Modulation Of GABA Receptors Research Articles

EXPRESSION OF NEUROFILAMENTS IN THE RETINA IN EXPERIMENTAL DIABETIC RETINOPATHY AND THE INFLUENCE OF THE BENZODIAZEPINE RECEPTOR AGONIST CARBACETAM

Background. One of the typical neurochemical pathogenetic mechanisms causing the dysfunction of retinal neurons in diabetic retinopathy (DR) is a deficiency of GABA-ergic mediation. To some extent, this justifies the prospect of using GABA receptor modulators, including benzodiazepines.
 Aim: To determine the expression of neurofilaments in the initial stages of the experimental DR development and the influence of the benzodiazepine receptor agonist Carbacetam.
 Materials and methods. DR was modeled in 35 three-month-old male Wistar rats by a single injection of streptozotocin (50 mg/kg; Sigma-Aldrich, Co, China). The rats were divided into 3 groups: control, with the introduction of Insulin (30 Units; Novo Nordisk A/S, Bagsvaerd, Denmark) and with the introduction of Insulin and Carbacetam (5 mg/kg). NF-H neurofilaments (ThermoFisher Scietific, USA) were detected in the retina by immunohistochemistry.
 Results. Before DR modeling, NF-H-positive staining was detected in the inner and outer layers of the retina in mainly longitudinal fibers of different lengths, which corresponded to the axons of horizontal and amacrine cells; as well as in fibers and axonal hills of ganglion neurons. In the dynamics of the DR development in the plexiform layers of the retina, a progressive decrease in the intensity of staining was observed. In the optic fiber layer, staining was concentrated around dilated microvessels that tended to form microaneurysms. On the 28th day, NF-H-positive staining disappeared in the inner plexiform layer. Administration of Insulin with Carbacetam prevented the loss of NF-H-positive staining in the layers of the retina.
 Conclusion. The use of the benzodiazepine receptor agonist Carbacetam may be a promising direction for the correction of retinal neurodegeneration in DR.

The Uses of Anabolic Androgenic Steroids Among Athletes; Its Positive and Negative Aspects- A Literature Review.

The use of anabolic androgenic steroids (AAS) for strength training and muscle building is a widespread practice among athletes and young individuals. Athletes and bodybuilders are using these substances for various purposes, such as enhancing muscle mass, strengthening their bodies, and enhancing their performances. AAS exert a wide range of physiological effects that result in the activation of central signaling, resulting in adverse effects. Moreover, excessive use of AAS which can be categorized as AAS abuse; is linked to biological and psychological pathologies, which can lead to mortality. Complications arising from steroid abuse involve both cellular and physiological complications. Cellular complications arise when activation of signaling proteins like mTOR, Akt, etc. leads to alteration in protein synthesis pathways, cell cycle, oxidative stress, and apoptosis, contributing to damage at the cellular level. Physiological complications are evident with cardiovascular pathologies, including an altered lipid profile, cardiac hypertrophy, hypogonadism after discontinuation of AAS, and modulation of GABA receptors in the brain, all contributed by the androgen receptor signaling. Clinical complications budding from these altered physiological processes lead to clinical effects like testicular dysfunction, acne, gynecomastia, and neuropsychiatric disorders. Despite potential therapeutic benefits, AAS use is prohibited by the World Anti-Doping Agency (WADA) due to concerns over adverse health effects. This review highlights the molecular mechanisms, physiological processes, and clinical complications arising from the excessive use of AAS among athletes.

Comparing Plasticity Effects of iTBS and 10-Hz rTMS with NMDA and GABA Receptor Modulation

Comparing Plasticity Effects of iTBS and 10-Hz rTMS with NMDA and GABA Receptor Modulation

Improvement in HAMD-17 Subscale Scores With 14-Day Treatment Course of Zuranolone in Postpartum Depression: Results From the SKYLARK Study [ID: 1372313

INTRODUCTION: Postpartum depression (PPD) is a serious perinatal complication. SKYLARK (phase 3, randomized, double-blind, placebo-controlled trial [NCT04442503]) evaluated zuranolone, an investigational, neuroactive steroid positive allosteric modulator of both synaptic and extrasynaptic GABA(A) receptors, in adult patients with PPD. The primary endpoint, change from baseline (CFB) in HAMD-17 total score at day 15, was met. Zuranolone was generally well tolerated. The HAMD-17 can be divided into subscales that group specific items from the HAMD-17 scale that measure different aspects of depression presentation. Here, we present HAMD-17 subscale data from SKYLARK. METHODS: Patients aged 18–45 years with severe PPD (HAMD 17 total score ≥26) were randomized 1:1 to oral, once-daily zuranolone 50 mg or placebo for 14 days. The secondary endpoint was day 15 CFB in HAMD-17 subscale (Core Depression, Anxiety, Bech-6, Maier) scores. Subscales were analyzed separately by a mixed-effects model for repeated measures. Institutional review board approval was obtained. RESULTS: One hundred ninety-five patients (zuranolone, 98; placebo, 97) were randomized, received study drug, and had valid baseline and one or more post-baseline efficacy assessments. At day 15, patients receiving a 14-day treatment course of zuranolone showed nominally significant improvements across all HAMD-17 subscales versus placebo (least squares mean [SE] CFB treatment difference: Core Depression, −5.9 [2.4], P=.0151; Anxiety, −5.7 [2.3], P=.0123; Bech-6, −8.6 [3.0], P=.0040; Maier, −7.6 [2.6], P=.0041). Improvement in all subscales was observed starting at day 3. CONCLUSION: In SKYLARK, zuranolone was associated with rapid improvement in depressive and anxiety symptoms in patients with PPD across multiple domains, supporting its development as a potential oral, rapid-acting treatment option for PPD.

Anxiety disorders in general medical practice – clinical picture, diagnosis, optimized approaches to therapy

Anxiety disorders are widespread in the population and in general medical practice and have a pronounced negative impact on the quality of life and functioning of patients. Currently, the prerequisites for the diagnosis and treatment of anxiety disorders outside the psychiatric network are accumulating by therapists, general practitioners and other non-psychiatric doctors. A review of the most significant factors contributing to a wider diagnosis and treatment of anxiety disorders in general medical practice is given. This review presents modern ideas about the pathogenesis of anxiety disorders, substantiates the modern idea of their multifactorial nature, the contribution of genetic and epigenetic, psychological and social factors, outlines the concepts of the neurobiological basis of pathological anxiety based on neuroimaging studies. In the future, information is provided on the general manifestations of anxiety disorders, the main clusters of anxiety, the systematics of anxiety disorders according to ICD-10. Modern ideas about the diagnosis of anxiety disorders using both scales and a clinical approach are given, a detailed review of currently available diagnostic scales validated for clinical practice is presented. The main approaches to conducting a clinical conversation are also presented, recommendations are given for the most successful collection of information about the clinical condition of patients. At the end of the review, information is given on existing approaches to psychopharmacotherapy and psychotherapy of anxiety disorders. Taking into account pharmacological and clinical studies, the place of drugs tofisopam (an atypical allosteric modulator of GABA receptors) and buspirone (a partial agonist of serotonin 1A receptors) in the treatment of anxiety disorders in general medical practice has been argued.

A GABA Receptor Modulator and Semiochemical Compounds Evidenced Using Volatolomics as Candidate Markers of Chronic Exposure to Fipronil in Apis mellifera

Among the various "omics" approaches that can be used in toxicology, volatolomics is in full development. A volatolomic study was carried out on soil bacteria to validate the proof of concept, and this approach was implemented in a new model organism: the honeybee Apis mellifera. Emerging bees raised in the laboratory in pain-type cages were used. Volatolomics analysis was performed on cuticles, fat bodies, and adhering tissues (abdomens without the digestive tract), after 14 and 21 days of chronic exposure to 0.5 and 1 µg/L of fipronil, corresponding to sublethal doses. The VOCs analysis was processed using an HS-SPME/GC-MS method. A total of 281 features were extracted and tentatively identified. No significant effect of fipronil on the volatolome could be observed after 14 days of chronic exposure. Mainly after 21 days of exposure, a volatolome deviation appeared. The study of this deviation highlighted 11 VOCs whose signal abundances evolved during the experiment. Interestingly, the volatolomics approach revealed a VOC (2,6-dimethylcyclohexanol) that could act on GABA receptor activity (the fipronil target) and VOCs associated with semiochemical activities (pheromones, repellent agents, and compounds related to the Nasonov gland) leading to a potential impact on bee behavior.

High Fat Diet Increases [3H] Flunitrazepam Binding in the Mouse Brain that is Dependent on the Expression of the Dopamine D2 Gene.

Dopamine is an important neuromodulator in the brain that binds to dopamine D1-like receptors (D1, D5) as well as dopamine D2-like receptors (D2, D3, D4). The D2 receptor is known to play an integral role in a variety of physiological processes including addictive behaviors, locomotion, motivation, feeding behavior, and more. It was recently reported that dopamine is a direct-acting modulator of mammalian GABA(A) receptors. To this end, we wanted to examine how the expression of the dopamine D2 gene impacts the expression of GABA(A) receptors in the brain under different dietary conditions. Adult female Drd2 wild-type (WT), heterozygous (HT), and knockout (KO) mice were given either normal or high-fat diet for a period of 30weeks. Following this, their brains were collected for [3H] Flunitrazepam binding in order to assess GABA(A) receptor expression. A high fat diet significantly increased [3H] Flunitrazepam binding in the regions of the somatosensory cortex, striatum, and various other cortical areas within WT mice. In contrast, no effect of diet was observed in HT or KO mice. As such, HT and KO mice displayed reduced [3H] Flunitrazepam binding in these areas relative to WT mice under high-fat dietary conditions. The effect of a high-fat diet on [3H] Flunitrazepam binding is consistent with recent evidence showing increases in GABA neurotransmitter levels following a high-fat diet. We demonstrate for the first time that the expression of the D2 gene plays a prominent role in the ability of a high-fat diet to impact GABA(A) receptors in the mouse brain.

Stigmasterol can be new steroidal drug for neurological disorders: Evidence of the GABAergic mechanism via receptor modulation

BackgroundGamma-aminobutyric acid A (GABAA) receptors have been implicated in anxiety and epileptic disorders. Hypothesis/PurposeThis study aimed to investigate the effects of stigmasterol, a plant sterol (phytosterol) isolated from Artemisia indica Linn on neurological disorders. MethodsStigmasterol was evaluated on various recombinant GABAA receptor subtypes expressed in Xenopus laevis oocytes and its anxiolytic and anticonvulsant potential was assessed using the elevated plus maze (EPM), light-dark box (LDB) test, and pentylenetetrazole- (PTZ-) induced seizure paradigms. Furthermore, computational modeling of α2β2γ2L, α4β3δ, and α4β3 subtypes was performed to gain insights into the GABAergic mechanism of stigmasterol. For the first time, a model of GABAδ subtype was generated. Stigmasterol was targeted to all the binding sites (neurotransmitters, positive and negative modulator binding sites) of GABAA α2β2γ2L, α4β3, and α4β3δ complexes by in silico docking. ResultsStigmasterol enhanced GABA-induced currents at ternary α2β2γ2L, α4β3δ, and binary α4β3 GABAAR subtypes. The potentiation of GABA-induced currents at extrasynaptic α4β3δ was significantly higher compared to the binary α4β3 subtype, indicating that the δ subunit is important for efficacy. Stigmasterol was found to be a potent positive modulator of the extrasynaptic α4β3δ subtype, which was also confirmed by computational analysis. The computational analysis reveals that stigmasterol preferentially binds at the transmembrane region shared by positive modulators or a binding site constituted by the M2-M3 region of α4 and M1-M2 of β3 at α4β3δ complex. In in vivo studies, Stigmasterol (0.5–3.0 mg/kg, i.p.) exerted significant anxiolytic and anticonvulsant effects in an identical manner of allopregnanolone, indicating the involvement of a GABAergic mechanism. ConclusionTo our knowledge, this is the first study reporting the positive modulation of GABAA receptors, anxiolytic and anticonvulsant potential of stigmasterol. Thus, stigmasterol is considered to be a candidate steroidal drug for the treatment of neurological disorders due to its positive modulation of GABA receptors.

GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice.

There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.

Drug Repurposing: A Network-based Approach to Amyotrophic Lateral Sclerosis.

The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study is aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets in the human interactome. We prioritized 403 SAveRUNNER-predicted drugs according to decreasing values of network similarity with ALS. Among catecholamine, dopamine, serotonin, histamine, and GABA receptor modulators, as well as angiotensin-converting enzymes, cyclooxygenase isozymes, and serotonin transporter inhibitors, we found some interesting no customary ALS drugs, including amoxapine, clomipramine, mianserin, and modafinil. Furthermore, we strengthened the SAveRUNNER predictions by a gene set enrichment analysis that confirmed modafinil as a drug with the highest score among the 121 identified drugs with a score > 0. Our results contribute to gathering further proofs of innovative solutions for therapy in ALS pathogenesis.

Застосування альфа-казозепіну (Lactium®) та вітаміну В6 у клінічній практиці (огляд літератури)

The article summarizes the literature data on the use of alpha-casozepine and its combination with vitamin B6 in clinical practice. It has been found that the properties of alpha-casozepine are similar to those of the benzodiazepine family of drugs, with the exception of such concomitant side effects of these drugs as addiction or sedation. Therefore, today alpha-casozepine has been increasingly used as a dietary supplement to improve sleep and to relieve stress disorders. The anxiolytic effects of alpha-casozepine have been confirmed in many experimental models over the past 20 years. It has been found that alpha-casozepin affects sleep by modulating its architecture, but has almost no sedative effect, which makes it similar to melatonin since both facilitate, rather than induce, sleep. The effect of alpha-casozepine on sleep is associated with GABA receptors. It was found that with transport of the peptide across the blood-brain barrier, the C-terminal residue of tryptophan, a precursor of serotonin, is released, which is an important neurotransmitter in the regulation of mood and satiety. Direct modulation of GABA receptors by alpha-casozepin, including in the neurons of the hypothalamus, has been proven. According to the results of clinical trials, alpha-casozepine has a positive effect on both physical and psychological symptoms of anxiety. It has been shown that the use of alpha-casozepine promotes faster recovery after a stress response, which is manifested by lower blood pressure and heart rate during the relaxation period (after stress) compared with the rest period (before stress induction). Studies show that anxiolytic peptides derived from milk are promising for use in a wide range of functional disorders of the nervous system, sleep disorders, anxiety, in the treatment of patients with arterial dystonia, including in childhood. It is worth noting the use of a combination of alpha-casozepine (Lactium®) and vitamin B6, including in children, because such a combination promotes good absorption of the drug and a positive effect on the nervous system. No conflict of interest was declared by the authors. Key words: alpha(casozepine, lactium, anxiety, sleep.

Anxiolytic-like effect of brominated compounds from the marine sponge Aplysina fulva on adult zebrafish (Danio rerio): Involvement of the GABAergic system

Benzodiazepines are commonly used to treat disorders of the central nervous system, including anxiety. However, due to their adverse effects, there is a continuing interest in discovering new safe and effective drugs. Marine natural products have emerged as a prolific source of bioactive nitrogenated compounds. Aiming to discover new biologically active natural compounds, the marine sponge Aplysina fulva, a nitrogen-bearing heterocyst producer, was investigated. The main isolated compounds (4, 6, and 9) were evaluated on adult zebrafish (Danio rerio). A group of fishes (n = 6) was preliminarily subjected to acute toxicity, and open field tests using 0.1, 0.5, and 1.0 mg/mL (v. o.) of those compounds was performed. The anxiolytic effect was further investigated in the light/dark assay based on the locomotor response at zebrafish. Interactions through the GABAergic system were investigated using flumazenil, a silent modulator of GABA receptors. To improve the results, a study of molecular docking using the GABAA receptor also was performed. Based on the results, the bromotyrosine derivative compounds 4, 6, and 9 exhibited anxiolytic-like effects mediated by the GABAergic system.

Prenatal sevoflurane exposure causes neuronal excitatory/inhibitory imbalance in the prefrontal cortex and neurofunctional abnormality in rats

The balance of excitatory and inhibitory neurons in the central nervous system is critical for maintaining brain function and sevoflurane, a general anesthetic and an GABA receptor modulator, may change the balance of excitatory and inhibitory neurons in the cortex during early brain development. Herein, we investigated whether prenatal sevoflurane exposure (PSE) disturbs cortical neuronal development and brain function. Pregnant rats at the gestational day 14.5 were subjected to sevoflurane exposure at 3.0% for 3 h and their offspring were studied thereafter. We found a significant increase of parvalbumin-positive neurons, vesicular GABA transporter (VGAT) and GAD67 expression, and GABA neurotransmitter, and a significant decrease of vesicular glutamate transporter 1 (VGLUT1) expression and glutamate in the medial prefrontal cortex (mPFC) of offspring. Pyramidal neurons showed atrophy with shorter dendrites, less branches and lower spine density visualized by Golgi stain and a decrease of excitability with the increased miniature inhibitory postsynaptic current (mIPSC) frequency and amplitude, the decreased miniature excitatory postsynaptic current (mEPSC) frequency and excitation/inhibition (E/I) ratio using whole-cell recording in offspring. There was a significant increase of inhibitory synapse in the mPFC detected by electron microscopy. Furthermore, PSE animals showed hypo-excitatory phenotype including depression-like behaviors and learning deficits. Thus, our studies provide novel evidence that PSE causes the persisted imbalance of excitatory and inhibitory neurons in the mPFC, and this is very likely the mechanisms of the sevoflurane-induced brain functional abnormalities.

Rational approaches for the design of various GABA modulators and their clinical progression.

GABA (γ-amino butyric acid) is an important inhibitory neurotransmitter in the central nervous system. Attenuation of GABAergic neurotransmission plays an important role in the etiology of several neurological disorders including epilepsy, Alzheimer's disease, Huntington's chorea, migraine, Parkinson's disease, neuropathic pain, and depression. Increase in the GABAergic activity may be achieved through direct agonism at the GABAA receptors, inhibition of enzymatic breakdown of GABA, or by inhibition of the GABA transport proteins (GATs). These functionalities make GABA receptor modulators and GATs attractive drug targets in brain disorders associated with decreased GABA activity. There have been several reports of development of GABA modulators (GABA receptors, GABA transporters, and GABAergic enzyme inhibitors) in the past decade. Therefore, the focus of the present review is to provide an overview on various design strategies and synthetic approaches toward developing GABA modulators. Furthermore, mechanistic insights, structure-activity relationships, and molecular modeling inputs for the biologically active derivatives have also been discussed. Summary of the advances made over the past few years in the clinical translation and development of GABA receptor modulators is also provided. This compilation will be of great interest to the researchers working in the field of neuroscience. From the light of detailed literature, it can be concluded that numerous molecules have displayed significant results and their promising potential, clearly placing them ahead as potential future drug candidates.

Treatment of Excessive Daytime Sleepiness in Patients with Narcolepsy.

The aim of this review is to discuss and summarize the main therapeutic strategies for the management of excessive daytime sleepiness (EDS) in patients with narcolepsy. An overview of novel therapies and potential future options are covered as well. First line treatments for EDS in narcolepsy patients include modafinil/armodafinil and sodium oxybate. Other options with a stimulant effect, such as methylphenidate and amphetamines are considered if the former do not control the symptoms. More recently, pitolisant (H3 receptor inverse agonist) was approved by the European Medicines Agency, and solriamfetol (dopamine and norepinephrine reuptake inhibitor) by the Food and Drug Administration, for the treatment of EDS in adult narcolepsy patients. Sodium oxybate was recently approved for EDS management in paediatric patients from the age of seven. Further studies involving the paediatric population are warranted to have solid evidence in the management of children with narcolepsy. Ongoing research of new molecules is based on several mechanisms of action (histamine antagonists/inverse agonists, GABA receptor modulators), and potential future strategies involve immunologic treatment and hypocretin-based therapies. Additionally to the wakefulness-promoting agents and stimulants classically used, other pharmacologic options have been recently approved for the treatment of EDS in Europe (pitolisant) and the US (solriamfetol). Emerging treatments are under development; newly developed wakefulness-promoting agents act via different mechanisms of action, whereas other forms of therapy are focused in the underlying hypocretin deficiency that characterizes narcolepsy type 1.

Allopregnanolone augments epileptiform activity of an in-vitro mouse hippocampal preparation in the first postnatal week

In the immature brain the neurotransmitter γ-amino butyric acid (GABA) mediates a membrane depolarization and can contribute to both, inhibition and excitation. Therefore the consequences of a positive modulation of GABA(A) receptors by neurosteroids on epileptiform activity are hard to predict. In order to analyze whether neurosteroids attenuate or exaggerate epileptiform activity in the immature brain, we investigated the effect of the neurosteroid allopregnanolone on epileptiform activity in an in-toto hippocampus preparation of early postnatal mice (postnatal days 4–7) using field potential recordings. These in-vitro experiments revealed that 0.5 μmol/L allopregnanolone had no effect on ictal-like epileptiform activity, but increased the occurrence of interictal epileptiform events. The allopregnanolone-induced enhancement of interictal epileptiform activity could be blocked by a selective inhibition of synaptic GABAA receptors. In contrast, allopregnanolone had no effect on interictal epileptiform activity upon enhanced extrasynaptic GABAergic activity. Patch-clamp experiments demonstrated that allopregnanolone prolonged the decay of GABAergic postsynaptic currents, but had no effect on tonic GABAergic currents. We conclude from these results that allopregnanolone can enhance excitability in the immature hippocampus viaprolonged synaptic GABAergic currents. This potential effect of neurosteroids on brain excitability should be considered if they are applied as anticonvulsants to premature or early postnatal babies.

Anxiolytic and anticonvulsant activity followed by molecular docking study of ceramides from the Red Sea sponge Negombata sp

The chemical investigation of the Red Sea sponge Negombata sp. led to isolation and structure elucidation of five new ceramides N ((2S,3R,4E,8E)-1,3-dihydroxyhexacosa-4,8-dien-2-yl)pentadecanamide (1), N-((2S,3R,E)-1,3-dihydroxynonadec-4-en-2-yl)stearamide (2), N-[(2S,3R,E)-1,3 dihydroxyhexacos-4-en-2-yl]palmitamide (3), N-((2S,3R)-1,3-dihydroxydodecan-2-yl)tetradecanamide (4), N-[(2S,3S,4R)-1,3,4- trihydroxypentadecan-2-yl] palmitamide (5). Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The isolated ceramides were tested for anti-anxiety action in the elevated plus maze and the light-dark transition box. Mice given diazepam or compounds number 1, 2, 3, and 5 spent longer time in the light area of the light-dark box. However, compound 4 did not produce a similar effect. Similarly, testing anti-anxiety action in the elevated plus maze test showed that the compounds number 2, 3, and 5 or diazepam were able to prolong the open arm time %. Meanwhile, compounds 1 and 4 failed to produce a similar response. In addition, the anticonvulsant action of the ceramides was assessed employing pentylenetetrazole-induced seizures, where some ceramides prolonged the time to death due to pentylenetetrazole in vivo. In silico testing of the isolated ceramides displayed reasonable GABA receptor modulator binding at the benzodiazepines site. Ceramide 1 showed slightly stronger interaction with the GABA receptor over other ceramides which is compatible with the results of their anxiolytic activity.

A photoswitchable GABA receptor channel blocker.

Background and PurposeAnion‐selective Cys‐loop receptors (GABA and glycine receptors) provide the main inhibitory drive in the CNS. Both types of receptor operate via chloride‐selective ion channels, though with different kinetics, pharmacological profiles, and localization. Disequilibrium in their function leads to a variety of disorders, which are often treated with allosteric modulators. The few available GABA and glycine receptor channel blockers effectively suppress inhibitory currents in neurons, but their systemic administration is highly toxic. With the aim of developing an efficient light‐controllable modulator of GABA receptors, we constructed azobenzene‐nitrazepam (Azo‐NZ1), which is composed of a nitrazepam moiety merged to an azobenzene photoisomerizable group.Experimental ApproachThe experiments were carried out on cultured cells expressing Cys‐loop receptors of known subunit composition and in brain slices using patch‐clamp. Site‐directed mutagenesis and molecular modelling approaches were applied to evaluate the mechanism of action of Azo‐NZ1.Key ResultsAt visible light, being in trans‐configuration, Azo‐NZ1 blocked heteromeric α1/β2/γ2 GABAA receptors, ρ2 GABAA (GABAC), and α2 glycine receptors, whereas switching the compound into cis‐state by UV illumination restored the activity. Azo‐NZ1 successfully photomodulated GABAergic currents recorded from dentate gyrus neurons. We demonstrated that in trans‐configuration, Azo‐NZ1 blocks the Cl‐selective ion pore of GABA receptors interacting mainly with the 2′ level of the TM2 region.Conclusions and ImplicationsAzo‐NZ1 is a soluble light‐driven Cl‐channel blocker, which allows photo‐modulation of the activity induced by anion‐selective Cys‐loop receptors. Azo‐NZ1 is able to control GABAergic postsynaptic currents and provides new opportunities to study inhibitory neurotransmission using patterned illumination.

Neurosteroids: current perspective in therapy of neuropsychiatric disorders

Neurosteroids are natural or synthetic steroid derivatives which act locally in brain by modulating neuronal excitability. The objective of this study is to analyze available literature on classification, biosynthesis and mechanism of action, and therapeutic potential of neurosteroids. A review of literature pertaining to neurosteroids published from inception to 2018 was carried on data bases like PUBMED, Google Scholar and Science Direct. The search terms used were neurosteroids, neuro-active steroids, ganaxolone and GABA-A receptor modulators. Review of literature suggests neurosteroids are powerful neuro-modulators, involving rapid non-genomic and non-hormone receptor mechanisms. They are classified based on structure as pregnane, androstane and sulphated neurosteroids, and based on function as excitatory or inhibitory neurosteroids. They act via GABAA receptor (primarily), rho- GABA (ρGABA), NMDA-glutamate and sigma receptor modulation. The inhibitory neurosteroids demonstrate sedative, anxiolytic and anticonvulsant actions, whereas the excitatory agents produce memory enhancing and anxiogenic effects. They show efficacy in various CNS and psychiatric conditions like epilepsy, anxiety, depression, learning and memory disorders and substance abuse. Endogenous neurosteroids have limited clinical use due to low bioavailability, lack of specificity and unwanted effects. Hence, synthetic agents like alphaxalone, ganaxolone, sepranolone and brexanolone which have better bioavailability and specificity, are being investigated in various phases of clinical trials. Neurosteroids are novel endogenous compounds with neuro-modulatory function and show promising effects in therapy of various neurological and psychiatric conditions. Further studies that prove their long term efficacy and safety may revolutionize the clinical approach to therapy of these conditions.

A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA's Ability to Inhibit Inflammatory T Cells.

A major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat β-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote β-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased β-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from β-cells to increase β-cell survival and replication. Treatment with both the PAM and GABA further enhanced human β-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process.