin and 55 received Cavinton. The data provided evidence that treatment with cerebrolysin was more effective than treatment with Cavinton in terms of slowing the progression of cognitive deficit and delaying the time at which the patients qualified for the diagnosis of Alzheimer’s disease. Cerebrolysin was more effective in patients with MCI and the ApoE4+ genotype, i.e., patients in the high risk group for Alzheimer’s disease. Adverse events were rare in both groups.