Search Results (69)

Beyond its canonical role as the principal inhibitory neurotransmitter in the central nervous system (CNS), peripheral GABAergic signaling has emerged as an important regulator of skin barrier immunity and tissue homeostasis. This review synthesizes current evidence on the expression, distribution, and function of both GABA-A and GABA-B receptors in keratinocytes, fibroblasts, melanocytes, sensory neurons, and cutaneous immune cells, including Langerhans cells, macrophages, mast cells, and T lymphocytes. Particular emphasis is placed on how GABAergic signaling regulates ion transport, calcium dynamics, epidermal differentiation, and immune homeostasis through coordinated interactions with ion channels within the broader cutaneous neuro-immuno-endocrine network. We further discuss evidence supporting the role of cutaneous GABAergic signaling in maintaining barrier integrity, modulating inflammatory responses, and contributing to skin–brain communication within the broader cutaneous neuro-immuno-endocrine network under physiological and pathological conditions. Finally, we summarize the therapeutic potential of targeting peripheral GABAergic pathways in atopic dermatitis, psoriasis, chronic pruritus, photoaging, and other stress-associated dermatoses, highlighting their promise as novel therapeutic strategies in precision dermatology. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by the accumulation of the toxic protein amyloid-β, formation of tau-containing neurofibrillary tangles, neuroinflammation, and synaptic dysfunction, highlighting the need for new therapeutic strategies capable of modulating multiple pathological pathways simultaneously. In this study, a structure-based in silico approach was applied to evaluate the multi-target potential of two previously reported pyrrole-based compounds (pyrrole 1 and pyrrole 2) with known monoamine oxidase-B (MAO-B) inhibitory activity and low neurotoxicity. Molecular docking studies were performed against a panel of key AD-related targets, including GSK-3β, APP, MAO-B, BACE1, AChE, BChE, COX-2, GABA-B receptor, NMDA receptor, and E3 ubiquitin ligase CHIP, using Glide XP docking. The results revealed that compound pyrrole 1 may have favorable predicted binding affinities across several targets, with relatively strong docking scores for GSK-3β and COX-2. The binding mode analysis indicated that pyrrole 1 adopts poses consistent with interaction patterns commonly observed for ATP-competitive GSK-3β inhibitors and COX-2 ligands. In silico ADMET profiling using the software SwissADME and ProTox 3.0 indicated distinct pharmacokinetic and safety profiles for the two compounds, with pyrrole 2 showing superior drug-likeness and predicted blood–brain barrier penetration, while pyrrole 1 displayed a more favorable overall toxicity profile. Collectively, these findings identify pyrrole 1 as a theoretically promising multi-target candidate for AD requiring experimental validation, while providing a strong structural basis for further optimizations and subsequent experimental confirmation. Full article

Background/Objectives: Magnesium (Mg) is essential for neuronal maturation, yet its role in human cortical development remains poorly defined. Here, we investigated the effects of physiological (1 mM) and elevated (5 mM) concentrations of MgSO₄ and magnesium pidolate (MgPid) on human brain organoids co-cultured with an in vitro blood–brain barrier (BBB) model. Methods: Human brain organoids derived from induced pluripotent stem cells were co-cultured with an in vitro BBB system and treated for 4 days with either MgSO₄ or MgPid at physiological and elevated concentrations. Cortical organization was assessed by transmission electron microscopy and immunofluorescence analysis. Western blotting for neurotransmitter receptors and Mg transporters, quantification of intraorganoid Mg²⁺ levels, ELISA-based measurement of GABA and dopamine, and analysis of glutamate were performed. Results: High Mg exposure enhanced cortical stratification and neuronal organization, as shown by the localization of CTIP2 in the outermost layer and TBR2 in the inner layer, together with ultrastructural features consistent with advanced differentiation. Elevated Mg increased intraorganoid Mg²⁺ levels without altering Mg transporter abundance and selectively modulated neurotransmitter receptor expression: NMDA-R levels were reduced by MgPid, whereas GABA_A-R and GABA_B-R were upregulated, particularly in response to MgPid. Levels of glutamate, GABA, and dopamine remained unchanged. Conclusions: These findings identify Mg, especially in the form of MgPid, as a modulator of cortical architecture and inhibitory–excitatory receptor balance in human organoids, supporting its potential relevance for neurodevelopmental regulation and Mg-based therapeutic strategies. These results also support organoids as human-relevant, animal-free tools for neuroscience and neuropharmacological research. Full article

This paper presents a modular mathematical model of neuronal activity, designed to simulate the dynamics of main molecular targets of antiepileptic drugs and their pharmacological effects. The model was developed based on several existing synaptic transmission models that capture cellular processes crucial to the pathology of epilepsy. It incorporates the primary molecular mechanisms involved in regulating excitation and inhibition within the neural network. Special attention is given to the dynamics of ion currents (Na⁺, K⁺, Ca²⁺), receptors (AMPA, NMDA, GABA_A, GABA_B and mGlu), and neurotransmitters (glutamate and GABA). Examples of simulations illustrating the inhibitory effects on synaptic transmission are provided. The numerical results are consistent with experimental data reported in the literature. Full article

Astrocytes are increasingly recognized as active participants of synaptic communication, yet their role in the basal ganglia circuitry remains poorly defined. Emerging evidence indicates that astrocytes in this region express a diverse array of neurotransmitter receptors thought to regulate intracellular calcium signaling, gliotransmitter release, synaptic plasticity, and neuroimmune responses. However, the literature is limited by methodological variability and a pronounced focus on the striatum, with comparatively little data on other basal ganglia nuclei. This review aims to organize the current literature on astrocytic receptor systems within the basal ganglia, including dopaminergic (D1–D5), glutamatergic (AMPA, NMDA, mGluRs), GABAergic (GABA-A, GABA-B), purinergic (P1, P2), and adrenergic (α, β) receptors. By organizing receptor-specific findings across basal ganglia structures, this review provides a foundation for future investigations into astrocytic function in this complex neural network. Full article

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. However, GABA receptors, notably at the neuromuscular junction (NMJ), have also been identified in the peripheral nervous system. Here, we studied GABA_B receptor (GABA_B–R)-mediated regulation of acetylcholine (ACh) release in mouse NMJs during early postnatal development. The results revealed that, depending on the age of the mice, the activation of GABA_B–R had the opposite effect on ACh release. At the NMJ in mice on the second postnatal (P2) day, the GABA_B–R blocker CGP 55845 (5 μM) significantly increased the level of ACh release, whereas the GABA_B–R agonist baclofen (10 μM) decreased ACh release. In P14-aged mice, CGP 55845 decreased ACh release, while the application of baclofen significantly increased the release. At the NMJ of P14 mice, the mechanism of the ACh release-potentiating effect of GABA_B–R activation involves N-type calcium ion channels and small-conductance calcium ion-activated potassium ion channels. Full article

Medulloblastoma (MB) is the most common malignant brain tumor in children and typically arises in the cerebellum, likely due to disruptions in neuronal precursor development. The primary inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), exerts its effects through GABA_A, GABA_B, and GABA_C receptors. GABA receptor activity regulates the development and function of cerebellar neurons, including glutamatergic cerebellar granule cells (CGCs). Beyond the nervous system, GABA is also a common metabolite in non-neuronal cell types. An increasing body of evidence indicates that GABA can influence cell proliferation, differentiation, and migration in several types of adult solid tumors, including brain cancers. GABA and GABA_A receptor agonists can impair the viability and survival of MB cells, primarily acting on GABA_A receptors containing the α5 subunit. A marked expression of the gene encoding the α5 subunit is found across all MB tumor molecular subgroups, particularly Group 3 MB, which has a poor prognosis. Importantly, high levels of the γ-aminobutyric acid type A receptor subunit α5 (GABRA5) gene are associated with shorter patient overall survival in Group 3 and Group 4 MB. In contrast, high γ-aminobutyric acid type A receptor subunit β1 (GABRB1) gene expression is related to longer survival in all MB subgroups. The GABAergic system may, therefore, regulate MB cell function and tumor progression and influence patient prognosis, and is worthy of further investigation as a biomarker and therapeutic target in MB. Full article

γ-amino butyric acid (GABA) is an inhibitory neurotransmitter whose deficiency has been associated with various neurological disorders. However, its low liposolubility limits its use as a supplement. Thus, multiple investigations have focused on searching for lipophilic GABA analogs that can modulate the activity of the GABA_B receptor, which could be associated with the etiology of some central nervous system disorders. The GABA analogs available on the market are Vigabatrin, Gabapentin as well as Pregabalin and Baclofen. In this work, we report on the synthesis of GABA analogs, taking the scaffold of GABA, Pregabalin, and Baclofen as a starting point. The analogs include structural features that could favor the affinity of the molecules for the GABA_B receptor, such as heterocyclic rings in the γ-position and alkyl or p-Cl-phenyl substituents (in analogy to Pregabalin and Baclofen, respectively). These analogs were synthesized by a sequence of reactions involving an N-alkylation, a 1,4-conjugated addition of dialkyl and diarylcuprates and a basic hydrolysis. Furthermore, a computational molecular docking over the GABA_B receptor was performed to evaluate the interaction of each compound in the Baclofen binding site. With this information, we evaluated our compounds as GABA_B agonists through a QSAR analysis. Finally, by means of molecular similarity analysis, and in silico ADME prediction, we support our three best compounds (8a–b, 8d) as potential GABA_B receptor agonists. Full article

Infantile spasms are common in Down Syndrome (DS), but the mechanisms by which DS predisposes to this devastating epilepsy syndrome are unclear. In general, neuronal excitability and therefore seizure predisposition results from an imbalance of excitation over inhibition in neurons and neural networks of the brain. Animal models provide clues to mechanisms and thereby provide potential therapeutic approaches. Ts65Dn mice have been the most widely used animal model of DS. In this model, there is evidence for both abnormal cerebral excitation and inhibition: infantile spasms-like clinical and electrographic activity can be elicited by the administration of gamma-aminobutyric acid (GABA)-B receptor agonist, gamma-butyrolactone (GBL), and depolarizing GABA-A responses persist beyond the age of their usual switch to hyperpolarized responses. But despite its widespread use, the Ts65Dn model may be suboptimal because of the absence of numerous genes that are triplicated in human DS and the presence of numerous genes that are not triplicated in human DS. Recently, a transchromosomic mouse artificial chromosome 21 (TcMAC21) mouse model has been developed, which carries a copy of human chromosome 21 and therefore has a genetic composition more similar to human DS. As in Ts65Dn mice, exposure of TcMAC21 mice to GBL results in epileptic spasms, and aberrant excitation has also been demonstrated. This review summarizes excitatory and inhibitory dysfunction in models of DS that may play a role in the generation of seizures and infantile spasms, providing a perspective on past studies and a prelude for future ones. Further elucidation will hopefully lead to rational therapeutic options for DS children with infantile spasms. Full article

GABAergic signaling and GABA_B receptors play crucial roles in regulating the physiology of oligodendrocyte-lineage cells, including their proliferation, differentiation, and myelination. Therefore, they are promising targets for studying how spinal oligodendrocyte precursor cells (OPCs) respond to injuries and neurodegenerative diseases like multiple sclerosis. Taking advantage of the temporally controlled and cell-specific genetic downregulation of GABA_B receptors from OPCs, our investigation addresses their specific influence on OPC behavior in the gray and white matter of the mouse spinal cord. Our results show that, while GABA_B receptors do not significantly alter spinal cord myelination under physiological conditions, they distinctly regulate the OPC differentiation and Ca²⁺ signaling. In addition, we investigate the impact of OPC-GABA_B receptors in two models of toxic demyelination, namely, the cuprizone and the lysolecithin models. The genetic downregulation of OPC-GABA_B receptors protects against demyelination and oligodendrocyte loss. Additionally, we observe the enhanced resilience to cuprizone-induced pathological alterations in OPC Ca²⁺ signaling. Our results provide valuable insights into the potential therapeutic implications of manipulating GABA_B receptors in spinal cord OPCs and deepen our understanding of the interplay between GABAergic signaling and spinal cord OPCs, providing a basis for future research. Full article

γ-Aminobutyric acid (GABA) has a significant impact on the functioning of not only the central but also the peripheral part of the nervous system. Recently, various elements of the GABAergic signaling system have been discovered in the area of the neuromuscular junction of mammals. At the same time, the functional activity of membrane-bound GABA transporters (GATs) and their role in neuromuscular transmission have not been identified. In the present study, performed on a neuromuscular preparation of the mouse diaphragm, the effect of GABA transporter inhibitors (nipecotic acid and β-alanine) on the force of muscle contraction was assessed. It was found that in the presence of both compounds in the bathing solution, the force of contractions caused by stimulation of the motor nerve dropped by 30–50%. However, when the muscle was stimulated directly, no effect of GABA transporter inhibitors on the contractile force was observed. The depressant effect of β-alanine induced by nerve stimulation was completely abolished by the GABA_B receptor blocker CGP 55845. GABA transporters were detected at the neuromuscular junction using immunohistochemistry. Thus, our results indicate that GABA transporters are localized in the area of the neuromuscular junction, and their activity affects the muscle contraction force. This influence is most likely due to the removal of GABA released during nerve stimulation and activating GABA receptors, which leads to a decrease in the contraction force of the striated muscles. Full article

Network dynamics are crucial for action and sensation. Changes in synaptic physiology lead to the reorganization of local microcircuits. Consequently, the functional state of the network impacts the output signal depending on the firing patterns of its units. Networks exhibit steady states in which neurons show various activities, producing many networks with diverse properties. Transitions between network states determine the output signal generated and its functional results. The temporal dynamics of excitation/inhibition allow a shift between states in an operational network. Therefore, a process capable of modulating the dynamics of excitation/inhibition may be functionally important. This process is known as disinhibition. In this review, we describe the effect of GABA levels and GABA_B receptors on tonic inhibition, which causes changes (due to disinhibition) in network dynamics, leading to synchronous functional oscillations. Full article

We aimed to analyze the increase in the sleep-promoting effects based on the mixed ratio of botanical extracts, Ziziphus jujuba seeds, Dimocarpus longan fruits, and Lactuca sativa leaves, using animal models. Behavioral analyses, including an analysis of the total sleep time of Drosophila melanogaster, were conducted to select the optimal mixed ratio of the three botanical extracts. The effects were verified in a caffeine-induced sleepless model, specific neurotransmitter receptor antagonists, and ICR mice. In D. melanogaster exposed to 2.0% of each extract, group behavior was significantly reduced, and the mixed extracts of Z. jujuba, D. longan, and L. sativa (4:1:1 and 1:4:1) significantly increased the total sleep time with individual fruit flies. In the caffeine-induced insomnia model, mixed extracts (4:1:1 and 1:4:1) led to the highest increase in total sleep time. An analysis of locomotor ability revealed a significant reduction in the mobility percentage in the mixed extract groups (0:0:1, 1:0:1, 1:1:1, 4:1:1, and 1:4:1). The administration of Z. jujuba extract and mixed extracts (4:1:1) significantly increased the expression of GABA_A-R, whereas the administration of the mixed extracts (4:1:1) and (1:4:1) significantly increased the expression of GABAB-_R1 and GABAB-_R2, respectively. D. longan extract and the mixed ratio (1:4:1) reduced the subjective nighttime movement and increased the total sleep time in the presence of flumazenil. An analysis of ICR mice indicated that the administration of mixed extracts (4:1:1) significantly increased sleep duration in a dose-dependent manner. These results indicated that the mixed ratio of Z. jujuba, D. longan, and L. sativa extracts, particularly the mixed ratio of 4:1:1, may have sleep-enhancing effects in fruit flies and mice. The study also identified changes in gene expression related to GABA receptors, indicating the potential mechanism for the observed sleep-promoting effects. Full article

The cell-surface targeting of neo-synthesized G protein-coupled receptors (GPCRs) involves the recruitment of receptors into COPII vesicles budding at endoplasmic reticulum exit sites (ERESs). This process is regulated for some GPCRs by escort proteins, which facilitate their export, or by gatekeepers that retain the receptors in the ER. PRAF2, an ER-resident four trans- membrane domain protein with cytoplasmic extremities, operates as a gatekeeper for the GB1 protomer of the heterodimeric GABA_B receptor, interacting with a tandem di-leucine/RXR retention motif in the carboxyterminal tail of GB1. PRAF2 was also reported to interact in a two-hybrid screen with a peptide corresponding to the carboxyterminal tail of the chemokine receptor CCR5 despite the absence of RXR motifs in its sequence. Using a bioluminescence resonance energy transfer (BRET)-based subcellular localization system, we found that PRAF2 inhibits, in a concentration-dependent manner, the plasma membrane export of CCR5. BRET-based proximity assays and Co-IP experiments demonstrated that PRAF2/CCR5 interaction does not require the presence of a receptor carboxyterminal tail and involves instead the transmembrane domains of both proteins. The mutation of the potential di-leucine/RXR motif contained in the third intracellular loop of CCR5 does not affect PRAF2-mediated retention. It instead impairs the cell-surface export of CCR5 by inhibiting CCR5’s interaction with its private escort protein, CD4. PRAF2 and CD4 thus display opposite roles on the cell-surface export of CCR5, with PRAF2 inhibiting and CD4 promoting this process, likely operating at the level of CCR5 recruitment into COPII vesicles, which leave the ER. Full article

Cleomin, a 1,3-oxazolidine-2-thione, was recently isolated from Neocalyptrocalyx longifolium, a species traditionally used for treating painful conditions. Reports about the pharmacological activities of cleomin are lacking. Here, the antinociceptive effects of cleomin were investigated using mice models of pain, namely the formalin, the cold plate, and the tail flick tests. Motor integrity was assessed in the rota-rod test. Antagonism assays and in silico docking analyses were performed to investigate the putative mechanisms of action. Cleomin (12.5–25 mg/kg), at doses that did not induce motor impairment, induced dose-dependent antinociception in both early and late phases of the formalin test and reduced nociceptive behaviors in both the cold plate and tail flick tests. Pretreatments with phaclofen and atropine attenuated the antinociceptive effects of cleomin, implicating the involvement of GABA_B and muscarinic receptors. In silico docking studies suggested satisfactory coupling between cleomin and GABA_B and M₂ receptors, hence corroborating their role in cleomin’s activity. Pretreatments with naloxone, yohimbine, bicuculline, and methysergide did not affect the antinociception of cleomin. In silico pharmacokinetics prediction showed a good drug ability profile of cleomin. In conclusion, cleomin promoted antinociception mediated by GABA_B and muscarinic receptors. These findings support further investigation of the analgesic potential of cleomin. Full article