Neurochemical Journal最新文献

Abstract—

Pannexins are capable of forming in the cell membrane anion channels with relatively low conductivity, as well as channels with high nonspecific conductivity that can transport from the cytoplasm into the extracellular space not only inorganic ions but also low molecular weight metabolites with a molecular weight below 1 kDa, in particular ATP, glutamate, glutathione and others. Due to substantial differences in specificity and conductivity, pannexins are involved both in the normal physiological regulation of body functions and in a variety of pathological processes. The review examines the role of pannexin 1 (Panx1) in the occurrence and progression of pathologies of the central nervous system such as ischemia, Parkinson’s and Alzheimer’s diseases, and neuropathic pain. Blockade of Panx1 diminishes the negative consequences of pathological processes, indicating that Panx1 channels may be a promising therapeutic target for the pharmacological correction of brain disorders.

Abstract—Extracellular vesicles (EVs) are a new and actively developing area of modern experimental and theoretical biology, which attracts researchers primarily by the possibility of using EVs as diagnostic biomarkers and therapeutic agents. Currently, the greatest amount of data has been accumulated on small extracellular vesicles (sEVs)—exosomes, vesicles of endosomal origin, and ectosomes (previously known as microvesicles), which are the product of direct budding from the plasma membrane. In this review, we address the major steps in the biogenesis of exosomes and ectosomes, the major processes of intracellular membrane trafficking, and signaling involving sEVs. The role of the sEVs in the physiology and pathophysiology of the nervous system is also discussed, as well as many promising aspects of the study of sEVs biology.

Abstract

The simplicity of collecting and evaluating tear fluid (TF) can potentially provide a convenient non-invasive diagnostic tool that easily fits into a personalized approach to medicine based on risk assessment. Though, to date, most tear biomarkers are not yet ready for routine use due to problems with their clinical validation, given the huge clinical advantage of TF and the emerging advanced technical approaches developed for proteomic, lipidomic and metabolomic analysis of tears, TF studies will doubtless become a routine test for health monitoring in the near future. A number of associations between the levels of different substances in TF and the brain makes TF an invaluable source of brain disease biomarkers helpful in early diagnostics and personalized treatment. TF is a promising biological material, an invaluable source for predictive, diagnostic, prognostic, and mechanistic biomarkers.

Abstract

Blunt-nosed viper venom in high doses causes severe pain, while in low doses an analgesic effect is observed. The opposite effects of different doses of venom are associated with the development of certain metabolic processes and the impact on receptors and channels of nociceptive afferent neurons. The response of the nociceptive system in the periphery and CNS depends on the dose-evoked neurochemical changes in neuronal activity. We studied the effect of various doses of MLO venom in order to understand the mechanisms of the transition of the pain effect of MLO venom into an analgesic one. Pain behavior was studied on outbred white mice at various doses of MLO venom, starting from LD₅₀ for intraplantar and in serial dilutions for intraperitoneal (1.0 and 1/5, 1/10, 1/20 and 1/30 of LD₅₀) administration during the formalin and the hot plate tests. At a dose of 1.0 LD50, experimental mice develop a strong sense of pain, which was examined in the hind paw biting/licking test. The maximum analgesic effect was expressed at 1/20 LD₅₀. To study the degree of participation of the venom’s phospholipase A2 (PLA2) enzymatic activity on pain processes, a venom with the inhibited enzymatic activity of PLA2 was tested. It was obtained, that both in the development of pain and in the analgesic effect, the enzymatic activity of PLA2 plays a significant role. It is proposed that in case of high doses the antinociceptive action of venom is masked.

Abstract

Stress is one of the major contributing factors to the development of neurodegenerative diseases and mental disorders. These pathologies are reportedly characterized by progressive loss of neurons and impaired motor and cognitive functions. Changes in stress-induced mechanisms, such as oxidative stress (OS) with corresponding neurotransmitters’ interplay are important for both, the mechanisms of defense and the progression of mental disorders. OS implies an imbalance in the pro-oxidant/antioxidant homeostasis resulting in the generation of aggressive radicals, reactive oxygen species (ROS), and exaggeration of neurodegenerative disease. However, in clinical trials, antioxidants such as alfa-tocopherol have not provided efficacious protection as an alternative therapy for neurodegenerative diseases. Norepinephrine (NE) is the main stress hormone capable of modulating the stress response and providing neuroprotection during neurodegeneration by limiting the production of ROS and stimulating the antioxidative defense, especially against the OH^• radical. This in turn leads to the protection of cells from ROS-mediated damage and the improvement of cognitive and behavioral functions. Mounting evidence from preclinical studies in the last decade suggests the α2-adrenoblockers-mediated increase of NE release in the brain to be a promising therapeutic approach in neurodegenerative diseases. In this review, we focus on the role of (1) OS in neurodegenerative diseases; (2) the role of adrenergic receptors (ARs) in disease pathology and mechanisms of defense during neurodegeneration, and (3) the adrenergic signaling system in cognitive functions and neuroprotection provided by NE and α2-adrenoblockers.

Abstract—The aim of the study was to determine the quantitative characteristics of small extracellular vesicles (sEV) in the blood of patients with non-suicidal self-injury (NSSI) and comparison of the concentration and size of sEVs in patients with major depressive disorder (MDD) with and without NSSI, as well as to assess the relationship between the size and concentration of sEVs in the sample with such parameters as the severity of situational and personal anxiety, depression, and suicidal risk. The study included 28 patients (11 m/17 f) with a current episode of major depression and at least five episodes of NSSI in the last 12 months (main group, mean age 28.3 years) and 28 patients with major depression identical in sex and age without NSSI throughout life (comparison group). Patients’ mental status was assessed using the MINI interview, the Beck Depression Inventory II (BDI II), and the Spielberger Anxiety Scale. Isolation of sEVs from blood was carried out using polyethylene glycol (PEG) precipitation and gel filtration. The size and concentration of isolated particles were estimated using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). The groups differed significantly in the severity of depression according to the BDI-II questionnaire, the Spielberger Situational Anxiety Scale, and the Spielberger Personality Anxiety Scale. The assessment of suicidal risk, carried out according to the corresponding module of the MINI questionnaire, revealed a significantly larger number of participants with medium and high suicidal risk in the group of patients with NSSI. The sEV fraction was isolated from the blood of the patients of the main group and the comparison group. There were no differences in the concentration or size of sEVs between groups of patients with depression with and without NSSI. In our study, we found no dependence of the concentration and size of sEVs on the severity of depression, situational and personal anxiety, and the severity of suicidal risk. Conclusion: NSSI in individuals with major depressive disorder is associated with a more severe course of the disorder (greater severity of depression, situational and personal anxiety), as well as a higher risk of suicide. Our study did not reveal any differences in the quantitative characteristics of sEV in patients with a depressive episode with and without NSSI. Future studies should focus on investigating the structural differences and functional features of sEVs in NSSI.

Abstract

Galantamine, a centrally-acting acetylcholinesterase (AChE) inhibitor, is currently used as a first-line therapy for the symptomatic treatment of Alzheimer’s disease. Long-term consumption of sugar-rich beverages has been shown to be associated with the development of various clinical conditions, including metabolic syndrome, impaired cholinergic transmission, and cognitive decline. The aim of this study was to determine the effect of long-term fructose consumption on changes in short-term plasticity (STP) parameters of rat brain lateral entorhinal cortex (lEC) neurons during high-frequency stimulation (HFS) of the cholinergic nucleus basalis magnocellularis (NBM) and to evaluate the therapeutic potential of Galantamine in neurodegeneration induced by diabetes. Using the method of determining AChE activity in brain slices from intact rats exposed to Galantamine, we revealed that AChE activity showed a declining trend in the NBM and lEC. Our findings indicated that STP changes were observed in the fructose group and were associated with degenerative disorders. Specifically, there was a dramatic decrease in the proportion and intensity of excitatory responses during HFS as well as a significant increase in the mean frequency of background spike activity in neuronal populations with all response types. Galantamine resulted in a recovery tendency for the balance and intensity of excitatory and inhibitory responses. A characteristic feature of the therapeutic effect of Galantamine is an increase in the share and expression of responses in the neuronal population, exhibiting tetanic depression and post-tetanic potentiation to NBM stimulation. This clearly indicates that these neurons play a key role in homeostatic plasticity and integration into neuronal chains of cholinergic projections.

Abstract

The search for effective treatment for neurodegeneration implies attacking the multiple mechanisms of this pathology. Such properties were found in disaccharide trehalose, which shows therapeutic effects in models of many diseases and has been approved by the FDA for use in humans. Trehalose consists of two glucose residues bonded together by a flexible α-1-1'-glycosidic bond, giving it chaperone-like activity. Due to this, it prevents abnormal folding of aberrant proteins and has the properties of a cryo- and bioprotector. However, the main therapeutic effect is determined by the induction of mTOR-independent autophagy mediated by AMPK kinase as the main target. The result is a weakening of the accumulation of cytotoxic proteins and factors and an increase in cell viability. Autophagy activation depends on trehalose-induced lysosome and autophagosome biogenesis through activation of transcription factors TFEB and FOXO1. Trehalose has an anti-inflammatory effect closely related to the inhibition of oxidative stress. Trehalose-induced enhancement of endogenous antioxidant defense involves the regulator Nrf2. The review considers the neuroprotective effects of trehalose in models of major neurodegenerative diseases such as Parkinson’s, Alzheimer’s, Huntington’s and others. Overall, trehalose shows high therapeutic potential in the treatment of experimental neurodegeneration and thus stimulating the study of its clinical application.

Abstract

The water and DMSO solutions of two new synthesized compounds, β-dimethylaminoethylamidine N-benzoyl-DL-valineiodomethylate (TVA) and 1-(β-diethylaminoethyl)-2-phenyl-4-benzylidene-5-imidazolone (TVS), were characterized by optical absorbance and fluorescence properties. Earlier, the antiacetylcholinesterase and antibutyrylcholinesterase activities of these compounds have been shown. To prove the eligibility of their use against Alzheimer’s disease, the present study demonstrates the ability of the compounds to reduce the aggregation degree of commercial Aβ(1-42) amyloid peptide in vitro. From the concentration dependences, their IC₅₀ values were estimated in the deceleration of Aβ(1-42) aggregation (1.56 ± 0.3 mM for TVA and 1.8 ± 0.28 mM for TVS). The effective destabilization of the preformed aggregates of the peptide was registered with the IC₅₀ values of 0.54 ± 0.06 and 0.67 ± 0.2 mM, for TVA and TVS, respectively. Cell culture experiments have shown the effectiveness of the synthesized compounds in protection the rat hippocampal cells against cytotoxic action of Aβ(1-42) aggregates: during 7 days incubation, the number of neurospheres per microscopic field in the presence of the peptide aggregates fallen down to 34% of the intact cells, but 2 μg/mL TVA kept the cells on the level of the intact, and 5 μg/mL TVS—on the level of 77% of the intact. Subsequent developments based on these compounds will allow the researchers to create the preparations valid for pre-clinical studies with goal to introduce into medical practice as new remedies in prevention/treatment of Alzheimer’s disease.

Abstract

Neuropeptides are among the most abundant chemical messengers produced in the brain that can function as neurotransmitters or hormones. Neuropeptides are synthesized and used by a neuron. There are over one hundred known neuropeptides, representing the largest and most diverse class of signaling molecules in the nervous system. Neuropeptides are often co-released with other neuropeptides and neurotransmitters in a single neuron, yielding a multitude of effects. The focus of this review is their role in cancer in general and mainly sarcomas. Neuropeptides and their receptors are no exception when it comes to their pro or antitumorigenic diverse functions defined by cellular and disease content. The molecular targets, pathways, and epigenetic regulation of sarcoma growth by neuropeptides are highlighted to better understand the importance of these molecules and suggest future alternative therapies for this challenging disease with unmet cancer needs.