scholarly journals Subunit compositions of GABAA receptors determining the diversity of physiological processes and neurotropic properties of medicines

2021 ◽  
Vol 25 (1) ◽  
pp. 13-23
Author(s):  
M.Ya. Golovenko
Keyword(s):  
Binding Site ◽  
Gaba Receptor ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Potential Applications ◽  
Α1 Receptors ◽  
Subtype Selective

Gamma-aminobutyric acid (GABA) became known as a potentially important chemical in the brain 50 years ago, but its significance as a neurotransmitter was fully found 16 years later. It is now known that at least 40 % of the inhibitory synaptic activity in the mammalian brain is accounted for by GABA.  Аim. To analyze achievements in the study of the physiological and pharmacological role of GABA receptor subtypes, their potential applications in drug development and updated information on the clinical development of subtype-selective GABA receptor compounds.  Results. The GABAA-receptor complex (GABA-RC) is ligand-gated ion channels with chloride conductance. These receptors contain α, β, and γ subunits, but δ, ε, θ, and ρ can be also present. The GABA binding site is located at the interface between α and β subunits where a number of important amino acids are also found. GABA-RC is sensitive to a wide range of drugs, e.g. benzodiazepines (BDZ), which are often used for their sedative/hypnotic and anxiolytic effects. Classical BDZ interact non-selectively with α1,3,5 βγ2 GABA-RС in the binding site located at the α+γ− interface.  Conclusions.  In addition to the potent and rapid pharmacotherapeutic action BDZ also possess some addictive potential (drug dependence), which appears after the interaction of molecules with α1-receptors. Using the selective targeting to separate subgroups not only the main effect of BDZ without side effects can be provided, but also one can use this approach in creating new analgesic medicines; we have demonstrated it on the example of propoxazepam (full agonist GABA-R).

scholarly journals Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            

2022 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Functional Studies ◽  
Tricyclic Compounds ◽  
Electrode Voltage ◽  
Functional Inhibition ◽  
Gaba Receptor Subunits

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The CPZ site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

scholarly journals Tricyclic antipsychotics and antidepressants can inhibit α5-containing GABAA receptors by two  distinct mechanisms            

2022 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Receptor Subtypes ◽  
Therapeutic Effects ◽  
Functional Studies ◽  
Tricyclic Compounds ◽  
Electrode Voltage ◽  
Functional Inhibition ◽  
Gaba Receptor Subunits

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal a5 subunit-containing GABA receptors. The purpose of this study is to investigate tricyclic compounds in a5 subunit-containing receptor subtypes. Experimental Approach: Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the a5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine exert functional inhibition on multiple GABA receptor subtypes, including a5-containing ones. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in a5 GABA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The C C C C C C site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABA receptor subtypes.

scholarly journals Interactions of tricyclic antipsychotic and antidepressant medications with a novel binding site in GABAA receptors

2021 ◽  
Author(s):  
Konstantina Bampali ◽  
Filip Koniuszewski ◽  
Luca Silva ◽  
Sabah Rehman ◽  
Florian Vogel ◽  
...  
Keyword(s):  
Binding Site ◽  
Gaba Receptors ◽  
Gaba Receptor ◽  
Antidepressant Drugs ◽  
Receptor Subtypes ◽  
Specific Information ◽  
Therapeutic Effects ◽  
The Novel ◽  
Antidepressant Medications ◽  
Functional Studies

Background and Purpose: Many psychotherapeutic drugs including clozapine have a polypharmacological profile and act on GABA receptors, where subtype-specific information is often lacking. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit containing GABA receptors. Experimental Approach: Functional studies of GABA modulatory effects by antipsychotic and antidepressant medications were performed in several GABA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Computational ligand analysis complemented the functional and mutational data. Key Results: We show that the antipsychotic drugs clozapine and chlorpromazine have negative modulatory effects on multiple GABA receptor subtypes, including α5-containing. On the latter we show negative modulatory effects for five additional antipsychotic and antidepressant drugs. Based on a chlorpromazine binding site observed in a GABA-gated bacterial homologue, we identified a novel site in α5 GABA receptor subunits. Conclusion and Implications: Our findings support previous studies suggesting a link between some of the therapeutic effects of clozapine and its negative modulatory action on certain GABA receptor subtypes. The novel site we describe in this study is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology.

Understanding Schizophrenia: Genetic Causes and Treatment

2019 ◽  
Vol 1 (1) ◽  
pp. 6-12
Author(s):  
Fatima Javeria ◽  
Shazma Altaf ◽  
Alishah Zair ◽  
Rana Khalid Iqbal
Keyword(s):  
Copy Number ◽  
Drug Targets ◽  
Disease Risk ◽  
Mental Disease ◽  
Copy Number Variants ◽  
Aminobutyric Acid ◽  
Epigenetic Mechanisms ◽  
Gamma Aminobutyric Acid ◽  
Wide Range ◽  
Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

scholarly journals A Slot-Die Technique for the Preparation of Continuous, High-Area, Chitosan-Based Thin Films

Polymers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1566
Author(s):  
Oliver J. Pemble ◽  
Maria Bardosova ◽  
Ian M. Povey ◽  
Martyn E. Pemble
Keyword(s):  
Thin Films ◽  
Mechanical Properties ◽  
High Volume ◽  
Mechanical Anisotropy ◽  
Diverse Range ◽  
Direction Parallel ◽  
High Area ◽  
Wide Range ◽  
Slot Die ◽  
Potential Applications

Chitosan-based films have a diverse range of potential applications but are currently limited in terms of commercial use due to a lack of methods specifically designed to produce thin films in high volumes. To address this limitation directly, hydrogels prepared from chitosan, chitosan-tetraethoxy silane, also known as tetraethyl orthosilicate (TEOS) and chitosan-glutaraldehyde have been used to prepare continuous thin films using a slot-die technique which is described in detail. By way of preliminary analysis of the resulting films for comparison purposes with films made by other methods, the mechanical strength of the films produced was assessed. It was found that as expected, the hybrid films made with TEOS and glutaraldehyde both show a higher yield strength than the films made with chitosan alone. In all cases, the mechanical properties of the films were found to compare very favorably with similar measurements reported in the literature. In order to assess the possible influence of the direction in which the hydrogel passes through the slot-die on the mechanical properties of the films, testing was performed on plain chitosan samples cut in a direction parallel to the direction of travel and perpendicular to this direction. It was found that there was no evidence of any mechanical anisotropy induced by the slot die process. The examples presented here serve to illustrate how the slot-die approach may be used to create high-volume, high-area chitosan-based films cheaply and rapidly. It is suggested that an approach of the type described here may facilitate the use of chitosan-based films for a wide range of important applications.

scholarly journals Health Benefits of Uses and Applications of Moringa oleifera in Bakery Products

Plants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 318
Author(s):  
Paula García Milla ◽  
Rocío Peñalver ◽  
Gema Nieto
Keyword(s):  
Moringa Oleifera ◽  
Essential Amino Acids ◽  
Bakery Products ◽  
Unani Medicine ◽  
Functional Value ◽  
Organoleptic Characteristics ◽  
Wide Range ◽  
Potential Applications ◽  
Medicinal Properties ◽  
Excellent Source

Moringa oleifera belongs to the Moringaceae family and is the best known of the native Moringa oleifera genus. For centuries, it has been used as a system of Ayurvedic and Unani medicine and has a wide range of nutritional and bioactive compounds, including proteins, essential amino acids, carbohydrates, lipids, fibre, vitamins, minerals, phenolic compounds, phytosterols and others. These characteristics allow it to have pharmacological properties, including anti-diabetic, anti-inflammatory, anticarcinogenic, antioxidant, cardioprotective, antimicrobial and hepatoprotective properties. The entire Moringa oleifera plant is edible, including its flowers, however, it is not entirely safe, because of compounds that have been found mainly in the root and bark, so the leaf was identified as the safest. Moringa oleifera is recognised as an excellent source of phytochemicals, with potential applications in functional and medicinal food preparations due to its nutritional and medicinal properties; many authors have experimented with incorporating it mainly in biscuits, cakes, brownies, meats, juices and sandwiches. The results are fascinating, as the products increase their nutritional value; however, the concentrations cannot be high, as this affects the organoleptic characteristics of the supplemented products. The aim of this study is to review the application of Moringa oleifera in bakery products, which will allow the creation of new products that improve their nutritional and functional value.

scholarly journals Sporulation in solventogenic and acetogenic clostridia

2021 ◽  
Author(s):  
Mamou Diallo ◽  
Servé W. M. Kengen ◽  
Ana M. López-Contreras
Keyword(s):  
Current Knowledge ◽  
Carbon Sources ◽  
Cost Effective ◽  
Biotechnological Production ◽  
Key Points ◽  
Wide Range ◽  
Potential Applications ◽  
A Cell ◽  
Sporulation Initiation ◽  
Solventogenic Clostridia

AbstractThe Clostridium genus harbors compelling organisms for biotechnological production processes; while acetogenic clostridia can fix C1-compounds to produce acetate and ethanol, solventogenic clostridia can utilize a wide range of carbon sources to produce commercially valuable carboxylic acids, alcohols, and ketones by fermentation. Despite their potential, the conversion by these bacteria of carbohydrates or C1 compounds to alcohols is not cost-effective enough to result in economically viable processes. Engineering solventogenic clostridia by impairing sporulation is one of the investigated approaches to improve solvent productivity. Sporulation is a cell differentiation process triggered in bacteria in response to exposure to environmental stressors. The generated spores are metabolically inactive but resistant to harsh conditions (UV, chemicals, heat, oxygen). In Firmicutes, sporulation has been mainly studied in bacilli and pathogenic clostridia, and our knowledge of sporulation in solvent-producing or acetogenic clostridia is limited. Still, sporulation is an integral part of the cellular physiology of clostridia; thus, understanding the regulation of sporulation and its connection to solvent production may give clues to improve the performance of solventogenic clostridia. This review aims to provide an overview of the triggers, characteristics, and regulatory mechanism of sporulation in solventogenic clostridia. Those are further compared to the current knowledge on sporulation in the industrially relevant acetogenic clostridia. Finally, the potential applications of spores for process improvement are discussed.Key Points• The regulatory network governing sporulation initiation varies in solventogenic clostridia.• Media composition and cell density are the main triggers of sporulation.• Spores can be used to improve the fermentation process.

Subcellular Localization and Complements of GABAA and GABAC Receptors on Bullfrog Retinal Bipolar Cells

2000 ◽  
Vol 84 (2) ◽  
pp. 666-676 ◽  
Author(s):  
Jiu-Lin Du ◽  
Xiong-Li Yang
Keyword(s):  
Subcellular Localization ◽  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Drug Application ◽  
Bipolar Cells ◽  
Visual Signals ◽  
Receptor Subtypes ◽  
Inner Retina ◽  
Axon Terminals ◽  
Retinal Bipolar Cells

γ-Aminobutyric acid (GABA) receptors on retinal bipolar cells (BCs) are highly relevant to spatial and temporal integration of visual signals in the outer and inner retina. In the present work, subcellular localization and complements of GABAA and GABACreceptors on BCs were investigated by whole cell recordings and local drug application via multi-barreled puff pipettes in the bullfrog retinal slice preparation. Four types of the BCs (types 1–4) were identified morphologically by injection of Lucifer yellow. According to the ramification levels of the axon terminals and the responses of these cells to glutamate (or kainate) applied at their dendrites, types 1 and 2 of BCs were supposed to be off type, whereas types 3 and 4 of BCs might be on type. Bicuculline (BIC), a GABAA receptor antagonist, and imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, were used to distinguish GABA receptor-mediated responses. In all BCs tested, not only the axon terminals but also the dendrites showed high GABA sensitivity mediated by both GABAA and GABACreceptors. Subcellular localization and complements of GABAA and GABAC receptors at the dendrites and axon terminals were highly related to the dichotomy of offand on BCs. In the case of off BCs, GABAA receptors were rather evenly distributed at the dendrites and axon terminals, but GABAC receptors were predominantly expressed at the axon terminals. Moreover, the relative contribution of GABAC receptors to the axon terminals was prevalent over that of GABAA receptors, while the situation was reversed at the dendrites. In the case of on BCs, GABAA and GABAC receptors both preferred to be expressed at the axon terminals; relative contributions of these two GABA receptor subtypes to both the sites were comparable, while GABAC receptors were much less expressed than GABAA receptors. GABAA, but not GABAC receptors, were expressed clusteringly at axons of a population of BCs. In a minority of BCs, I4AA suppressed the GABAC responses at the dendrites, but not at the axon terminal, implying that the GABAC receptors at these two sites may be heterogeneous. Taken together, these results suggest that GABAA and GABAC receptors may play different roles in the outer and inner retina and the differential complements of the two receptors on off and on BCs may be closely related to physiological functions of these cells.

scholarly journals Click Chemistry Enabling Covalent and Non-Covalent Modifications of Graphene with (Poly)saccharides

Polymers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 142
Author(s):  
Hu Li ◽  
Raffaello Papadakis
Keyword(s):  
Click Chemistry ◽  
Life Science ◽  
Environmental Applications ◽  
Energy Materials ◽  
Sensors And Actuators ◽  
Polar Solvents ◽  
Wide Range ◽  
Potential Applications ◽  
Covalent Modifications

Graphene is a material with outstanding properties and numerous potential applications in a wide range of research and technology areas, spanning from electronics, energy materials, sensors, and actuators to life-science and many more. However, the insolubility and poor dispersibility of graphene are two major problems hampering its use in certain applications. Tethering mono-, di-, or even poly-saccharides on graphene through click-chemistry is gaining more and more attention as a key modification approach leading to new graphene-based materials (GBM) with improved hydrophilicity and substantial dispersibility in polar solvents, e.g., water. The attachment of (poly)saccharides on graphene further renders the final GBMs biocompatible and could open new routes to novel biomedical and environmental applications. In this review, recent modifications of graphene and other carbon rich materials (CRMs) through click chemistry are reviewed.

scholarly journals State of the Science in Dried Blood Spots

2018 ◽  
Vol 64 (4) ◽  
pp. 656-679 ◽  
Author(s):  
Jeffrey D Freeman ◽  
Lori M Rosman ◽  
Jeremy D Ratcliff ◽  
Paul T Strickland ◽  
David R Graham ◽  
...  
Keyword(s):  
Systematic Approach ◽  
Full Range ◽  
Dried Blood Spots ◽  
Blood Spots ◽  
Highly Sensitive ◽  
Wide Range ◽  
Potential Applications ◽  
Review Of Reviews ◽  
Near Term ◽  
State Of The Science

Abstract BACKGROUND Advancements in the quality and availability of highly sensitive analytical instrumentation and methodologies have led to increased interest in the use of microsamples. Among microsamples, dried blood spots (DBS) are the most well-known. Although there have been a variety of review papers published on DBS, there has been no attempt at describing the full range of analytes measurable in DBS, or any systematic approach published for characterizing the strengths and weaknesses associated with adoption of DBS analyses. CONTENT A scoping review of reviews methodology was used for characterizing the state of the science in DBS. We identified 2018 analytes measured in DBS and found every common analytic method applied to traditional liquid samples had been applied to DBS samples. Analytes covered a broad range of biomarkers that included genes, transcripts, proteins, and metabolites. Strengths of DBS enable its application in most clinical and laboratory settings, and the removal of phlebotomy and the need for refrigeration have expanded biosampling to hard-to-reach and vulnerable populations. Weaknesses may limit adoption in the near term because DBS is a nontraditional sample often requiring conversion of measurements to plasma or serum values. Opportunities presented by novel methodologies may obviate many of the current limitations, but threats around the ethical use of residual samples must be considered by potential adopters. SUMMARY DBS provide a wide range of potential applications that extend beyond the reach of traditional samples. Current limitations are serious but not intractable. Technological advancements will likely continue to minimize constraints around DBS adoption.

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