Neurotrophic Factors In Brain Research Articles

Can neurocognition, brain neurotrophic factor, triglyceride, and total cholesterol predict suicidal ideation in first-episode Han Chinese patients with schizophrenia?

Previous studies have suggested that the suicide rate of patients with schizophrenia is high. This study investigates factors influencing suicidal ideation in first-episode schizophrenia patients, focusing on cognitive function, brain-derived neurotrophic factor (BDNF), triglyceride (TG), and total cholesterol (TC) in patients with first-episode schizophrenia. A total of 123 patients with first-episode schizophrenia and 38 healthy controls were included in the study. The patients were divided into suicidal and nonsuicidal ideation groups based on the Beck Scale for Suicidal Ideation, and they were assessed with Positive and Negative Syndrome Scale(PANSS). Cognitive function was assessed using the Chinese version of the MATRICS consensus cognitive battery (MCCB) and the serum BDNF, TG, and TC were detected. The main statistical methods include t-test, χ2 test, multivariate logistic regression analysis, receiver operating characteristic (ROC) curve analysis, and the DeLong test. 26.02% of patients exhibited suicidal ideation. Higher PANSS and TC levels were risk factors, while higher MCCB scores and BDNF levels were protective factors. ROC analysis indicated AUCs of 0.630, 0.724, and 0.762 for serum BDNF, PANSS, and MCCB, respectively, with a combined AUC of 0.870. Serum BDNF level, PANSS score, and MCCB score can be used as auxiliary predictors of suicidal ideation in schizophrenic patients. Combining these three indicators can effectively predict suicidal ideation in schizophrenic patients.

Brain neurotrophic factor BDNF: new data, functions and questions

The brain-derived neurotrophic factor (BDNF) is a key modulator of neurogenesis, synaptogenesis, neuroregeneration, and cell differentiation in the nervous system. Impaired BDNF functioning is a characteristic of various neurological diseases, such as Alzheimer’s disease, multiple sclerosis, and depressive disorders. There is recent evidence that patients with COVID-19 have reduced BDNF levels in the blood plasma. Furthermore, exogenous BDNF and its mimetics have demonstrated therapeutic potential.
 In this review, we systematized data of the BDNF gene structure, epigenetic and microRNA-mediated regulation of its expression, transcriptional variants of BDNF, and the effects of BDNF on neuronal and oligodendroglial differentiation. Further, we point out the gaps in the current knowledge about BDNF and propose experiments that can expand such knowledge and the range of possibilities for using BDNF in biomedicine. These include determining the expression pattern of all BDNF gene transcripts at different stages of differentiation and in different cell subpopulations and studying the role of receptor-independent BDNF signaling, circadian fluctuations in BDNF levels, and their role in physiological and pathophysiological conditions. Finally, for translational medicine, evaluating the effect of BDNF mimetics (including those immobilized on three-dimensional scaffolds for tissue engineering) on neuronal and oligodendroglial differentiation of pluripotent and polypotent cells and identifying molecular regulators of BDNF transcription, including small molecules and microRNAs capable of regulating BDNF gene expression, are crucial.

Effects of Gestational Exercise on Nociception, BDNF, and Irisin Levels in an Animal Model of ADHD

Abnormal cognitive and sensorial properties have been reported in patients with psychiatric and neurodevelopmental conditions, such as attention deficit hyperactivity disorder (ADHD). ADHD patients exhibit impaired dopaminergic signaling and plasticity in brain areas related to cognitive and sensory processing. The spontaneous hypertensive rat (SHR), in comparison to the Wistar Kyoto rat (WKY), is the most used genetic animal model to study ADHD. Brain neurotrophic factor (BDNF), critical for midbrain and hippocampal dopaminergic neuron survival and differentiation, is reduced in both ADHD subjects and SHR. Physical exercise (e.g. swimming) promotes neuroplasticity and improves cognition by increasing BDNF and irisin. Here we investigate the effects of gestational swimming on sensorial and behavioral phenotypes, striatal dopaminergic parameters, and hippocampal FNDC5/irisin and BDNF levels observed in WKY and SHR. Gestational swimming improved nociception in SHR rats (p = 0.006) and increased hippocampal BDNF levels (p = 0.02) in a sex-dependent manner in adolescent offspring. Sex differences were observed in hippocampal FNDC5/irisin levels (p = 0.002), with females presenting lower levels than males. Our results contribute to the notion that swimming during pregnancy is a promising alternative to improve ADHD phenotypes in the offspring.

Prospects for the pharmacological validation of the use of platelets as a “peripheral model” of neurons

Depressive disorders often occur in patients with cardiovascular pathologies and are a predictor of the development of thrombotic events, such as myocardial infarction, acute ischemic cerebrovascular accident, and pulmonary embolism. These are believed to be caused by the structural and biochemical relationship between platelets and brain neurons, which allows us to consider platelets as a marker of central nervous system (CNS) pathologies. This review aimed to assess the relationship between the hemostasis system and the development of depressive disorders using platelets as a “peripheral model” of neurons and evaluate the effectiveness of drugs for the treatment of depression. The study was conducted in accordance with the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A systematic literature search was conducted using PubMed, Cochrane, and CINAHL databases from 2018 to 2023, according to the following keywords: “hemostasis,” “acute cerebrovascular accident,” “depression,” “depressive disorders,” “platelets,” “cardiovascular diseases.” The data obtained indicate both a clinical link between depressive disorders and vascular events and the commonality of platelets and CNS cells because of the commonality of the following proteins: transporters and receptors of serotonin or 5-hydroxytryptamine, amyloid precursor protein, and brain neurotrophic factor, which were previously considered specific neural proteins. In addition, a relationship exists between hemostasis dynamics and drug therapy for depression. In this review, changes in hemostasis in terms of platelet activation in patients with depression and vascular disease were critically analyzed. The literature presents diverse mechanisms of platelet induction, which require further study. A rational study of the pathways of platelet activation in patients with depressive disorders will provide a comprehensive understanding of the molecular mechanisms underlying the relationship between hemostasis and depression in various vascular pathologies. Platelet activation in patients with depression and the dynamics of changes in hemostasis parameters during the treatment of depressive disorders allow us to consider hemostasis as a peripheral marker of the CNS and pharmacotherapy.

BDNF content and catalase activity in the blood of children with autism spectrum disorders

BACKGROUND: With the increasing prevalence of autism spectrum disorders worldwide, it is relevant to study the mechanisms contributing to their development and progression. The participation of brain-derived neurotrophic factor and oxidative stress in the pathogenesis of the disease is considered, however, their role in this process remains unclear. The relationship between BDNF levels and oxidative stress in the blood of patients with autism spectrum disorders has not been studied.
 AIM: The aim was to evaluate the content of brain neurotrophic factor, BDNF, and catalase, an antioxidant defense enzyme, in children with various clinical forms of autism spectrum disorders.
 MATERIALS AND METHODS: BDNF content and catalase activity were assessed in the blood plasma of 78 children with autism spectrum disorders, including 41 patients with childhood autism, 19 children with atypical autism, 6 patients with Aspergers syndrome, and 12 patients with other general developmental disorders (with elements of autism). The control group consisted of 20 conditionally healthy children. The diagnosis was established in accordance with the ICD-10. The severity of disorders was determined using the Childhood Autism Rating Scale. The content of BDNF was evaluated using the method of enzyme immunoassay, catalase activity was determined by colorimetric method.
 RESULTS: The content of BDNF in blood plasma was reduced in children with autism spectrum disorders compared to its levels in control group subjects. BDNF levels depended on the clinical form of the disease: the content of BDNF was reduced in patients with childhood autism, atypical autism, Aspergers syndrome compared to control group subjects; in patients with atypical autism it is lower than in patients with childhood autism; BDNF levels in the group of patients with other general developmental disorders and in control group did not differ. The content of BDNF did not depend on gender, age and severity of autism spectrum disorders. A negative correlation was found between BDNF levels and the age of control group children. There were no differences in the activity of catalase in the blood of children with autism spectrum disorders and in control group. A positive correlation was found between BDNF levels and catalase activity in children with autism spectrum disorders and control group subjects.
 CONCLUSIONS: A decrease in the content of BDNF in the blood of children with autism spectrum disorders was revealed. Neurotrophin content differed in children with separate clinical forms of the disease. To varying degrees the decrease in BDNF levels in patients with childhood autism, atypical autism, Aspergers syndrome and the absence of changes in patients with other general developmental disorders compared with controls could be associated with a different contribution of neurotrophin to the pathogenesis of clinical forms of autism spectrum disorders. In children with autism spectrum disorders, there were no age-related changes in neurotrophin levels, while in healthy children a negative correlation was found between the content of BDNF and age. The absence of changes in the activity of catalase in the blood of children with autism spectrum disorders indicated the safety of the antioxidant defense system in terms of this indicator. The positive correlation between BDNF levels and catalase activity in the blood of patients with autism spectrum disorders and control group subjects reflected the protective role of neurotrophin from the damaging effects of oxidative stress.

Exercise Training to Improve Brain Health in Older People Living With HIV: Study Protocol for a Randomized Controlled Trial.

With the advent of antiretrovirals, people living with HIV are living near-normal lifespans. However, people living with HIV are at greater risk of experiencing cognitive impairment and reduced brain integrity despite well-controlled viremia. A robust literature supports exercise interventions as a method of improving cognition and structural brain integrity in older individuals without HIV. The effects of exercise on cardiometabolic, neurocognitive, and neural structures in middle-aged to older people living with HIV are less well known, with few prospective studies examining these measures. This prospective randomized clinical trial will examine the effects of a 6-month exercise training intervention compared to a 6-month stretching intervention (control) on cardiorespiratory fitness, physical function and strength, cognition, and neuroimaging measures of brain volumes and cerebral blood flow in people living with HIV. Sedentary middle-aged to older people living with HIV (ages≥40; n=150) with undetectable HIV viral load (<20 copies/mL) will be enrolled in the study. At the baseline and final visit, fasting plasma lipid, insulin, glucose, and brain neurotrophic factor concentrations; cardiorespiratory fitness; cognitive performance; brain volumes; and cerebral blood flow via a magnetic resonance imaging scan will be measured. Participants will be randomized in a 2:1 ratio to either the exercise or control stretching intervention. All participants will complete their assigned programs at a community fitness center 3 times a week for 6 months. A professional fitness trainer will provide personal training guidance at all sessions for individuals enrolled in both arms. Individuals randomized to the exercise intervention will perform endurance and strength training exercises, while those randomized to the control intervention will perform stretches to increase flexibility. A midpoint visit (at 3 months) will assess cognitive performance, and at the end point visit, subjects will undergo cardiorespiratory fitness and cognition testing, and a magnetic resonance imaging scan. Physical activity throughout the duration of the trial will be recorded using an actigraph. Recruitment and data collection are complete as of December 2020. Data processing, cleaning, and organization are complete as of December 2021. Data analysis began in January 2022, with the publication of study results for primary aims 1 and 2 expected by early 2023. This study will investigate the effects of a 6-month aerobic and resistance exercise training intervention to improve cardiometabolic risk factors, cognitive performance, cerebral structure, and blood flow in sedentary people living with HIV. Results will inform clinicians and patients of the potential benefits of a structured aerobic exercise training program on the cognitive, functional, and cardiometabolic health status of older people living with HIV. Assessment of compliance will inform the development and implementation of future exercise programs for people living with HIV. ClinicalTrials.gov NCT02663934; https://clinicaltrials.gov/ct2/show/NCT02663934. DERR1-10.2196/41421.

Theaflavins in Black Tea Mitigate Aging-Associated Cognitive Dysfunction via the Microbiota-Gut-Brain Axis.

Aging-associated cognitive dysfunction has a great influence on the lifespan and healthspan of the elderly. Theaflavins (TFs), a mixture of ingredients formed from enzymatic oxidation of catechins during the manufacture of tea, have a positive contribution to the qualities and antiaging activities of black tea. However, the role of TFs in mitigating aging-induced cognitive dysfunction and the underlying mechanism remains largely unknown. Here, we find that TFs effectively improve behavioral impairment via the microbiota-gut-brain axis: TFs maintain gut homeostasis by improving antioxidant ability, strengthening the immune response, increasing the expression of tight junction proteins, restructuring the gut microbiota, and altering core microbiota metabolites, i.e., short-chain fatty acids and essential amino acids (SCFAs and AAs), and upregulating brain neurotrophic factors. Removing the gut microbiota with antibiotics partly abolishes the neuroprotective effects of TFs. Besides, correlation analysis indicates that the decrease in gut microbiota, such as Bacteroidetes and Lachnospiraceae, and the increase in microbiota metabolites' levels are positively correlated with behavioral improvements. Taken together, our findings reveal a potential role of TFs in mitigating aging-driven cognitive dysfunction via the microbiota-gut-brain axis. The intake of TFs can be translated into a novel dietary intervention approach against aging-induced cognitive decline.

Brain-derived neutrophic factor, glutamate and markers of apoptosis in the blood of patients with prolonged disorders of consciousness

Aim of the work was to analyze the content of factors with neuroprotective, neurotoxic and apoptotic eff ects in the blood of patients with prolonged disorders of consciousness (pDOC), depending on the level of consciousness disorder and neuroprotective therapy.Material and methods. Research included 53 patients with pDOC, who were divided into 2 groups. Group 1 included 19 vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, group 2–34 minimally conscious state (MCS “minus” and “plus”) patients. Firstly at admission and then at the end of treatment course (after 1 month on average), plasma concentrations of brain neurotrophic factor (BDNF), apoptosis antigen (APO-1), apoptosisinducing ligand (Fas-L) and glutamate were studied. Control group consisted of 16 patients without measured once.Results. Decrease of BDNF serum level was revealed in patients with pDOC,which was less pronounced those who had TBI as a etiological factor of pDOC. BDNF level signifi cantly increased after a month against the background of neuroprotective therapy. Glutamate level was higher in the fi rst group (VS/UWS). No signifi cant diff erence in the content of apoptosis factors was observed.Conclusion. In patients with pDOC, decrease serum BDNF level was observed, less pronounced in TBI as etiology of pDOC. In patients who matched MCS criteria at the admission, there was a signifi cant increase of BDNF serum level during treatment course, which could indicate that patients with a higher initial level of consciousness have better potential for realizing the eff ect of neuroprotective therapy. Levels of apoptosis factors did not correspond to the consciousness level.

НЕЙРОПРОТЕКТОРНОЕ ДЕЙСТВИЕ ТЕАФЛАВИНА В УСЛОВИЯХ ЭКСПЕРИМЕНТАЛЬНОГО ХРОНИЧЕСКОГО НАРУШЕНИЯ МОЗГОВОГО КРОВООБРАЩЕНИЯ

Introduction. Theaflavin is a polyphenol derived from black tea, known for its antioxidant properties. The high pharmacological activity of theaflavine, as well as the availability of raw materials, make this compound a promising neuroprotector agent. Materials and methods. The experiment was carried out on male Wistar rats, in which a chronic cerebrovascular accident was modeled by partial bilateral occlusion of the common carotid arteries. Tefalavin was administered orally at doses of 25, 50 and 100 mg/kg after simulation of ischemia and then once a day for 14 days. During the experiment, the following indicators were analyzed: cognitive deficit, changes in brain neurotrophic factor, succinate deigdrogenase and cytochrome c oxidase activity. Results. As a result, the use of theaflavine at a dose of 25 mg / kg was found to contribute to an increase in the activity of succinate dehydrogenase and cytochrome c oxidase of 45.7% (p &lt;0.05) and 100.2% (p &lt;0.05), respectively. The level of brain neurotrophic factor in rats treated with theaflavine was significantly higher dose-independent than in untreated animals. There was also a decrease in cognitive deficits in animals treated with theaflavine. Conclusion. Theaflavin in the experiment has a neuroprotective effect by restoring mitochondrial function and increasing the concentration in the neurotrophic factor of the brain, making it a promising object for further study.

Direct and Inherited Epigenetic Changes in the Nervous System Caused by Intensive Locomotion: Possible Adaptive Significance

This review is devoted to the analysis of works that investigated the long-term effects of species-specific forms of intensive locomotion on the cognitive functions of animals and humans, which can be transmitted to the next generation. To date, the anxiolytic and cognitive-enhancing long-term effects of intensive locomotion have been demonstrated in humans, rodents, fish, insects, mollusks, and nematodes. In rodents, changes in the central nervous system caused by intense locomotion can be transmitted through the maternal and paternal line to the descendants of the first generation. These include reduced anxiety, improved spatial learning and memory, increased levels of brain neurotrophic factor and vascular endothelial growth factor in the hippocampus and frontal cortex. The shift of the balance of histone acetylation in the hippocampus of rodents towards hyperacetylation, and the balance of DNA methylation towards demethylation manifests itself both as a direct and as a first-generation inherited effect of motor activity. The question about the mechanisms that link locomotion with an increase in the plasticity of a genome in the brain of descendants remains poorly understood, and invertebrate model organisms can be an ideal object for its study. Currently, there is a lack of a theoretical model explaining why motor activity leads to long-term improvement of some cognitive functions that can be transmitted to the next generation and why such an influence could have appeared in evolution. The answer to these questions is not only of fundamental interest, but it is necessary for predicting therapeutic and possible side effects of motor activity in humans. In this regard, the article pays special attention to the review of ideas on the evolutionary aspects of the problem. We propose our own hypothesis, according to which the activating effect of intensive locomotion on the function of the nervous system could have been formed in evolution as a preadaptation to a possible entry into a new environment.

NEW MARKERS FOR DIAGNOSIS AND PROGNOSIS OF COGNITIVE IMPAIRMENT IN PATIENTS WITH MULTIPLE SCLEROSIS (review)

The article presents modern approaches about the diagnosis of brain damage and the development of cognitive impairment in patients with multiple sclerosis. Neurodegenerative changes are considered, which take place in the early stages of the disease and play an important role in the formation of irreversible neurological deficits. Cognitive impairment in patients with multiple sclerosis is quite common, but they are not always noticed, but they significantly reduce patients' quality of life. The article describes the possibilities of neuroimaging methods to identify structural changes in the parts of the brain responsible for cognitive functions. The importance of brain neurotrophic factor (BDNF) as a promising biomarker of multiple sclerosis is presented. Further study of BDNF remains interesting, which will allow to develop algorithms for early diagnosis and prediction of disease progression, that will provide an opportunity to deepen the understanding of the place of BDNF in the pathomorphological chain of nervous system damage in multiple sclerosis.

A Brief Overview on BDNF-Trk Pathway in the Nervous System: A Potential Biomarker or Possible Target in Treatment of Multiple Sclerosis?

The growing incidence of neurodegenerative disorders in our populations is leading the research to identify potential biomarkers and targets for facilitating their early management and treatments. Biomarkers represent the crucial indicators of both physiological and pathological processes. Specific changes in molecular and cellular mechanisms of physiological processes result in biochemical alterations at systemic level, which can give us comprehensive information regarding the nature of any disease. In addition, any disease biomarker should be specific and reliable, able to consent of distinguishing the physiological condition of a tissue, organ, or system from disease, and be diverse among the various diseases, or subgroups or phenotypes of them. Accordingly, biomarkers can predict chances for diseases, facilitate their early diagnosis, and set guidelines for the development of new therapies for treating diseases and disease-making process. Here, we focus our attention on brain neurotrophic factor (BDNF)–tropomyosin receptor kinase (Trk) pathway, describing its multiple roles in the maintenance of central nervous system (CNS) health, as well as its implication in the pathogenesis of multiple sclerosis (MS). In addition, we also evidence the features of such pathway, which make of it a potential MS biomarker and therapeutic target.

The mimetic of the brain neurotrophic factor GSB-106 has neuroprotective and neuroregenerative effects in experimental ischemic stroke

Background. A dimeric dipeptide mimetic of the brain-derived neurotrophic factor loop 4, bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106), which activates TrkB, PI3K/AKT, MAPK/ERK and PLC-γ1 was created at the V. V. Zakusov Research Institute of Pharmacology. GSB-106 showed neuroprotective activity in vitro and in vivo at systemic administration. Objective. In the present study, we studied the effect of GSB-106 on the brain infarct volume, as well as on neurogenesis and synaptogenesis under conditions of experimental ischemic stroke induced by transient occlusion of the middle cerebral artery in rats, when it was first administered 24 h after ischemia onset. Methods. Dipeptide GSB-106 was administered i.p. in a dose of 0.1 mg/kg 24 h after surgery and then once a day, with the end of administration on theday 6 after surgery. On the day 7 brain samples were collected for morphometric and biochemical (Western-blot) analysis. Results. It was established that GSB-106 reduced the brain damage volume by 24%, restores impaired neurogenesis and/or gliogenesis (by Ki-67) in the hippocampus and in the striatum and completely restored the reduced immunoreactivity to synaptic markers synaptophysin and PSD-95 in the striatum. Conclusions. Thus, the dimeric dipeptide BDNF mimetic GSB-106 exhibits neuroregenerative properties at clinically relevant time window (24 h) in a model of ischemic stroke presumably due to stimulation of neurogenesis (and / or gliogenesis) and synaptogenesis.

Application of a New Gene-Cell Construct Based on the Olfactory Mucosa Escheating Cells Transduced with an Adenoviral Vector Encoding Mature BDNF in the Therapy of Spinal Cord Cysts.

A gene-cell construct based on rat olfactory mucosa ensheathing cells transduced with an adenoviral vector encoding a mature form of brain neurotrophic factor (mBDNF) was transplanted into post-traumatic cysts of rat spinal cord. Transplantation of the gene-cell construct improved motor activity of the hind limbs and reduced the size of cysts in some animals. However, comparison of the effects of transduced and non-transduced ensheathing cells revealed no significant differences. In parallel in vitro experiments, a decrease in the proliferation of transduced cells compared to non-transduced cells was observed. It is likely that mBDNF reduces proliferation of transduced cells, which can affect their efficiency. The therapeutic efficacy of the new gene-cell construct is most likely provided by the cellular component.

Prediction of the Development of Depression in Patients with Autoimmune Thyroiditis and Hypothyroidism

BACKGROUND: Hypothyroidism is frequently accompanied by depression symptoms, whereas depression is considered the most common mental disorder. AIM: It is crucial to analyze the associations of the brain neurotrophic factor (BDNF) gene polymorphism (rs6265), the VDR gene polymorphism (rs2228570), and the NMDA gene polymorphism (rs4880213) with the depression in patients with autoimmune thyroiditis and hypothyroidism in the Western Ukrainian population and predict the development of depressive disorders in these patients. METHODS: The study involved a total of 153 patients with various forms of thyroid pathology. BDNF levels in the sera of the patients and healthy individuals were quantified using enzyme-linked immunosorbent assay with highly sensitive Human BDNF ELISA Kit (Elabscience®, United States, Catalog No: E-EL-H0010) on E.I.A. Reader Sirio S (Seac, Italy). Genotyping of the VDR (rs2228570), BDNF (rs6265), and NMDA (rs4880213) gene polymorphism using TaqMan probes and TaqMan Genotyping Master Mix (4371355) on CFX96™Real-Time Polymerase chain reaction (PCR) Detection System (Bio-Rad Laboratories, Inc., USA). PCR for TaqMan genotyping was carried out according to the kit instructions (Applied Biosystems, USA). We used the Student’s t-test, ANOVA, Pearson’s Chi-square test, ROC-analysis, odds ratio test, relative odds ratio test. The odds ratio and 95% confidence interval were computed by binary logistic regression. RESULTS: When comparing the presence of depression on the Hamilton scale, statistically significant differences were found depending on BDNF gene polymorphism (rs6265) (p &lt; 0.001), and non-statistically noticeable differences were detected depending on the VDR gene polymorphism (rs2228570) and NMDA gene polymorphism (rs4880213). Our study revealed a marked inverse connection between depression and BDNF levels (p &lt; 0.001) and a reverse moderate correlation between depression and fT4 (p &lt; 0.001) and 25-OH Vitamin D levels (p &lt; 0.001). In addition, we identified a direct moderate correlation between pronounced levels of depression and thyroid-stimulating hormone (TSH) in the blood (p &lt; 0.001). CONCLUSIONS: Indicators such as BDNF, TSH, fT4, anti-TPO, and 25-OH Vitamin D levels were found to be prognostically significant criteria for the risk of developing depression.

Нейротрофічний фактор мозку як маркер відновлення моторних та когнітивних функцій у гострому періоді кардіоемболічного та атеротромботичного ішемічного інсульту

церебральний ішемічний інсульт - одне з найбільш поширених захворювань, що спричиняють психоемоційні, когнітивні та рухові розлади. Сучасні дослідження спрямовані на пошук біологічних маркерів ураження головного мозку при діагностиці інсультів, зокрема, фізичних, візуалізаційних, електрофізіологічних, гістологічних, генетичних та нейрональних, визначення яких може прискорити диференційну діагностику. Мета дослідження – оцінити рівень нейротрофічного фактору мозку в крові, стан моторних і когнітивних функцій в гострому періоді ішемічного інсульту на 1 та 14 добу, а також можливість використання рівня нейротрофічного фактору мозку крові в якості маркера відновлення рухової та інтелектуально-мнестичної сфери при атеротромботичному та кардіоемболічному підтипах ішемічного інсульту. У дослідження було включено 34 особи з діагнозом гострий ішемічний інсульт. Залежно від результатів клінічного обстеження пацієнтів було розподілено на 2 групи: група 1 – пацієнти, в яких ішемічний інсульт виник внаслідок атеросклеротичного ураження судин каротидної системи з розвитком оклюзії за механізмом атеротромбозу (17 осіб), група 2 – пацієнти, у яких ішемічний інсульт виник внаслідок ураження судин каротидної системи з розвитком оклюзії за кардіоемболічним механізмом (17 осіб). Для порівняння клініко-лабораторних показників додатково було виділено контрольну групу (пацієнти неврологічного відділення, які не мали ураження центральної нервової системи - 11 осіб). Обстеження пацієнтів проведено на 1 та 14 добу захворювання. Моторні функції оцінювали за ступенем повсякденної активності життя, що визначали за індексом Бартел, стан когнітивних функцій - за шкалою Mini-Mental State Examination. Індекс Бартел на 1 добу гострого періоду ішемічного інсульту перебував в межах легкої залежності для кардіоемболічного підтипу та помірної - для атеротромботичного. Протягом 14 днів у досліджуваних пацієнтів обох груп відбувалося зростання індексу до рівня повної незалежності у групі 1 та легкого ступеню залежності у групі 2. У обстежених пацієнтів із ішемічним інсультом було визначено середні значення за шкалою Mini-Mental State Examination на рівні помірного когнітивного дефіциту на 1 добу при обох підтипах ішемічного інсульту. Відновлення когнітивних функцій протягом 14 днів після ішемічного інсульту відбувалося тільки у другій групі до легких когнітивних розладів. Концентрація нейротрофічного фактору мозку на 1 добу ішемічного інсульту різко знижувалася порівняно з контрольною групою. Отримані результати дозволяють розглядати визначення мозкового нейротрофічного фактору об’єктивним біомаркером як тяжкості перебігу кардіоемболічного та атеротромботичного ішемічного інсульту, так і прогнозу відновлення моторних і когнітивних функцій.

BDNF-ОПОСРЕДОВАННЫЙ МЕХАНИЗМ АНТИСТРЕССОРНОГО ДЕЙСТВИЯ МЕЛАНОКОРТИНОВ

In recent years studies devoted to the study of the mechanisms of regulation of physiological and pathophysiological processes are of particular interest in connection with the active development of molecular medicine. Stress caused by various biological, social and technogenic factors is an integral part of modern human life and is a non-specific reaction of the body to various extreme influences. Despite the formation of adaptive mechanisms under stress in the form of generalized activation of the body, focusing of attention and memory, stress-induced analgesia, under conditions of intense and prolonged influence of a negative factor, the central nervous system loses its ability to adapt and the processes of neurogenesis are often disturbed as a result of distress. This fact explains the development of stress-induced pathological processes in the central nervous system, which emphasizes the relevance of the search and study of the mechanisms of action of pharmacological agents exhibiting stress-protective and neurotropic properties. Melanocortins (N-terminal fragments of adrenocorticotropic hormone, fragments of proopiomelanocortin and their synthetic analogs) are characterized by pronounced neurometabolic, neuroregenerative and antistress activity. One of the possible mechanisms of action of melanocortins is the influence on the levels of expression in the central nervous system of neurotrophic factors that provide the main processes of regulation of homeostasis of the body. Brain Derived Neurotrophic Factor (BDNF) which is able to reduce the negative effects of hypoxic, toxic and stressful damage to brain cells, which is due to binding to tyrosine kinase B receptor and activation of the main metabolic cascades, is one of the effective regulatory proteins. Taking into account the fact that the question of the mechanisms of the stress-protective action of substances capable of protecting brain cells from the damaging effect of stress factors is relevant, the study of the effect of melanocortins on the level of neurotrophic factors is of scientific interest. The study was carried out on 70 male white rats of 6 months of age. Sensory contact in the absence of physical contact with the subsequent formation of aggressive and submissive types of behavior was used as an experimental model of «social» stress. Laboratory animals, taking into account the gradation by types of behavior, were divided into groups: a group of control / intact animals; a group of rats exposed to «social» stress for 20 days; a group of individuals who received Semax (ACTH(4-7)-Pro-Gly-Pro) at a dose of 100 μg / kg / day intraperitoneally from the 1st day of stress exposure for a course of 20 days; a group of animals that received ACTH(6-9)-Pro-Gly-Pro at a dose of 100 μg/kg/day intraperitoneally from day 1 of stress exposure for a course of 20 days. The BDNF level in the blood serum of white rats was assessed by the enzyme-linked immunosorbent assay using ELISA Kit for Brain Derived Neurotrophic Factor (BDNF) (USA). It was found that under conditions of «social» stress, a decrease in the level of BDNF was observed. The introduction of the studied melanocortins (ACTH(4-7)-Pro-Gly-Pro (Semax) and ACTH(6-9)-Pro-Gly-Pro) under conditions of induced «social» stress increases the concentration of BDNF in the blood serum of experimental animals. The study of the mechanisms of disturbances induced by experimental stress in various models showed that stress provokes the development of a depression-like state in rodents, which is accompanied by neuroplastic changes, including inhibition of neurogenesis in the hippocampus. Currently a large amount of experimental data has been accumulated, indicating that a pathological stress response contributes to a decrease in the level of BDNF. Deficiency of BDNF plays an important role in the pathophysiology of stress, inducing impairments of neurogenesis associated with impaired neuroplasticity, as well as dysfunction of the hypothalamic-pituitary-adrenal and neurotransmitter serotonergic systems. The effectiveness of therapy with stress protectors and antidepressants is due to their effect on neurogenesis and neuronal plasticity. Thus the fact of a decrease of BDNF under conditions of «social» stress established in the work and the positive effect of melanocortins (ACTH(4-7)-Pro-Gly-Pro (Semax) and ACTH(6-9)-Pro-Gly-Pro), contributing to the restoration of these parameters, indicates the effect of neuropeptides on the expression of BDNF and allows us to suggest a possible mechanism of the antistress effect. It should be noted that the serum level of brain neurotrophic factor can be considered as a biomarker of stress-induced disorders and affective disorders, as well as an indicator of the effectiveness of therapy with stress protectors. In addition, the level of BDNF in the blood serum can be considered as indicators of prognosis and evaluation of the effectiveness of therapy.

ВЗАИМОСВЯЗЬ БИОХИМИЧЕСКИХ И ГЕНЕТИЧЕСКИХ ПАРАМЕТРОВ, ХАРАКТЕРИЗУЮЩИХ МОЗГОВОЙ НЕЙРОТРОФИЧЕСКИЙ ФАКТОР (BDNF), С ТЯЖЕСТЬЮ АЛКОГОЛЬНОГО АБСТИНЕНТНОГО СИНДРОМА

The purpose of this work is to determine the level of brain neurotrophic factor (BDNF, brain-derived neurotrophic factor) in the blood serum of individuals with alcohol dependence syndrome in the dynamics of alcohol withdrawal syndrome (COA), as well as to compare the results obtained with the clinical picture and the effectiveness of the therapeutic program. Material and methods. The level of BDNF in the blood serum was determined using ELISA. The dynamics of the severity of alcohol withdrawal syndrome (COA), as well as indicators characterizing the psychoemotional status and cognitive abilities of patients, were evaluated using appropriate psychometric scales. The studies were conducted on the 2nd, 8th and 21st days of abstinence. There were examined 70 patients with alcohol dependence syndrome in the dynamics of COA, who met the inclusion criteria and gave informed voluntary consent to participate in the study. Results and discussion. As the symptoms of COA decreased, there was a significant increase in the level of BDNF in the blood serum: on the 21st day of abstinence, the level of BDNF was significantly higher than the values on the 2nd and 8th day of abstinence. On the 8th day of abstinence, BDNF in the blood serum forms a direct correlation with the level of personal anxiety measured using the H scale Ch. Spielberger in the modification of Y.L. Khanin. According to multiple regression analysis on the 21st day of abstinence, BDNF can predict the severity of attraction to alcohol, established using the Pennsylvania scale of attraction to alcohol. Conclusion. Thus, the content of BDNF in the blood serum can act as an independent prognostic marker of the success of care in the treatment of COA.

Development of a method for the identification of rs6265 polymorphism in the human brain neurotrophic factor gene

The analysis and generalization of data from the literature sources characterizing the structural organization, regulation of expression, and functional activity of the neurotrophic factor of the human brain, which is one of the most common regulators of biological processes in the nervous system, is carried out. The results of numerous studies demonstrating the association of the brain-derived neurotrophic factor (BDNF) gene with the pathophysiology of the affective disorders are noted, and its contribution to the development of neuroplasticity is confirmed. The results of the design of a pair of primers and adaptation of the amplification reaction of the BDNF region with a length of 433 nucleotide pairs containing the polymorphic locus RS6265 are presented. Restriction endonuclease was selected. The sequence of primers, their localization, and correlation with the restriction site provided the separation of alternative alleles necessary for the successful identification of this marker. The use of the proposed technique made it possible to uniquely identify the genotype in 38 examined whole blood samples and identify the rare allelic variants. Also, the frequency of polymorphic variants of RS6265 of the BDNF gene was established in all the samples. There was an increase in the proportion of genotypes G/A and A/A of the RS6265 polymorphism of the BDNF gene in the group of examined systematically exposed to extreme factors. Identification of people with a rare A/A genotype of the RS6265 polymorphic locus of the BDNF gene is of a great importance for the monitoring system of long-term potentiation processes leading to the development of neuropsychic pathology. The possibility of implementing this method of genotyping in a typical laboratory using a polymerase chain reaction is proved. The proposed version of the polymerase chain reaction with the subsequent analysis of the polymorphism of the lengths of restriction fragments could be used as a fast, inexpensive, and reliable system for identifying single-nucleotide genetic polymorphisms.

EFFECT OF GLYPROLINES ON THE LEVEL OF APOPTOTIC AND NEUROTROPHIC FACTORS UNDER CONDITIONS OF “SOCIAL” STRESS

The aim of the article was to study the effect of glyproline neuropeptide compounds Thr–Lys–Pro–Arg–Pro–Gly–Pro (Selank), Pro–Gly–Pro and Pro–Gly–Pro–Leu, on the level of apoptotic factors (caspase-3, caspase-8, the tumor necrosis factor) and neurotrophic factors (the nerve growth factor and the brain neurotrophic factor) in the blood serum of white rats under the experimental modeling of “social” stress.Materials and methods. The experimental studies were carried out on 90 nonlinear white male rats aged 6 months. By the type of behavior, in the process of “social” stress modeling, all the rats were divided into “aggressors” and “victims”. In the study, the following experimental groups (n=10) were formed: control individuals; groups of the rats exposed to stress for 20 days; groups of the animals treated intraperitoneally at the dose of 100 μg/kg/day, starting from the 1st day of the stress factor exposure, with a course of 20 days of glyproline compounds Thr–Lys–Pro–Arg–Pro–Gly–Pro (Selank), Pro–Gly–Pro and Pro–Gly–Pro–Leu. The effect of the compounds on the level of apoptotic and neurotrophic factors was assessed by determining the level of caspase-3, caspase-8, the tumor necrosis factor, the nerve growth factor and the brain neurotrophic factor of white rat blood serum by enzyme immunoassay.Results. According to the results of the study, it was found out that under the conditions of “social” stress, there was an increase in the apoptotic processes accompanied by an increase in the level of caspase-3, caspase-8, TNF-α in the blood serum of white rats, as well as a decrease in the concentration of neurotrophic factors – BDNF and NGF. The administration of giproline compounds against the background of stress, contributed to the restoration of the studied indicators level, which is most likely due to the presence of antiapoptotic and neuroprotective effects in giprolines due to the inhibition of the caspase-dependent cascade of apoptosis reactions, as well as the induction of the synthesis of neurotrophic factors with the antiapoptotic activity.Conclusion. Thus, the administration of glyproline neuropeptide compounds Thr–Lys–Pro–Arg–Pro–Gly–Pro (Selank), Pro–Gly–Pro and Pro–Gly–Pro–Leu under stress conditions, contributes to the restoration of the initiating and effector caspases level, as well as of neurotrophic factors. As a result of the experiment, an anti-apoptotic effect is observed due to the inhibition of the caspase-dependent cascade of reactions, as well as a stress-protective effect is observed due to the restoration of the brain neurotrophic factors level.