Neurotrophins and Neurotrophic Therapy (Based on the Cerebrolysin Model) in the Treatment of Elderly Patients with Cognitive Disorders and Depression. Part 1

Background: Alzheimer’s disease (AD) is the most common neurocognitive disorder and a global health problem. The prevalence of AD is increasing dramatically, and will double in two decades to reach 100 million cases worldwide. Therefore, the development of disease-modifying therapies that can delay or even prevent the onset and progression of AD has become a global priority.Objective: to present a review of domestic and foreign modern studies covering the pathogenesis of AD and disease-modifying therapy.Material and methods: the keywords “Alzheimer’s disease, late age, mild cognitive impairment, depression, therapy, cerebrolysin, effectiveness” were used to search for scientifi c articles in MEDLINE and PUBMED databases for the period 1980–2020.Results and conclusions: since the pathophysiology of AD is multifactorial, it is not surprising that all attempts to change the course of the disease with drugs aimed at a single therapeutic goal were unsuccessful. Thus, combined multimodal therapy using several drugs with a single mechanism of action or multi-purpose drugs seems to be the most promising strategy for both effective therapy of AD and its prevention. Cerebrolysin, acting as a multimodal peptidergic drug with a proven neurotrophic effect, has not only an immediate therapeutic effect on AD, which may refl ect its potential benefi t for modifying the course of the disease. Numerous clinical trials have shown that cerebrolysin is safe and effective in the treatment of AD, and can also enhance and prolong the effectiveness of cholinergic drugs, especially in patients with moderate AD. In this review, we summarize the achievements in the study of the therapeutic signifi cance of the drug and its effect on the pathogenesis of AD, paying special attention to the mechanisms of neurotrophic action. The review presents the results of both preclinical and clinical studies of cerebrolysin in the treatment of AD and pre-dementia cognitive disorders, as well as late depression.

NEUROBIOLOGICAL EFFECTS OF TENUIGENIN AND THE OPPORTUNITY OF IT’S USING IN THE THERAPY OF ALZHEIMER’S AND PARKINSON’S DISEASES (LITERATURE REVIEW)

В обзоре представлен анализ экспериментальных и отчасти клинических данных по исследованию нейробиологических эффектов тенуигенина - важнейшего биологически активного соединения истода тонколистного (Polygala tenuifolia Willd.). Подробно описывается нейропротекторное и нейротрофическое действие данного вещества. Отмечается, что способности тенуигенина уменьшать секрецию бета-амилоида и защищать нейроны от повреждения уже образовавшимся бета-амилоидом, ингибировать процессы гиперфосфорилирования таубелков и воспалительные реакции в микроглии, а также усиливать основную синаптическую передачу могу быть использованы при разработке эффективных терапевтических средств, направленных на ослабление патогенеза болезни Альцгеймера. Эффекты защиты дофаминергических нейронов и митохондриального мембранного потенциала, а также сниженияфосфорилирования α-синуклеина могут оказывать влияние на процессы, развивающиеся при болезни Паркинсона. Делается общий вывод, что тенуигенин заслуживает дальнейшего изучения и, возможно, сможет найти применение в качестве средства аугментации терапии болезней Альцгеймера и Паркинсона и других нейродегенеративных заболеваний. The analysis of experimental and partially clinical data about researches of neurobiological effects of tenuigenin - the most important bioactive substance of Polygala tenuifolia Willd. in this review was given. The neuroprotective and neurotrophic action of given substance were described in detail. It was noted, that the capacities of the tenuigenin to decrease the secretion of beta amyloid and to protect of neurons from damage by already made beta ameloids, to inhibit the processes of the tau proteins` hyperphosphorylation and inflammations in microglia, as well as increase the main synaptic transmission can be used by the development of effective therapeutic drugs aimed to reduce the pathogenesis of Alzheimer`s disease. The effects of dopaminergic neurons and mitochondrial membrane potential protection as well as reduction of α-synuclein phosphorylation can influence the processes by Parkinson`s disease. It was concluded, that the tenuigenin deserves further study and possibly will be used as augmentation of Alzheimer`s, Parkinson`s and other neurodegenerative diseases therapy.

The Potential Role of Hepatocyte Growth Factor in Degenerative Disorders of the Synovial Joint and Spine

This paper aims to provide a comprehensive review of the changing role of hepatocyte growth factor (HGF) signaling in the healthy and diseased synovial joint and spine. HGF is a multifunctional growth factor that, like its specific receptor c-Met, is widely expressed in several bone and joint tissues. HGF has profound effects on cell survival and proliferation, matrix metabolism, inflammatory response, and neurotrophic action. HGF plays an important role in normal bone and cartilage turnover. Changes in HGF/c-Met have also been linked to pathophysiological changes in degenerative joint diseases, such as osteoarthritis (OA) and intervertebral disc degeneration (IDD). A therapeutic role of HGF has been proposed in the regeneration of osteoarticular tissues. HGF also influences bone remodeling and peripheral nerve activity. Studies aimed at elucidating the changing role of HGF/c-Met signaling in OA and IDD at different pathophysiological stages, and their specific molecular mechanisms are needed. Such studies will contribute to safe and effective HGF/c-Met signaling-based treatments for OA and IDD.

Modulation of ERK1/2 and Akt Pathways Involved in the Neurotrophic Action of Caffeic Acid Alkyl Esters

Neurodegenerative diseases affect millions of human lives all over the world. The number of afflicted patients is rapidly growing, and disease-modifying agents are urgently needed. Caffeic acid, an important member of the hydroxycinnamic acid family of polyphenols, has considerable neurotrophic effects. We have previously shown how caffeate alkyl ester derivatives significantly promote survival and differentiation in neuronal cells. In this study, the mechanisms by which these ester derivatives exert their neurotrophic effects are examined. A series of eight caffeic acid esters with different alkyl chain lengths, ranging from methyl (CAF1) to dodecyl esters (CAF8), were synthesized and studied for their influence on neurotrophic signaling pathways. Caffeate esters did not induce tropomyosin-receptor kinase A (TrkA) phosphorylation, which was assessed by immunoblotting up to a concentration of 25 µM. NIH/3T3 cells overexpressing TrkA were generated to further examine phosphorylation of this receptor tyrosine kinase. None of the esters induced TrkA phosphorylation in these cells either. Assessment of the effect of caffeate derivatives on downstream neurotrophic pathways by immunoblotting showed that the most potent esters, decyl caffeate (CAF7) and dodecyl caffeate (CAF8) caused extracellular signal-regulated kinase (ERK1/2) and Akt serine threonine kinase phosphorylation in PC12 cells at 5 and 25 µM concentrations. In conclusion, this study shows that caffeate esters exert their neurotrophic action by modulation of ERK1/2 and Akt signaling pathways in neuronal cells, and further demonstrates the potential therapeutic implications of these derivatives for neurodegenerative diseases.

Morphological study of idiopathic epiretinal membranes and their cytokine profile

The article presents comparative morphological analysis and assessment of response to antigens of fibronectin, laminin, glial fibrillary acidic protein (GFAP) in idiopathic epiretinal membranes (iERM). Authors found a comparable positive iERM reaction to fibronectin and GFAP, which indicates the involvement of these cytokines in the development and progression of the posterior segment neurodegenerative process. Cellular elements in the vitreous gel responsible for iERM formation were fibroblasts, myofibroblasts, hyalocytes, and retinal radial glial cells. Retinal radial glial cells play the main role in the recurrent iERM formation.Conclusion. Due to its hemodynamic, nootropic, neurotrophic action, the investigated bioregulatory complex increases the optic nerve tolerance to the stress effect of IOP, SBP, and DBP asynchronous fluctuations, and improves the ocular blood perfusion.