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Neurodegenerative diseases pose a significant health challenge for the elderly. The escalating presence of toxic metals and chemicals in the environment is a potential contributor to central nervous system dysfunction and the onset of neurodegenerative conditions. Transition metals play a crucial role in various pathophysiological mechanisms associated with prevalent neurodegenerative diseases such as Alzheimer's and Parkinson's. Given the ubiquitous exposure to metals from diverse sources in everyday life, the workplace, and the environment, most of the population faces regular contact with different forms of these metals. Disturbances in the levels and homeostasis of certain transition metals are closely linked to the manifestation of neurodegenerative disorders. Oxidative damage further exacerbates the progression of neurological consequences. Presently, there exists no curative therapy for individuals afflicted by neurodegenerative diseases, with treatment approaches primarily focusing on alleviating pathological symptoms. Within the realm of biologically active compounds derived from plants, flavonoids and curcuminoids stand out for their extensively documented antioxidant, antiplatelet, and neuroprotective properties. The utilization of these compounds holds the potential to formulate highly effective therapeutic strategies for managing neurodegenerative diseases. This review provides a comprehensive overview of the impact of abnormal metal levels, particularly copper, iron, and zinc, on the initiation and progression of neurodegenerative diseases. Additionally, it aims to elucidate the potential of fisetin and curcumin to inhibit or decelerate the neurodegenerative process. [ABSTRACT FROM AUTHOR]

Objective: to conduct chemoreactomic, pharmacoinformatic and chemoneurocytological analyzes of the properties of racetams (piracetam, aniracetam, pramiracetam, levetiracetam, fonturacetam).Material and methods. Chemoreactomic, pharmacoinformatic and chemoneurocytological methods of molecule properties analyzis are based on chemoreactomic methodology – the latest direction in the application of machine learning systems in the field of postgenomic pharmacology. Analysis of pharmacological capabilities of molecules within the framework of chemoreactomic methodology is carried out by comparing the chemical structure of racetam molecules with the structures of molecules for which pharmacological properties were studied using training artificial intelligence algorithms based on big data information presented in PubChem, HMDB, STRING, PharmGKB databases. Based on the entire complex of differences between molecules in interactions with receptor proteins, an “anti-obesity” score was calculated for each one as a serial number of this molecule in descending order by corresponding IC50, EC50 chemoreactomic constants values.Results. The lipolytic effect is predicted specifically for fonturacetam as a result of activation by this molecule of β3-adrenoceptors, adenosine receptors, glucagon-like peptide, sphingosine phosphate and peroxisome proliferators, as well as specific inhibition of cannabinoid, opioid, histamine, glutamate, nociceptin, orexin and neuropeptide Y receptors. Due to these mechanisms fonturacetam will contribute to normalizing appetite and improving adipose tissue metabolism. The total lipolytic effect score was calculated for all established interactions with receptors and amounted to 4.3±0.9 for fonturacetam, 3.0±1.4 for pramiracetam, and 2.5±1.5 for all other molecules.Conclusion. The results of the analysis suggest that the lipolytic effects of fonturacetam (Actitropil – Pharmstandard, Russia) will be much stronger than for other racetams (piracetam, aniracetam, pramiracetam, levetiracetam). Chemoreactomic analysis of fonturacetam indicated new mechanisms of pharmacological action of the molecule, providing a decrease in excess appetite and body weight normalization. Fonturacetam is the only nootropic drug indicated for the treatment of obesity.

Three new bibenzochromenones named phanogracilins A–C (1–3) were isolated from the crinoid Phanogenia gracilis. The structure of 1 was established using X-ray crystallography as 5,5′,6,6′,8,8′-hexahydroxy-2,2′-dipropyl-4H,4′H-[7,9′-bibenzo[g]chromene]-4,4′-dione. This allowed us to assign reliably 2D NMR signals for compound 1 and subsequently for its isomer 2 that differed in the connecting position of two benzochromenone moieties (7,10′ instead of 7,9′), and compound for 3 that differed in the length of the aliphatic chain of one of the fragments. Compound 4 was derived from 1 in alkaline conditions, and its structure was elucidated as 5,5′,6′,8,8′-pentahydroxy-2,2′-dipropyl-4H,4′H-[7,9′-bibenzo[g]chromene]-4,4′,6,9-tetraone. Even though compounds 1–4 did not contain stereo centers, they possessed notable optical activity due to sterical hindrances, which limited the internal rotation of two benzochromenone fragments around C(7)–C(9′/10′) bonds. Isolated bibenzochromenones 1–4 were tested for their antiradical, neuroprotective and antimicrobial activities. Compounds 1, 3 and 4 demonstrated significant antiradical properties towards ABTS radicals higher than the positive control trolox. Compounds 1 and 4 exhibited moderate neuroprotective activity, increasing the viability of rotenone-treated Neuro-2a cells at a concentration of 1 µM by 9.8% and 11.8%, respectively. Compounds 1 and 3 at concentrations from 25 to 100 μM dose-dependently inhibited the growth of Gram-positive bacteria S. aureus and yeast-like fungi C. albicans, and they also prevented the formation of their biofilms. Compounds 2 and 4 exhibited low antimicrobial activity. [ABSTRACT FROM AUTHOR]

Introduction. Thyronamines belong to agonists of TAAR1 - trace amine receptors in the brain. The mechanism of activation of the processes of autophagy and neuroplasticity under the action of a synthetic analogue of thyronamines – 4-(4-(2-aminoethoxy)benzyl)aniline is described. Since cerebrovascular disorders remain the most common among neurological diseases, the development and implementation of drugs with neuroprotective properties is considered a promising strategy for the treatment and rehabilitation of patients with ischemic stroke. The aim of the study was to elucidate the effect of 4-(4-(2-aminoethoxy)benzyl)aniline on the activity of GPO, SOD and the dynamics of changes in the level of TBARS in the brain of rats after modeling focal ischemia by transient occlusion of the left middle cerebral artery. Materials and methods. The 4-(4-(2-aminoethoxy)benzyl)aniline was synthesized. Changes in the activity of antioxidant enzymes and the accumulation of secondary LPO products that react with thiobarbituric acid (TBARS) in rat brain homogenates were observed after injection of the studied compound in different dosages, as well as 24 hours after modeling focal ischemia. A neurological deficit in experimental rats was detected by the Garcia scale and the vibrissae-evoked forelimb placing test. Results. Compilation of data made it possible to find a strong relationship between the amount of the injected analogue and the growth of GPO activity in the neurons of healthy animals. In 80% of rats, occlusion of the middle cerebral artery induced evident sensorimotor disorders. 24 hours after the administration of a synthetic analogue of thyronamine in the homogenates of the affected left hemisphere, the activity of glutathione peroxidase significantly increased, and the content of TBARS decreased, and a tendency to activation of SOD was also observed. Conclusions. The obtained data indicate a positive effect of 4-(4-(2-aminoethoxy) benzyl) aniline on antioxidant enzymes in the intact rat brain and after modeling of focal ischemia, which is the basis to continue research for the purpose of finding long-term neuroprotective effects.

Polyphenols are potential neuroprotectors that increase lifespan and slow down aging. Red clover (Trifolium pratense L.) is a promising source of biologically active substances. Its extracts contain biochanin A and chlorogenic acid. This research used Caenorhabditis elegans to study the effect of polyphenols extracted from red clover callus cultures on SOD-3 and HSP-16.2 genes, as well as their anti-amyloid potential. The chlorogenic acid and biochanin A (200, 100, 50, and 10 µM) with a purity of 95% were isolated from callus extracts of T. pratense L. The effect of polyphenols on SOD-3 and HSP-16.2 was assessed after 5 and 2 h of heat stress (35°C), respectively, using C. elegans N2 Bristol as model organism. The neuroprotective potential was measured by counting paralyzed nematodes after 18, 40, and 62 h of incubation. The research established a dose-dependent effect between the concentration of biologically active substances and the percentage of paralyzed nematodes after 18 h of cultivation. The lowest paralysis phenotype count occurred at a concentration of 200 μM. The activity of 200 μM biochnin A was 1.18 times as high as that of a 200 μM chlorogenic acid solution. Biochanin A solutions increased SOD-3 expression by 3.7 times, compared to the control. The biologically active substances exhibited relative neuroprotective activity and affected the expression of antioxidant defense gene in C. elegans.

Introduction. Cerebrovascular diseases (CVD) are one of the most pressing medical and social problems due to the high rate of mortality and disability. Stroke is the leading cause of CVD. About 15 million strokes are registered annually in the world according to the World Federation of Neurological Societies. It should be noted that CVD of ischemic origin has a tendency to rejuvenation and growth. Traditionally, in clinical practice, antihypoxic, antioxidant agents, as well as drugs with neuroprotective and neurorehabilitation effects are used to treat CVD. In connection with the increase in the incidence of CVD, there is an urgent need to search for promising neuroprotectors.Aim. To study the neuroprotective activity of 5-ethoxy-2-ethylthiobenzimidazole (etomerzol) and 2-ethylthiobenzimidazole (bemityl) in a model of middle cerebral artery occlusion.Materials and methods. Occlusion of the middle cerebral artery (ОMCA) was used as a model. The object of the study was inbred male rats of the Dark Agouti line, randomized into five groups: a group of intact animals and four groups with OSMA: a control group, a group with the introduction of 5-ethoxy-2-ethylthiobenzimidazole (etomerzole, 25 mg/kg), a group with the introduction 2-ethylthiobenzimidazole (bemityl, 25 mg/kg) and a group with the reference drug dimethyl fumarate (DMF, 100 mg/kg). On the 1st, 3rd, and 7th days after the operation, the "Limb Stimulation" (SC) test was performed. On the 7th day, the tests "Open field" (OP) and "Elevated plus maze" (EPM) were performed. Euthanasia was performed on the 7th day in an induction chamber (Bioscape GmbH, CO2 box for euthanasia, Germany).Results and discussion. The study showed a pronounced pharmacological effect of etomerzole in a model of acute ischemic stroke. The introduction of bemitil, etomerzol and DMF significantly reduced the neurological deficit 24 hours after OSMA and improved the psycho-functional state on the 7th day. Thus, in the etomerzol group on the first day after surgery, the neurological deficit was reduced by 1.9 times (p < 0.05), and by 3 and 2.0 times (p < 0.05) compared with the control group. While bemityl and DMF reduced the index by 1.3 (p < 0.05) and 1.4 times (p < 0.05) on the 3rd day and by 1.5 times (p < 0.05) on the 7th day. In the OP test in the etomerzol group, an increase in HDA by 2.7 times (p < 0.05) was observed compared with the control. The rate of peering into minks in the etomersol and bemitil groups was higher than in the control group by 2.6 (p < 0.05) and 3.4 times (p < 0.05), respectively. Search and research activity was increased in the same groups by 2.0 (p < 0.05) and 2.2 times (p < 0.05) compared to control animals. In the PCL test, the etomerzol and DMF groups showed an increase in the number of uprights in the sleeves compared to the control group by 2.7 (p < 0.05) and 3.8 times (p < 0.05), respectively. In the etomerzol and bemityl groups, there was an increase in the number of overhangs by 3.4 (p < 0.05) and 6.2 times (p < 0.05).Conclusion. The data obtained during the study of the activity of benzimidazoles after ischemic stroke indicate a significant increase in the motor activity of animals in the OP tests, which may indicate a psychostimulating and potential nootropic effect of etomerzole and bemitil, and an increase in the number of racks and hangings in the PCL test can be regarded as manifestation of anxiolytic activity. In our study, the severity of the pharmacological effects of DMF was inferior to benzimidazoles. However, a significant decrease in neurological deficit in the SC test and an increase in the number of uprights in the sleeves in the PCL may indicate the presence of anxiolytic activity in the drug. The results obtained underline the importance of conducting additional studies to evaluate the effectiveness of DMF in OSMA.

The crystal structure and the biological activity of a new coordination compound of magnesium ions with comenic acid, magnesium comenate, was characterized and studied. Quantitative and qualitative analysis of the compound was investigated in detail using elemental X-ray fluorescent analysis, thermal analysis, IR-Fourier spectrometry, UV spectroscopy, NMR spectroscopy, and X-ray diffraction analysis. Based on experimental analytical data, the empirical formula of magnesium comenate [Mg(HCom)2(H2O)6]·2H2O was established. This complex compound crystallizes with eight water molecules, six of which are the hydration shell of the Mg2+ cation, and two more molecules bind the [Mg(H2O)6]2+ aquacation with ionized ligand molecules by intermolecular hydrogen bonds. The packing of molecules in the crystal lattice is stabilized by a branched system of hydrogen bonds with the participation of solvate water molecules and oxygen atoms of various functional groups of ionized ligand molecules. With regard to the biological activity of magnesium comenate, a neuroprotective, stress-protective, and antioxidant effect was established in in vitro and in vivo models. In in vitro experiments, magnesium comenate protected cerebellar neurons from the toxic effects of glutamate and contributed to the preservation of neurite growth parameters under oxidative stress caused by hydrogen peroxide. In animal studies, magnesium comenate had a stress-protective and antioxidant effect in models of immobilization–cold stress. Oral administration of magnesium comenate at a dose of 2 mg/kg of animal body weight for 3 days before stress exposure and for 3 days during the stress period led to a decrease in oxidative damage and normalization of the antioxidant system of brain tissues against the background of induced stress. The obtained results indicate the advisability of further studies of magnesium comenate as a compound potentially applicable in medicine for the pharmacological correction of conditions associated with oxidative and excitotoxic damage to nerve cells. [ABSTRACT FROM AUTHOR]

Background. Phenol and parabens exert bactericidal properties, are relatively low-toxic (in acute toxicity tests) and are used in pharmaceutical, cosmetic and food industries as stabilizers/preservatives for the final product. Despite their widespread use, the long-term toxicological effects of phenol and parabens remain largely unexplored.Objective: to conduct an analysis of the results of basic and clinical studies on chronic toxicity of phenol and parabens.Material and methods. The study included 544 articles found using the query “Preservatives, Pharmaceutical [MeSH Terms] AND Phenol [MeSH Terms]” in the PubMed/MEDLINE biomedical publications database. Methods of topological and metric analysis of big data were applied, developed in the scientific school of Academician of the Russian Academy of Sciences Yu.I. Zhuravlev. Keywords were sorted by empirical Rudakov–Torshin informativeness functionals in the context of combinatorial theory of solvability, followed by combinatorial testing of solvability to find terms with the greatest informativeness.Results. Despite the existence of individual studies on the acute toxicity of phenol and its derivatives (including parabens), the chronic toxicity of phenol and parabens remains poorly understood. This fact is indicated not only by a lack of carefully performed research, but also by the information in safety data sheets supplied by manufacturers of the relevant substances. The associations of phenol and paraben blood levels with certain chronic pathologies in humans have been insufficiently studied. At the same time, the authors of fundamental research, if not “sound the alarm,” then strongly underline the need to conduct large-scale clinical trials on the long-term toxic effects of phenol and parabens. Firstly, this is due to complex estrogen-like effect of phenol and parabens, including (1) effects on estrogen sulfotransferases, (2) direct interactions with estrogen receptors, (3) influence on the expression of steroid receptor genes. Secondly, the available data from fundamental research indicate that phenol/parabens obviously stimulate the the molecular mechanisms of oncogenesis pathophysiology (systematic disturbances in gene expression and corresponding changes in the structure of organ tissues). Thirdly, teratogenic and other toxic effects on the embryo and pregnancy were demonstrated not only in experimental studies (neurotoxicity and teratogenesis in animal models), but also in clinical observations (metabolic disorders in a pregnant woman, including the metabolism of purines and fatty acids beta-oxidation, hyperactivity and/or excess body weight in children, asthma, thyroid dysfunction, etc.).Conclusion. Findings from basic research and selected clinical studies dictate an urgent need to examine the association of phenol/paraben blood levels with chronic pathologies in large-scale clinical trials with cross-sectional and longitudinal design. The lack of indication on toxic effects of parabens and phenols in certain clinical studies may just be an artifact of incorrect data analysis.

The vitreous body of the eye of human fetuses contains serum albumin (SA) and alpha-fetoprotein (AFP), which is normally characteristic of human embryos and fetuses. In the second trimester, both proteins are found in the vitreous body at a concentration comparable to that in the blood serum, after which their content decreases sharply. In this analytical review, taking into account the biological properties of SA and AFP, the role of these proteins in the processes of growth and differentiation of the structures of the developing eye is discussed. [ABSTRACT FROM AUTHOR]

Three new bibenzochromenones named phanogracilins A–C (1–3) were isolated from the crinoid Phanogenia gracilis. The structure of 1 was established using X-ray crystallography as 5,5′,6,6′,8,8′-hexahydroxy-2,2′-dipropyl-4H,4′H-[7,9′-bibenzo[g]chromene]-4,4′-dione. This allowed us to assign reliably 2D NMR signals for compound 1 and subsequently for its isomer 2 that differed in the connecting position of two benzochromenone moieties (7,10′ instead of 7,9′), and compound for 3 that differed in the length of the aliphatic chain of one of the fragments. Compound 4 was derived from 1 in alkaline conditions, and its structure was elucidated as 5,5′,6′,8,8′-pentahydroxy-2,2′-dipropyl-4H,4′H-[7,9′-bibenzo[g]chromene]-4,4′,6,9-tetraone. Even though compounds 1–4 did not contain stereo centers, they possessed notable optical activity due to sterical hindrances, which limited the internal rotation of two benzochromenone fragments around C(7)–C(9′/10′) bonds. Isolated bibenzochromenones 1–4 were tested for their antiradical, neuroprotective and antimicrobial activities. Compounds 1, 3 and 4 demonstrated significant antiradical properties towards ABTS radicals higher than the positive control trolox. Compounds 1 and 4 exhibited moderate neuroprotective activity, increasing the viability of rotenone-treated Neuro-2a cells at a concentration of 1 µM by 9.8% and 11.8%, respectively. Compounds 1 and 3 at concentrations from 25 to 100 μM dose-dependently inhibited the growth of Gram-positive bacteria S. aureus and yeast-like fungi C. albicans, and they also prevented the formation of their biofilms. Compounds 2 and 4 exhibited low antimicrobial activity.

The combined effect of protective agents (helium-neon laser, ibuprofen, mexidol) and 3 Gy of accelerated carbon ions (12C) on the cognitive abilities of mice was studied. It was shown that the irradiated animals did not exhibit an altered behavior pattern: the level of anxiety was not increased, there was a slower positive dynamics of learning compared to the control, and there was no deficit in the hippocampus-dependent memory. Analysis of variance of learning curves revealed different coefficients of skill acquisition within the experimental groups, with the lowest characteristic for the group irradiated with a dose of 3 Gy 12C without protective agents. In addition, the analysis of the preference for novelty when testing for recognition of a new object showed that this group of animals has a violation of the nonspatial hippocampus-mediated short-term memory. [ABSTRACT FROM AUTHOR]

Potential mechanisms for the realization of the neuroprotective action of nicotinamide during acute lethal short-term hypoxia were evaluated based on current knowledge about its effect on metabolic processes. Attention was drawn to the role of mitochondrial dysfunction and excitotoxicity followed by axonal degeneration and apoptosis of neurocytes and neuroglia during the development of an inflammatory response in trauma and cerebral ischemia. A decrease in the level of ATP in the cells during hypoxia affects the generation of the mitochondrial membrane potential, promotes an increase in membrane permeability, the release of NAD from mitochondria, the entry of sodium into the cell, and the development of intracellular edema. Activation of poly (ADP-ribose)-polymerase 1, induced by DNA damage during reoxygenation, reduces the level of NAD in the cell as a substrate for its reaction and causes dysfunction of the respiratory mitochondrial complex. High doses of nicotinamide have neuroprotective properties in traumatic brain injury, ischemia and stroke, as well as in neurodegenerative Alzheimer's, Parkinson's and Huntington's diseases. It is generally accepted that the neuroprotective effect of nicotinamide, firstly, is because, being a substrate for the synthesis of nicotinamide mononucleotide and NAD+, it can maintain and prevent the NAD+ content decrease under conditions of acute hypoxia. Secondly, nicotinamide, being a blocker of poly (ADP-ribose) polymerase 1, can provide the required level of NAD+ in the cell and reduce its use in the reactions with this polymerase. Thirdly, nicotinamide is a substrate for NAD+ synthesis and maintains the NAD+/NADH complex, which is important for the functioning of the antioxidant system of the mitochondrial respiratory chain under conditions of acute hypoxia. It is doubtful that these mechanisms are sufficient to implement the action of nicotinamide for the reason that there was no decrease in the level of NAD in mitochondria during the death of animals under conditions of short-term lethal hypoxia. A variant of the mechanism of nicotinamide action through GABA/benzodiazepine receptors, which causes inhibition of the activation of neurocyte glutamate receptors during acute hypoxia, was considered. In hypoxia, there is an excessive hyperactivation of glutamate receptors and the development of acute cellular hypoxia, which leads to cell death from overexcitation (excitotoxicity). Nicotinamide reduces the death of neurocytes from excitotoxicity by acting on benzodiazepine receptors. GABA agonists prevent the effect of glutamate during excitotoxicity in this way. [ABSTRACT FROM AUTHOR]

Deposition of beta-amyloid peptide in the brain observed in Alzheimer's disease contributes to the development of cognitive deficits. We studied the abilities of different neuroprotectors to prevent or reduce degeneration of hippocampal neurons in rat brain 14 and 45 days after single intrahippocampal injection of beta-amyloid peptide 25-35 (Aβ25-35). Cytological analysis of the neurons of the hippocampal CA1 and CA3 fields showed predominant damage to CA1 neurons in 14 days and CA3 neurons in 45 days after Aβ25-35 administration. Single preliminary administrations of neuroprotectors fullerene C60FWS (antioxidant), neuromedin (nonselective inhibitor of acetylcholinesterase), and AM404 (activator of the endocannabinoid system) largely prevented neurodegeneration of neurons. Fullerene produced the most pronounced protective effect, which can be explained by its ability to prevent aggregation of proteins and destroy Aβ25-35 fibrils. The combined use of these neuroprotectors can provide the basis for the development of new approaches to prevention and treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Deposition of beta-amyloid peptide in the brain observed in Alzheimer's disease contributes to the development of cognitive deficits. We studied the abilities of different neuroprotectors to prevent or reduce degeneration of hippocampal neurons in rat brain 14 and 45 days after single intrahippocampal injection of beta-amyloid peptide 25-35 (Aβ25-35). Cytological analysis of the neurons of the hippocampal CA1 and CA3 fields showed predominant damage to CA1 neurons in 14 days and CA3 neurons in 45 days after Aβ25-35 administration. Single preliminary administrations of neuroprotectors fullerene C60FWS (antioxidant), neuromedin (nonselective inhibitor of acetylcholinesterase), and AM404 (activator of the endocannabinoid system) largely prevented neurodegeneration of neurons. Fullerene produced the most pronounced protective effect, which can be explained by its ability to prevent aggregation of proteins and destroy Aβ25-35 fibrils. The combined use of these neuroprotectors can provide the basis for the development of new approaches to prevention and treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objective: to elucidate whether cerebrolysin contains peptide fragments that promote geroprotection.Material and methods. The peptide composition of cerebrolysin underwent a comprehensive mass spectrometric analysis, followed by a systemic biological assessment.Results and discussion. Thirty-six peptides with geroprotective properties were isolated in the multipeptide composition of cerebrolysin. These peptides included those of mimetics of adrenomedullin and enkephalins; those of inhibitors of seven targeted human proteins (the protein kinases MAPK1, VPRBP, and PKC, the gamma-secretase PS1, the kinases CDK1, SGK1 and mTOR). The established cerebrolysin peptides were shown to be competitive inhibitors of the seven targeted proteins. In particular, inhibition of PKC and mTOR stimulated the increased autophagy (the utilization of waste and abnormal proteins), which contributes to an increase in the survival of cells and model organisms.Conclusion. Cerebrolysin can have geroprotective effects, by inhibiting the seven targeted proteins, by activating endorphinergic neurotransmission, and can be indirectly involved in vascular tone normalization.

Parkinsonism in rats induced by the pesticide rotenone is one of the most adequate models of Parkinson's disease (PD). Isatin (indole-2,3-dione) is an endogenous regulator found in mammals and humans and exhibiting a wide range of biological activities mediated by numerous isatin-binding proteins, including those associated with neurodegenerative pathology. A course of rotenone administration to rats caused behavioral impairments and changes in the profile and relative content of isatin-binding proteins in the brain. In this study, we have investigated the delayed neuroprotective effect of isatin (5 days after completion of the course of rotenone administration) on behavioral reactions and the relative content of isatin-binding proteins in the brain of rats with rotenone-induced experimental parkinsonism. Although during this period the rats retained locomotor dysfunction, the proteomic analysis data (profile of isatin-binding proteins in the brain and changes in their relative content) differed from the results obtained immediately after completion of the course of rotenone administration. Moreover, all isatin-binding proteins with altered relative content changed during this period are associated to varying degrees with neurodegeneration (many with Parkinson's and Alzheimer's diseases).

Introduction: Acute traumatic spinal cord injury is a complex injury affecting the nervous tissue of the spinal cord, vertebrae, joints, innervation and local vasculature, resulting in high mortality, physical dependence, stress, financial losses, lifelong risk of medical complications and reduced longevity. The complexity of the clinical repercussions of acute spinal cord trauma (SCI) makes early interventions necessary to ensure better prognosis. Emerging therapies with neuroprotective agents emerge Methodology: For the integrative literature review, the PubMed databases were used, Scielo, Google Scholar, Cochrane and the descriptors "spinal injury"; "spinal cord trauma"; "neuroprotective" and "drug therapy". Results: Therapies with corticosteroids, ion channel blockers, agonists and antagonists of neurotransmitters, cellular and genetic agents, vitamin D, progesterone, erythropoietin and caspase inhibitors demonstrated different neuroprotective effects involving reduction of secondary spinal cord injury and acceleration of neuronal recovery. in uneven research phases. Conclusion: It is concluded that preclinical studies with neuroprotectors as a potential treatment for TRM are promising, however, not all of them evolve into clinical trials, which limits the application of these therapies in humans. Therefore, it is necessary to improve research and clinical trials related to the use of neuroprotective agents in the management of traumatic acute spinal cord injury. [ABSTRACT FROM AUTHOR]

Cellular models are a very important research tool in modern neurobiology. The presented review of Russian and international literature summarizes the main data of experimental studies, conducted over the past 15 years, aimed at modeling in vitro acute and chronic forms of cerebral pathology in order to reveal the mechanisms of their pathogenesis and to develop approaches to their pharmacological correction. The results of modeling of ischemic neurodestructive processes, epilepsy, Parkinson's disease, Alzheimer's disease and Huntington's disease, obtained using modern cellular research methods, such as cell cultivation in a multielectrode system and technology of induced pluripotent stem cells, are presented. A number of key concepts related to this problem are illustrated with the data obtained by the author and his laboratory. In conclusion, the short-term goals and prospects of in vitro studies of pathogenic mechanisms of neurological diseases and of the search for new neuroprotectors are formulated.

Currently, the molecular characteristics of the occurrence and course of neurodegenerative diseases, which are among the most serious and still incurable illnesses, remain to be fully elucidated. Therefore, the search for novel medicines for the removal, relief, or postponement of symptoms in these pathologies remains relevant. In view of the complexity of undertaking this research in human, the identification of genes associated with developing neurodegenerative changes and the study of their functions in different (neuronal and glial) tissues and at different stages of ontogenesis are carried out in model systems. Drosophila melanogaster is one of the best and available objects for the identification of molecular genetic mechanisms underlying the development of neurodegeneration as well as for the initial tests of novel compounds with neuroprotective properties. This article discusses the methods of genetic analysis in Drosophila, the use of D. melanogaster as a model of human neurodegenerative disorders, and a possibility of using its model as test systems for the study of potential neuroprotectors. [ABSTRACT FROM AUTHOR]

γ-Carboline derivatives were synthesized by the addition of fluorinated vinylpyridines to 2,6-dimethyl-2,3,4,5-tetrahydro-γ-carboline. The effect of repeated intraperitoneal injections of the synthesized derivatives on the progression of motor and cognitive dysfunctions was studied in comparison with Dimebon in 5xFAD transgenic mice as a model of neurodegenerative diseases induced by cerebral amyloidosis. [ABSTRACT FROM AUTHOR]

Isatin (indoldione-2,3) is an endogenous biological regulator found in the brain, peripheral tissues, and biological fluids of humans and animals. Its biological activity is realized via isatin-binding proteins, many of which were identified during proteomic profiling of the brain of mice and rats. A number of these proteins are related to the development of neurodegenerative diseases. Previously, using a model of experimental Parkinsonism induced by a seven-day course of rotenone injections, we have observed behavioral disturbances, as well as changes in the profile and relative content of brain isatin-binding proteins. In this study, we have investigated behavioral responses and the relative content of brain isatin-binding proteins in rats with rotenone-induced Parkinsonism 5 days after the last administration of this neurotoxin. Despite the elimination of rotenone, animals exhibited motor and coordination impairments. Proteomic profiling of isatin-binding proteins revealed changes in the relative content of 120 proteins (the relative content of 83 proteins increased and that of 37 proteins decreased). Comparison of isatin-binding proteins characterized by the changes in the relative content observed in the brain right after the last injection of rotenone (n=16) and 5 days later (n=11) revealed only two common proteins (glyceraldehyde-3-phosphate dehydrogenase and subunit B of V-type proton ATPase). However, most of these proteins are associated with neurodegeneration, including Parkinson's and Alzheimer's diseases.

Speech disorders are a common complication of encephalitis in children (15-38%). They often lead to permanent disability, significantly complicate rehabilitation during the recovery period, reduce the quality of life of both the patients themselves and those around them, cause negative psychoemotional reactions, and increase the economic costs of treatment. Compared with patients with other brain pathologies, but without speech disorders, the quality of life is lower in patients with post-infectious aphasia, and they stay in hospital longer. Predictors of good recovery of speech function are mild and moderate severity of speech disorders in the acute period of encephalitis, the amount of brain damage (the smaller the encephalitis focus, the higher the chances of recovery), young age. In addition to the treatment of the underlying disease, patients with speech disorders need systematic speech therapy and taking drugs to optimize cerebral neuroreparative processes. [ABSTRACT FROM AUTHOR]

The mechanism of the neuroprotective action of α2-adrenergic receptor agonists in a model of oxygen-glucose deprivation (OGD) in vitro was investigated. Using fluorescent microscopy, immunostaining, inhibitor analysis, and real-time PCR analysis, we demonstrated that OGD evokes a biphasic [Ca2+]i increase in all cells. Initial Ca2+ impulse in astrocytes and Ca2+ oscillations in neurons were followed by a slower global increase of [Ca2+]i in both cell populations. Accumulation of pro-inflammatory factors, such as IL1b and TNFα, was observed during 40-min OGD. It was established that reoxygenation is followed by hyperexcitation of neurons, caspase-3 activation, and subsequent cell death. We showed that a 24-h pretreatment of cell cultures with selective α2-adrenergic receptor agonists guanfacine and UK-14,304 abolished the global [Ca2+]i increase in astrocytes and neurons but did not suppress the first phase of the OGD-induced Ca2+ impulse in astrocytes. In addition, the number of dead cells after OGD was decreased in cell cultures pretreated with the α2-agonists. Guanfacine inhibited caspase-3 activation and suppressed apoptosis in our experiments. In particular, the expression of antiapoptotic genes Stat3 and Bcl-2 was enhanced after the pretreatment with guanfacine. On the contrary, the expression of proapoptotic genes (Socs-3, p53, fas, and Ikk) was decreased. Moreover, application of guanfacine evoked Ca2+ response in astrocytes and led to Ca2+-mediated ATP release and this way suppressed hyperexcitation of the neurons. Thus, activation of astrocytes and Ca2+-mediated ATP release possibly contribute to the complex neuroprotective effects of the α2-adrenergic receptor agonists. [ABSTRACT FROM AUTHOR]

Abstract—This review summarizes the current understanding of the regulatory role of melatonin in the formation of the nervous system in the antenatal and early postnatal period of body development. We discuss questions concerning the involvement of melatonin and the suprachiasmatic nuclei of the hypothalamus, which are the central oscillator of biorhythms, in the synchronization of the functions of various body systems. The mechanisms of protection of the developing brain from the damage caused by oxidative stress and inflammation are discussed. We presented a detailed list of biomarkers of this process, whose analysis may help to evaluate disturbances of the cognitive functions in early ontogeny, which often have remote consequences. Special attention is paid to the neuroprotective effect of melatonin on offspring during hyperhomocysteinemia, which disturbs epigenetic regulation by affecting the methylation processes (methyltransferase activity) in the nervous system and entire body. This material justifies the prospects for the use of melatonin in clinics for the treatment of disorders of the functional activity of the brain of the fetus and newborn. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is characterized by high prevalence, mortality, and disability rates. Therapy aimed to correct one biochemical or molecular stage of ischemic cell injury fails to treat stroke, suggesting that it is necessary to study multimodality therapy affecting several related pathophysiological components.The paper gives the January 2016 results of the randomized placebo-controlled multicenter study CARS that demonstrates the positive effect of cerebrolysin versus placebo according to the primary efficiency criterion, the Action Research Arm Test (ARAT) scale, and total outcome 90 days after disease onset. The investigation enrolled mainly patients with moderate or severe IS (the mean National Institutes of Health Stroke Scale score was 9 at baseline).The specific features of the CARS study versus those of other clinical trials of neuroprotectors were the initial planning of narrower end criteria of efficiency (arm motor function recovery whereas the major goal of many investigations was to reduce mortality rates), as well as a standardized rehabilitation program in both treatment groups. Such investigations did not previously take into account the nature and volume of rehabilitation measures although the latter may have a substantial impact on the outcome of stroke.The CARS study is the first among the previously conducted clinical trials of neuroprotectors, which has attained the primary objective (to restore motor function), which opens up fresh opportunities for the medical support of rehabilitation measures in patients with IS.

Purpose. To study an efficiency in the system of pathogenetic treatment of patients with anterior ischemic optic neuropathy (AION).Material and methods. The research included 43 patients with an acute AION phase. The average age of patients was 52.3±4.5 years. All patients were divided into two groups. The study group consisted of 23 patients. The system of treatment included retrobulbar implantation of a silicone catheter to the posterior pole of the eye with infusion of medicinal preparations (MP): Cerepro (dose 0.5 ml), then with interval of 1 hour, 0.5 ml of 5% Mexidol solution for injections and then 5 mg of Cortexin. After a two-hour break, retrobulbar MP infusions were repeated. The control group consisted of 20 patients who underwent the traditional method of injections of Cerepro, Mexidol and Cortexin. At the same time the patients of both groups of study within 10 days received daily a course of magnetic stimulation using the AMO-ATOS device with the OGOLOVE attachment («Trima», Russia).Results. After the end of treatment in a hospital, in the main group of patients there were noted: increase of visual acuity, expansion of visual field limits, electrophysiological indices authentically exceeded the similar data obtained in patients of the control group. According to degrees of functional disorders severity after one year of the treatment the degree I prevailed in the main group of patients, less often the degree II of optic nerve atrophy (ONA) (9 individuals, 40%). According to degrees of functional disorders severity one year after the treatment in the main group of patients the degree I prevailed, and less often the degree II of optic nerve atrophy (ONA) (9 individuals, 40%). Among the patients of the control group the ONA degrees II-III were met more often.Conclusions. The therapeutic effect of system of treatment, including sub-Tenon’s retrobulbar infusion of MP for neuroprotection, of patients with AION was manifested in: increase of visual acuity by 1.5 times, expansions of the total of the visual field limits on the average by 69.5±4.9 degrees, decrease of number of absolute and relative scotomas by 1.6 times, increase of amplitude by 1.35 times and decrease of latency of visual evoked potential by 1.2 times, in comparison with traditional methods of implantation of MP. More significant favorable functional results in AION patients of the main group were achieved thanks to an increase of blood flow indices in short posterior ciliary arteries.

Cerebrovascular diseases (CVDs) are one of the leading causes of death and disability In Russia: they rank second in the structure of mortality from diseases of the circulatory system and in the overall mortality of the population. Successful treatment of CVD involves an integrated approach to the problem, taking into account the compensation of cardiovascular disorders, the elimination of neurological and psychopathological syndromes, the improvement of cerebral circulation and the use of neuroprotective agents that increase the resistance of brain tissue to hypoxia and ischemia. Insufficient clinical efficacy of neuroprotectors is due to a number of objective reasons, of which only two are universal. The first of these reasons is the timing of the start of therapy in the clinic, as a rule, is outside the «therapeutic window»; the second reason is the fact that disturbance of the patency of the cerebral vessels in the affected area makes it difficult or impossible to deliver the drug to the penumbra area. The way out of this situation is the intranasal route of drug administration, which is characteristic for the analogs of regulatory peptides such as for H-Met-Glu-His-Phe-Pro-Gly-Pro-OH (MGHPPGP). The review of clinical studies indicates that MGHPPGP is clinically effective in the treatment of ischemic stroke both in the acute period of stroke and in the recovery period. The clinical efficacy of MGHPPGP was shown both in atherothrombotic and cardioembolic subtypes of stroke, against the background of blood flow disturbances in both the carotid and vertebrobasilar systems.

Effects of the endogenous neuroprotector isatin and the pharmacological drug afobazole (exhibiting neuroprotective properties) on behavioral reactions and quantitative changes in the brain proteomic profile have been investigated in rats with experimental rotenone Parkinsonism. A single dose of isatin (100 mg/kg subcutaneously on the last day of a 7-day course of rotenone administration) improved the motor activity of rats with rotenone-induced Parkinsonism in the open field test (horizontal movements) and the rotating rod test. Afobazole (10 mg/kg intraperitoneally, daily during the 7-day course of rotenone administration) reduced the manifestations of rigidity and postural instability. Proteomic analysis, performed using brain samples obtained the day after the last administration of rotenone and neuroprotectors, revealed similar quantitative changes in the brain of rats with rotenone Parkinsonism. An increase in the relative content of 65 proteins and a decrease in the relative content of 21 proteins were detected. The most pronounced changes - an almost ninety-fold increase in the alpha-synuclein content - were found in the brains of rats treated with isatin. In animals of the experimental groups treated with "Rotenone + Isatin", as well as "Rotenone + Afobazole", the increase in the relative content of this protein in the brain was almost 60 and 50 times higher than the control values. Taking into consideration the known data on the physiological role of alpha-synuclein, an increase in the content of this protein in the brain upon administration of neuroprotectors to animals with rotenone Parkinsonism may represent a compensatory reaction, at least in the early stages of this disease and the beginning of its treatment.

Primary Objective: To identify risk factors for intracerebral lesion (ICL) in older adults with mild traumatic brain injury (MTBI) and evaluate the influence of comorbidities on outcomes. Research Design: Prospective cohort study. Methods and Procedures: Information was gathered on clinical history/examination, cranial computed tomography, admission Glasgow Coma Scale (GCS) score, analytical and coagulation findings, and mortality at 1 week post-discharge. Bivariate and multivariate logistic regression analyses were performed, calculating odds ratios for ICL with 95% confidence interval. P < 0.05 was considered significant. Main Outcomes and Results: Data were analyzed on 504 patients with mean±SD age of 79.37 ± 8.06 years. Multivariate analysis showed that traffic accident, GCS score of 14/15, transient consciousness loss, nausea, and receipt of antiplatelets were predictors of ICL, while SRRI and/or benzodiazepine intake was a protective factor. A score was assigned to patients by rounding OR values, and a score ≥1 indicated moderate/high risk of ICL. Conclusions: MTBI management should be distinct in over-60 year-olds, who may not present typical symptoms, with frequent comorbidities. Knowledge of risk factors for post-MTBI ICL, associated with higher mortality, is important to support clinical decision-making. Further research is warranted to verify our novel finding that benzodiazepines and/or SSRI inhibitors may act as neuroprotectors. [ABSTRACT FROM PUBLISHER]

New N-(pyridin-3-ylmethyl)-2-aminothiazolines containing various substituents at the 5 position of the thiazoline ring and the 4- tert-butylbenzyl, 4-isopropylbenzyl, or 4-fluorobenzyl moiety at the nitrogen atom of the amino group were synthesized. The inhibitory activity of the synthesized compounds against human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), equine serum butyrylcholinesterase (BChE, EC 3.1.1.8), and porcine liver carboxylesterase (CaE, EC 3.1.1.1) was evaluated and their antioxidant properties were studied by ABTS assay. N-(Pyridin-3-ylmethyl)-2-aminothiazolines proveded to be very weak AChE inhibitors, while their inhibitory activity against BChE and CaE was structure-dependent. 2-Aminothiazolines containing the 4- tert-butylbenzyl moiety are more efficient BChE inhibitors compared to the derivatives containing the 4-isopropylbenzyl or 4-fluorobenzyl substituent. An analysis of the dependence of the esterase profile of N-(pyridin-3-ylmethyl)-2-aminothiazolines on the structure of the substituent at the 5 position of the thiazoline ring of these compounds demonstrated that the derivatives containing the iodomethyl substituent possess the highest anti-BChE activity, the compounds with R = H and R = CHI have the optimal esterase profile. Regardless of the structure of the substituents in the benzyl moiety, all N-(pyridin-3-ylmethyl)-2-aminothiazolines containing the iodomethyl substituent at the 5 position of the thiazoline ring exhibited high radical scavenging activity comparable with that of the standard antioxidant Trolox. N-(Pyridin-3-ylmethyl)-2-aminothiazolines were shown to be a new promising class of compounds for the design of multifunctional agents for the treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Cognitive dysfunction draws more and more attention of doctors and researchers. The article contains a detailed analysis of risk factors, clinical features and possibilities for cognitive rehabilitation. Neuroprotective therapy in conjunction with adequate correction of homeostasis and hemodynamic is of high practical importance. The suggested methodology directed towards improvement of cholinergic transmission with the use of Mildronat, Actovegin and Ceraxon is rather efficient and can be recommended as medicine of choice not only as cognitive preserved but also as cognitive restoring medicines.

Cerebrovascular accident (CA) is a nowadays widely spread, highly incapacitating and often lethal event that poses a prominent clini- cal problem. Cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) ? an ?epidemic? of the century, ? are known to be its primary risk factors. Hyperglycemia promotes CA risks by induction of protein glycosylation, elevation of blood plasma atherogenic potential, activation of coagulation system with higher risk for thrombosis and disturbance of microcirculation on tissue and organ lev- els. Influence of hyperglycemia on severity and extent of neurologic damage is still under evaluation. Development of macroangiopathy is thought to be associated with media calcification, distal polyneuropathy and renal disorders, all of which are cardiovascular risk factors. Application of so-called metabolic drugs resulted in certain disillusionment, as these agents failed to prove their efficacy during clinical trials. Incidence of pulmonary edema in patients with ischemic CA and T2DM is important as it dictates the necessity for use of loop diuretics. Incidence and severity of heart failure and its correlation with degree of glycemic disorders, incidence of pulmonary em- bolism, as well as tactics of management and prognosis in patients with ischemic CA and T2DM, remains a relevant research problem.

Cognitive disorders (CDs) are diagnosed in most patients within the first months after stroke. Moreover, the prevalence of poststroke dementia, the most severe type of CDs, is 7-40% in relation to patient age and prior stroke severity. The major risk factors of poststroke CDs are elderly age, recurrent stroke, low education level, pronounced leukoareosis, and/or hippocampal atrophy, as evidenced by magnetic resonance imaging (MRI), and left-hemisphere stroke. Prestroke CDs is an important predictor of poststroke dementia that is commonly detected retrospectively during the directed interview of relatives. This fact suggests that stroke is not the only cause of CDs, but frequently decompensates or engages a physician's attention to already existing CDs. Three clinical and pathogenetic types of poststroke CDs may be identified. These include sequels of strategic infarction crucial for cognitive functions; poststroke vascular CSs associated with reinfarctions and/or leukoareosis; and mixed (vascular and degenerative) CDs caused by a decompensated latent degenerative process. Approaches to managing poststroke CDs are the same as those in CDs as a whole. The study of the preventive effect of neuroprotective agents against the development of poststroke CDs and dementia in the rehabilitative period of stroke is promising.

The article discusses the questions of usage of the drug Trigamma® as a therapy of patients with lesions of the nervous system as well as some other diseases based on the experience of Russian and foreign experts. The advantages of the drug Trigamma® are based on a balanced composition, and synergistic action of its components. We consider the therapeutic potential of Trigammа® and the possibilities to prescribe it to a wide range of patients as an effective, highly secure, affordable and easy-to-use drug.

The increase of many deadly diseases like infections by multidrug-resistant bacteria implies re-inventing the wheel on drug discovery. A better comprehension of the metabolisms and regulation of diseases, the increase in knowledge based on the study of disease-born microorganisms’ genomes, the development of more representative disease models and improvement of techniques, technologies, and computation applied to biology are advances that will foster drug discovery in upcoming years. In this paper, several aspects of current methodologies for drug discovery of antibacterial and antifungals, anti-tropical diseases, antibiofilm and antiquorum sensing, anticancer and neuroprotectors are considered. For drug discovery, two different complementary approaches can be applied: classical pharmacology, also known as phenotypic drug discovery, which is the historical basis of drug discovery, and reverse pharmacology, also designated target-based drug discovery. Screening methods based on phenotypic drug discovery have been used to discover new natural products mainly from terrestrial origin. Examples of the discovery of marine natural products are provided. A section on future trends provides a comprehensive overview on recent advances that will foster the pharmaceutical industry.

Hybrid γ-carboline-based compounds containing a nitrooxy group as an NO-donor were prepared. It was shown that the introduction of this group did not affect the inhibitory activity of γ-carboline pharmacophore against acetyl- and butyrylcholinesterase. [ABSTRACT FROM AUTHOR]

We studied the dynamics of the intracellular concentration of calcium ions ([Ca]) and the influence of the endogenous cannabinoid N-arachidonoyldopamine (N-ADA) on disturbances of calcium homeostasis in cultured hippocampal neurons in the model of postischemic epileptogenesis (PE) in vitro, in accordance with a previously published method. It was found that 24 h after treatment with 20 μM glutamate, its application at a concentration of 50 μM results in a persistent increase in [Ca] whereas in neurons that were not previously subjected to glutamate treatment an increase in [Ca] after the application of 50 μM glutamate was reversible. The presence of N-ADA (5 μM) in the incubation medium both simultaneously with 20 μM glutamate exposure and for 24 h after it promoted recovery of the [Ca] level to the initial level. The results indicate that application of N-ADA promotes normalization of neuronal calcium homeostasis in a PE model in vitro. [ABSTRACT FROM AUTHOR]

We reviewed the literature data on the cellular and molecular mechanisms of postischemic epileptogenesis, which is modeled in a culture of dissociated neurons and organotypic culture of nervous tissue. We summarized the data on the involvement of glutamate excitotoxicity in the development of epileptiform discharges generated by neurons in culture after glutamate application and on the involvement of neuronal calcium overload in the formation of seizure activity. We also presented data on the effects of neuroprotectors in models of postischemic epileptogenesis in vitro. [ABSTRACT FROM AUTHOR]

A number of N-(4-tert-butylbenzyl)- N-(pyridin-3-ylmethyl)-2-aminothiazolines with different substituents at position 5 of thiazoline ring was synthesized and their inhibitory activity against human erythrocyte acetylcholinesterase (AChE, EC 3.1.1.7), horse serum butyrylcholinesterase (BChE, EC 3.1.1.8), and porcine liver carboxylesterase (CaE, EC 3.1.1.1) was studied, as well as their antioxidant properties in DPPH and ABTS tests (DPPH is the 2,2-diphenyl-1-picrylhydrazyl, ABTS is the 2,2´-azinobis(3-ethylbenzthiazolino-6-sulfonic acid)). All the studied compounds virtually do not inhibit AChE, whereas the inhibition degree of BChE and CaE depends on the substituent structure. The presence of radical-binding activity comparable with the standard antioxidant ascorbic acid was shown for compounds containing a iodomethyl substituent. The found lead compound (R = H, R = CHI) combines the antioxidant properties and the ability to efficiently inhibit BChE, simultaneously possessing an optimal esterase profile. The performed studies showed that N-(4- tert-butylbenzyl)- N-(pyridin-3-ylmethyl)-2-aminothiazolines are a new promising class of compounds, which can be used for the development of multifunctional agents for treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The mechanisms of the neuroprotective action of the hexapeptides HLDF-6 encoded by the amino acid sequence 41–46 of Human Leukemia Differentiation Factor and its homoserine derivative HLDF-6H were studied in an experimental 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of Parkinson's disease (PD). C57Bl/6 mice received two intraperitoneal injections of 18 mg/kg MPTP-HCl, with an interval of 2 hours. MPTP-induced motor dysfunction was assessed using horizontal grid test. Our data show that chronic intranasal administration of peptides (3 weeks, 300 μg/kg/day) restored normal levels of dopamine and improved its turnover rates in the striatum. Furthermore, peptide administration increased serum estradiol levels and led to a significant improvement in motor functions in MPTP-treated mice. Additionally, peptide treatment increased the levels of mRNA encoding neurotrophin BDNF, but normalized the levels of mRNA encoding the inflammatory mediators TGFβ1, IL1β and IFNγ in the brain. Collectively, our behavioral and biochemical studies demonstrate that HLDF-6 peptides have a therapeutic potential for treating PD. We propose that HLDF-6 peptides may exert their neuroprotective mechanism, at least in part, by normalizing estradiol levels and modulating the expression of key factors involved in neurotrophic support and neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Insulin-like Growth Factor-1 (IGF- 1) and Insulin-like Growth Factor Binding Protein- 3 (IGFBP-3) have been ascribed neuroprotective effects. We sought to determine whether levels of IGF-1 and IGFBP-3 predict functional outcome after ischemic stroke. Methods: IGF-1 and IGFBP-3 levels were measured in the first week after stroke in patients with first ischemic stroke who were enrolled in the Berlin Cream&Sugar Study. National Institutes of Health Stroke Scale (NIHSS) was collected at admission. Lesion volume was determined from acute MRI if available. Functional outcome according to the modified Rankin Scale (mRS) was assessed after one year. In multivariate analyses we identified parameters associated with unfavourable functional outcome (mRS > 2). Results: We included 100 patients. 21 patients had an unfavourable functional outcome. IGF-1 levels were < - 2 standard deviation score (SDS) in 7 patients, and > 2 SDS in 12 patients. IGFBP-3 levels were < the 5th percentile in 13 patients, and no patient had IGFBP-3 levels > the 95th percentile. Low levels of IGFBP-3 (p = 0.002), NIHSS at admission (p = 0.043) and age (p = 0.001) were associated with unfavourable functional outcome in the univariate analyses. In multivariate analysis including IGFBP-3, IGF-1, age, thrombolysis and NIHSS only low IGFBP-3 levels (OR 7.2, 95 %CI 1.8-29.0, p = 0.006) were associated with unfavourable functional outcome. If lesion volume was incuded (n = 71), only IGFBP-3 levels (OR 7.2, 95 %CI 1.5-35.5, p = 0.015) were associated with unfavourable functional outcome. Conclusion: IGFBP-3 levels after ischemic stroke may independently predict functional outcome after one year. [ABSTRACT FROM AUTHOR]

Adipokines are fatty tissue hormones, a relatively recently discovered class of compounds regulating energy metabolism in virtually all organs and tissues. They include leptin, discovered before and studied better than other adipokines, and evidently associated with the development of a whole series of diseases and pathological states: insulin resistance and diabetes mellitus, cardiovascular system pathology, and oncological and chronic inflammatory diseases. All these states are in one way or another mediated by the influences of leptin on the metabolism of energy substrates and the formation of a proinflammatory state. However, recent years have seen the appearance in the literature of intriguing data on fundamentally different, neurotropic, effects of leptin, suggesting that it has a direct influence on the preservation of neural structures, as well as synapse functioning and transmitter processes. These data allow leptin to be regarded as a neuroprotector, i.e., a neuroplastic factor, and possibly a significant element in realizing specific brain functions. The role of leptin deficiency in lesions to nervous structures and the establishment of the symptoms of central nervous system diseases can also be assessed from this point of view. [ABSTRACT FROM AUTHOR]

To study the mechanisms of the action of neuroglutam (beta-phenylglutamic acid hydrochloride, RGPU-135), which is a drug with antidepressant and anxiolytic activities, we examined the influence of the antagonist of GABA receptors bicuculline (1 mg/kg) and the antagonist of GABA receptors phaclofen (2 mg/kg) on the type and strength of the effects of neuroglutam (26 mg/kg) in behavioral tests. Anxiolytic effects were examined in the open-field test and dark-light box; antidepressant effects were examined in the tail-suspension test. During combined treatment with neuroglutam and bicuculline, anxiolytic and antidepressant effects of neuroglutam did not occur, i.e., development of these effects requires activation of GABA receptors. Phaclofen counteracted the antidepressant effect of neuroglutam, which, to a certain degree is related to activation of GABA receptors. Neuroglutam (26-650 mg/kg) suppressed seizures that were induced by the blockers of GABA receptors picrotoxin (5 mg/kg) and pentylenetetrazol (90 mg/kg), which reflects its capacity to influence this channel. Analysis of the neuroglutam influence (10-10-10-4 M) on the rat brain GABA and GABA receptors by the method of radioligand binding in vitro using tritiated [G-H]SR95531 (for GABA) and [G-H](-)Baclofen (for GABA receptors) did not reveal direct interaction of neuroglutam with these receptors. Subchronic systemic administration of neuroglutam (26 mg/kg, daily for 5 days) to rats induced an increase in the density of GABA receptors in the prefrontal cortex, which points to its capacity to modulate the expression of GABA receptors. These data suggest that one of the aspects of the neuropsychotropic effects of neuroglutam is interaction with the GABAergic neurotransmitter system. [ABSTRACT FROM AUTHOR]

Impairments to glutamatergic synaptic transmission are seen in many pathological CNS states. Excess glutamate actions, inducing persistent depolarization of neurons and massive calcium influx, can lead to cell death. Despite the obvious importance of developing antiglutamate agents as neuroprotectors, the only one of the ionotropic glutamate receptor antagonists which has been introduced into practice is memantine. One of the causes of the multiple side effects occurring when glutamate receptor antagonists are used is that these pharmacological agents inhibit the whole of the receptor pool, both those receptors involved in pathological processes and those performing normal physiological functions. One possible approach to overcoming this problem consists of developing pharmacological agents whose actions are enhanced in potential pathological states, such as high-frequency stimulation of receptors, high glutamate concentrations, decreases in neuron membrane potential, etc. The efficacies of many types of antagonists, such as channel blockers, depends on the membrane potential and the nature of receptor activation. The present article provides a discussion of some of the characteristics of the mechanisms of blockade of glutamate receptor ion channels from the point of view of the potential to create neuroprotective agents. In particular, blockers with different interactions with channel gate structures and different types of blockade voltage dependence are compared, with analysis of the characteristics of the actions of blockers able to penetrate channels to enter cells. We suggest that only detailed study of the mechanisms of action of antagonists on glutamate receptors can bring us towards the ability to predict the results of using blockers in vivo on the basis of data obtained in vitro. [ABSTRACT FROM AUTHOR]