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• Expression of GABAergic markers and scaffolding proteins increases in the early stages of development. • Oxytocin increases GABAergic synaptic puncta in the piriform cortex. • Oxytocin did not affect neurite branching in GABAergic neurons isolated from the olfactory bulb. Oxytocin affects social recognition, interactions, and behavior in adults. Despite growing data on the role of oxytocin in the sensory systems, its effects on early olfactory system development remain poorly understood. The present study aimed to investigate the developmental impact of oxytocin on selected parameters of the GABAergic system in olfactory brain regions. We found a significant increase in the expression of GABAergic markers and scaffolding proteins in the olfactory bulb during the early stages of development in both male and female rats, regardless of oxytocin treatment administered on postnatal days 2 and 3 (P2 and P3, 5 µg/pup). Oxytocin administration markedly reduced the expression of the scaffolding protein Gephyrin in male rats and it led to a significant increase in the number of GABAergic synaptic puncta in the piriform cortex of male rats at P5, P7, and P9. Our data suggest that the developmental action of oxytocin in relation to the GABAergic system may represent a mechanism by which the plasticity and maturation of olfactory brain regions are regulated. [ABSTRACT FROM AUTHOR]

Ageing induces a decline in GABAergic intracortical inhibition, which seems to be associated not only with decremental changes in well‐being, sleep quality, cognition and pain management but also with impaired motor control. So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly. Therefore, the present study investigated whether age‐related cortical dis‐inhibition could be reversed after 6 months of balance learning and whether improvements in postural control correlated with the extent of reversed dis‐inhibition. The results demonstrated that intracortical inhibition can be upregulated in elderly subjects after long‐term balance learning and revealed a correlation between changes in balance performance and intracortical inhibition. This is the first study to show physical activity‐related upregulation of GABAergic inhibition in a population with chronic dis‐inhibition and may therefore be seminal for many pathologies in which the equilibrium between inhibitory and excitatory neurotransmitters is disturbed. Key points: Ageing induces a decline in GABAergic intracortical inhibition.So far, little is known regarding whether targeted interventions can prevent the decline of intracortical inhibition in the primary motor cortex in the elderly.After 6 months of balance learning, intracortical inhibition can be upregulated in elderly subjects.The results of this study also revealed a correlation between changes in balance performance and intracortical inhibition.This is the first study to show physical activity‐related upregulation of GABAergic inhibition in a population with chronic dis‐inhibition. [ABSTRACT FROM AUTHOR]

Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro‐ and anti‐tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA‐producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial‐derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)‐induced proliferation and interleukin‐6 (IL‐6) expression in these cells. Gene expression correlations were assessed using the "Cancer Exploration" suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase‐2 and IL‐6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti‐tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer. [ABSTRACT FROM AUTHOR]

Etizolam is a thienodiazepine derivative which produces an anxiolytic effect similar to benzodiazepines such as alprazolam (Xanax). Like classic benzodiazepines, etizolam has a high affinity towards the GABAA receptor, and allosterically potentiates the effects of GABA resulting in neuronal hyperpolarization related to chloride influx. When taken in therapeutic doses, etizolam produces a similar effect to Xanax. Counterfeit Xanax tablets contain variable amounts of etizolam. Tablets with high amounts of etizolam can cause toxicity if ingested, especially when combined with other substances. When toxic symptoms occur in patients, they may include severe sedation, unconsciousness, and depression of the medullary respiratory center. In this regard, there is the potential for death. Additionally, the rise in fake Xanax tablets containing etizolam and other counterfeit medications has been exacerbated by the difference in regulations regarding these substances in different countries as well as the illegal drug trade. Healthcare providers may also play a role through the over- or underprescribing of certain medications. Thus, in order to combat the rise in counterfeit medications such as fake Xanax, international cooperation, regulation, and enforcement of laws pertaining to the manufacture, prescription, and distribution of these substances are needed. [ABSTRACT FROM AUTHOR]

When 2-chloro-6-(trichloromethyl) pyridine (nitrapyrin) is applied alone, it typically does not significantly increase crop yield. Therefore, we combined gamma-aminobutyric acid (GABA) with nitrapyrin to address the limitations of nitrapyrin in enhancing yield. We conducted indoor incubation experiments and pot experiments in Chernozem and Calcic Kastanozem, respectively. The results demonstrated that GABA exerted an influence on the effectiveness of nitrapyrin by altering its degradation rate. In Chernozem, GABA accelerated nitrapyrin degradation, whereas, in Calcic Kastanozem, the results were the opposite. The pot experiment results showed that the combination of nitrapyrin and GABA increased rice total biomass by 5%, grain yield by 18 ± 2%, and plant nitrogen (N) uptake by 9 ± 1% compared to nitrapyrin applied alone. The increase in yield was attributed to the combined effect of nitrapyrin and GABA, which elevated root biomass and leaf area. In contrast, the effect of GABA on yield through altering the degradation rate of nitrapyrin was weaker. Therefore, the combination of nitrapyrin and GABA combined with urea increases rice yields in Chernozem and Calcic Kastanozem. The aim of this endeavour was to foster the development of a novel fertiliser product that offers both favourable agronomic outcomes and environmental benefits. [ABSTRACT FROM AUTHOR]

Adolescence is characterized by changes in reward-related behaviors, social behaviors, and decision-making. These behavioral changes are necessary for the transition into adulthood, but they also increase vulnerability to the development of a range of psychiatric disorders. Major reorganization of the dopamine system during adolescence is thought to underlie, in part, the associated behavioral changes and increased vulnerability. Here, we utilized fast scan cyclic voltammetry and microdialysis to examine differences in dopamine release as well as mechanisms that underlie differential dopamine signaling in the nucleus accumbens (NAc) core of adolescent (P28-35) and adult (P70-90) male rats. We show baseline differences between adult and adolescent-stimulated dopamine release in male rats, as well as opposite effects of the α6 nicotinic acetylcholine receptor (nAChR) on modulating dopamine release. The α6-selective blocker, α-conotoxin, increased dopamine release in early adolescent rats, but decreased dopamine release in rats beginning in middle adolescence and extending through adulthood. Strikingly, blockade of GABAA and GABAB receptors revealed that this α6-mediated increase in adolescent dopamine release requires NAc GABA signaling to occur. We confirm the role of α6 nAChRs and GABA in mediating this effect in vivo using microdialysis. Results herein suggest a multisynaptic mechanism potentially unique to the period of development that includes early adolescence, involving acetylcholine acting at α6-containing nAChRs to drive inhibitory GABA tone on dopamine release. [ABSTRACT FROM AUTHOR]

BACKGROUND RESULTS CONCLUSION This study investigated the effects of γ‐aminobutyric acid (GABA) combined with ultrasonic stress germination (AUG) treatment on the phenolic content and antioxidant activity of highland barley (HB). Key variables, including germination times (ranging from 0 to 96 h), ultrasonic power (200–500 W), and GABA concentration (5–20 mmol/L), were optimized using response surface methodology (RSM) to enhance the enrichment of phenolic compounds. Furthermore, the study assessed the content, composition, and antioxidant activities of phenolic compounds in HB under various treatment conditions such as germination alone (G), ultrasonic stress germination (UG), and AUG treatment.The study identified optimal conditions for the phenolic enrichment of HB, which included a germination time of 60 h, an ultrasound power of 300 W, and a GABA concentration of 15 mmol L−1. Under these conditions, the total phenolic content (TPC) in HB was measured at 7.73 milligrams of gallic acid equivalents per gram dry weight (mg GAE/g DW), representing a 34.96% enhancement compared to untreated HB. Notably, all treatment modalities – G, UG, and AUG – significantly increased the phenolic content and antioxidant activity in HB, with the AUG treatment proving to be the most effective.These obtained results suggest that AUG treatment is a promising processing method for enriching phenolic compounds and improving antioxidant activity in HB. Subsequently, the AUG‐treated HB can be used to develop phenolic‐rich germinated functional foods to further broaden the application of HB. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Simple Summary: Live fish transport often induces stress, while gamma-aminobutyric acid (GABA) is considered to exhibit anti-stress effects. This study aims to explore the effects of GABA on alleviating the transport stress of tawny puffer (Takifugu flavidus) by detecting water quality parameters, plasma biochemical indices, energy metabolism indicators, and antioxidant indexes. The results indicated that 50 and 150 mg/L GABA treatments exert anti-stress effects significantly on the tawny puffer, which provides a scientific basis for the development of GABA as an effective additive for aquatic animals' live transport. Live fish transportation is crucial for managing aquaculture but can pose health risks to fish due to stressors encountered during transportation. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that plays a crucial role in the central nervous system and is considered to exhibit anti-stress effects. This study aims to investigate the effects of GABA on the transport water quality, plasma biochemical indices, energy metabolism, and antioxidant capacity of tawny puffer (Takifugu flavidus) under transport stress. Tawny puffer were pretreated by immersing in aquariums containing GABA (final concentrations at 0, 5, 50, and 150 mg/L) seawater for 3 days; then, simulated transport was conducted using oxygen-filled polyethylene bags containing the same concentration of GABA seawater as the pretreatment period. Water samples, plasma, and liver were collected after 0, 6, and 12 h of transport. The results revealed that with the prolongation of transportation time, the control group's water quality deteriorated, stress-related plasma biochemical indices increased, glycolytic substrate contents decreased, glycolytic enzyme activities and product contents increased, and aerobic metabolic enzyme activities exhibited initial increases followed by declines, ATPase activities decreased, antioxidant enzyme activities decreased, and the lipid peroxidation marker contents increased. It is noteworthy that GABA treatment could avoid water quality deterioration during transportation, inhibit an elevation in stress-related biochemical indicators, regulate energy metabolism, and reduce oxidative damage in tawny puffer, especially at 50 and 150 mg/L concentrations. In summary, GABA treatment can effectively alleviate the transport stress of tawny puffer. [ABSTRACT FROM AUTHOR]

Arising out of a PhD project more than 50 years ago to synthesise analogues of the neurotransmitter GABA, a series of new chemical entities were found to have selective actions on ionotropic GABA receptors. Several of these neurochemicals are now commercially available. A new subtype of these receptors was discovered that could be a target for the treatment of myopia, the facilitation of learning and memory, and the improvement of post‐stroke motor recovery. The development of these new chemical entities over many years demonstrates the importance of neurochemicals with which to investigate selective aspects of GABA receptors and illustrates the significance of collaboration between chemists and biologists in neurochemistry. Vital were the improvements in synthetic organic chemistry and the use of functional human receptors expressed in oocytes. Current interest in ionotropic GABA receptors includes the clinical development of subtype‐specific agents and the role of gain‐of‐function receptor variants in epilepsy. Dietary flavonoids were found to cross the blood–brain barrier to influence brain function. Natural and synthetic flavonoids had a range of effects on GABA receptors, ranging from positive, silent, and negative allosteric modulators, to even second‐order modulation of first‐order modulators. Flavonoids have been called "a new family of benzodiazepines." Like benzodiazepines, flavonoids reduce stress. Stress produces changes in GABA receptors in the brain that may be because of changes in endogenous modulators, such as neurosteroids and corticosteroids. GABA also occurs naturally in the diet leading to studies of the effects of oral GABA on brain function. This finding has resulted in studies of GABA and related neurochemicals as neuro‐nutraceuticals. GABA systems in the gut microbiome are essential to such studies. The actions of oral GABA and of GABA‐enriched beverages and foodstuffs are now an area of considerable scientific and commercial interest. GABA is a deceptively simple chemical that can take up many shapes, which may underlie its complex functions. The need for new chemical entities with selective actions for further studies highlights the need for continuing collaboration between chemists and biologists. [ABSTRACT FROM AUTHOR]

We studied the effect of enteral administration of GABA on the gastric mucosa in male Wistar rats (n=47) with modeled metabolic stress (food deprivation for 9 days with free access to water). The relative weights of the adrenal glands and thymus were determined, and histological examination of the stomach was performed. In control rats, modeling the metabolic stress was accompanied by the development of erosive damage to the gastric mucosa related to blood supply disturbances. Administration of GABA prevented erosions and exhibited a pronounced gastroprotective effect. Thus, administration of GABA can be a promising method for the prevention and treatment of erosive gastric lesions associated with metabolic stress. [ABSTRACT FROM AUTHOR]

γ‐aminobutyric acid (GABA) has shown promise in enhancing crop tolerance to heavy metal stress. To improve the cadmium (Cd) phytoremediation capacity of hyperaccumulator Solanum nigrum var. humile, the effects of exogenous GABA on the growth and Cd accumulation of S. nigrum var. humile were studied. When exposed to Cd stress (0.1 mg/L) through irrigation, S. nigrum var. humile exhibited inhibited growth, characterized by decreased biomass and contents of photosynthetic pigments (chlorophyll a, chlorophyll b, total chlorophyll, and carotenoid). However, the application of exogenous GABA at 1 and 2 g/L increased various organs biomass and photosynthetic pigment content of S. nigrum var. humile to certain degree under Cd stress. Compared with the Cd treatment, the concentrations of 1 and 2 g/L GABA increased the shoot biomass by 8.24% and 16.62%, respectively. GABA also increased the Cd contents, bioconcentration factors, and Cd extractions in various organs of S. nigrum var. humile. Compared with the Cd treatment, the concentrations of 1 and 2 g/L GABA increased the shoot Cd extraction by 17.66% and 24.47%, respectively. Moreover, correlation and gray relational analyses showed that the shoot biomass, chlorophyll b content, and total chlorophyll content were the top three parameters closely related to shoot Cd extraction. These findings suggest that GABA can alleviate Cd‐induced stress in S. nigrum var. humile, thus enhancing its phytoremediation capacity for Cd‐contaminated soils. [ABSTRACT FROM AUTHOR]

Background: Changing climate is causing erratic rainfall and prolonged drought periods, thus posing serious threats to crop productivity. Owing to severity of drought events, it is imperative to take proactive measures to enhance the resilience of drought sensitive crops like rice. Therefore, the present study was carried out to improve the drought stress tolerance in rice through gamma amino butyric acid (GABA) application. Methods: The experiment was included four GABA concentrations i.e., 0 mM as control, 1 mM, 1.5 mM, and 2 mM, two water levels i.e., 100% and 50% field capacity (referred as FC100 for well-watered and FC50 for drought conditions, respectively), and two fragrant rice cultivars i.e., Super Basmati and Basmati-515. Results: The findings unveiled a comprehensive improvement in various parameters with GABA application in fragrant rice under both well-watered (FC100) and water-limited (FC50) conditions, compared to the control. Specifically, GABA induced enhancements were observed in plant height, root length, fresh weight, dry weight, total soluble protein content, and total free amino acid content across both cultivars. Moreover, GABA application significantly improved peroxidase (POD) and catalase (CAT) enzyme activities, alongside elevating anthocyanin levels, while concurrently reducing H2O2 contents in both FC100 and FC50 treatments. Furthermore, the positive impact of GABA extended to morphological traits, with notable increases in panicle length, total tillers and productive tillers per hill, branch and grain numbers per panicle, and 1000-grain weight for Super Basmati and Basmati 515 cultivars under both water regimes, compared to Ck. Similarly, the grain yield increased by 31.01% and 27.32% under FC100 and 36.85% and 27.71% under FC50 in Super Basmati and Basmati-515, respectively, in response to GABA application, compared to Ck. Additionally, principal component analysis (PCA) revealed significant variances attributed to Dim1 and Dim2, with 86.1% and 4.0% of the variance, respectively, across three bi-plots encompassing rice cultivars, water levels, and GABA treatments. Notably, all tested indices, except for H2O2 and non-productive tillers per hill, exhibited positive correlations amongst themselves and with rice yield, further emphasizing the beneficial effects of GABA application on fragrant rice under well-watered and drought conditions. Conclusions: GABA significantly improved fragrant rice performance under both well-watered (FC100) and water-limited (FC50) conditions. Moreover, integrating GABA application into rice cultivation practices could not only improve the crop resilience to drought stress but also potentially benefiting the future food and nutritional security globally. However, however; further research is needed to understand the cellular and molecular mechanisms of the functionality of GABA in fragrant rice, particularly under drought conditions. [ABSTRACT FROM AUTHOR]

Huanglian Wendan Decoction (HWD) is a traditional Chinese medicine (TCM) prescribed to patients diagnosed with insomnia, which can achieve excellent therapeutic outcomes. As positively modulating the γ-aminobutyric acid (GABA) type A receptors (GABAARs) is the most effective strategy to manage insomnia, this study aimed to investigate whether the activation of GABAARs is involved in the anti-insomnia effect of HWD. We assessed the metabolites of HWD using LC/ MS and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and tested the pharmacological activity in vitro and in vivo using whole-cell patch clamp and insomnia zebrafish model. In HEK293 cells expressing α1β3γ2L GABAARs, HWD effectively increased the GABA-induced currents and could induce GABAAR-mediated currents independent of the application of GABA. In the LC-MS (QToF) assay, 31 metabolites were discovered in negative ion modes and 37 metabolites were found in positive ion modes, but neither three selected active metabolites, Danshensu, Coptisine, or Dihydromyricetin, showed potentiating effects on GABA currents. 62 active metabolites of the seven botanical drugs were collected based on the TCMSP database and 19 of them were selected for patch-clamp verification according to the virtual docking simulations and other parameters. At a concentration of 100 μM, GABA-induced currents were increased by (+)-Cuparene (278.80% ± 19.13%), Ethyl glucoside (225.40% ± 21.77%), and β-Caryophyllene (290.11% ± 17.71%). In addition, (+)-Cuparene, Ethyl glucoside, and β-Caryophyllene could also serve as positive allosteric modulators (PAMs) and shifted the GABA doseresponse curve (DRC) leftward significantly. In the PCPA-induced zebrafish model, Ethyl glucoside showed anti-insomnia effects at concentrations of 100 μM. In this research, we demonstrated that the activation of GABAARs was involved in the anti-insomnia effect of HWD, and Ethyl glucoside might be a key metabolite in treating insomnia. [ABSTRACT FROM AUTHOR]

Nickel (Ni) is a heavy metal that adversely affects the growth of different crops by inducing oxidative stress and nutrient imbalance. The role of rhizobacteria (RB) is vital to resolve this issue. They can promote root growth and facilitate the uptake of water and nutrients, resulting in better crop growth. On the other hand, γ-aminobutyric acid (GABA) can maintain the osmotic balance and scavenge the reactive oxygen species under stress conditions. However, the combined effect of GABA and RB has not been thoroughly explored to alleviate Ni toxicity, especially in fenugreek plants. Therefore, in the current pot study, four treatments, i.e., control, A. fabrum (RB), 0.40 mM GABA, and 0.40 mM GABA + RB, were applied under 0Ni and 80 mg Ni/kg soil (80Ni) stress. Results showed that RB + 0.40 mM GABA caused significant improvements in shoot length (~ 13%), shoot fresh weight (~ 47%), shoot dry weight (~ 47%), root length (~ 13%), root fresh weight (~ 60%), and root dry weight (~ 15%) over control under 80 Ni toxicity. A significant enhancement in total chlorophyll (~ 14%), photosynthetic rate (~ 17%), stomatal CO2 concentration (~ 19%), leaves and roots N (~ 10 and ~ 37%), P (~ 18 and ~ 7%) and K (~ 11 and ~ 30%) concentrations, while a decrease in Ni (~ 83 and ~ 49%) concentration also confirmed the effectiveness of RB + 0.40 mM GABA than control under 80Ni. In conclusion, fabrum + 0.40 mM GABA can potentially alleviate the Ni toxicity in fenugreek plants. The implications of these findings extend to agricultural practices, environmental remediation efforts, nutritional security, and ecological impact. Further research is recommended to elucidate the underlying mechanisms, assess long-term effects, and determine the practical feasibility of using A. fabrum + 0.40GABA to improve growth in different crops under Ni toxicity. [ABSTRACT FROM AUTHOR]

There are many facts about the possible role of gamma-aminobutyric acid (GABA) in the development and differentiation of cells not only in nervous but also in muscle tissue. In the present study, a primary culture of rat skeletal muscle myocytes was used to evaluate the correlation between the content of GABA in the cytoplasm and the processes of myocyte division and their fusion into myotubes. The effect of exogenous GABA on the processes of culture development was also estimated. Since the classical protocol for working with myocyte cultures involves the use of fetal bovine serum (FBS) to stimulate cell division (growth medium) and horse serum (HS) to activate the differentiation process (differentiation medium), the studies were carried out both in the medium with FBS and with HS. It was found that cells grown in medium supplemented with FBS contain more GABA compared to cultures growing in medium supplemented with HS. Addition of exogeneous GABA leads to a decrease in the number of myotubes formed in both media, while the addition of an amino acid to the medium supplemented with HS had a more pronounced inhibitory effect. Thus, we have obtained data indicating that GABA is able to participate in the early stages of skeletal muscle myogenesis by modulating the fusion process. [ABSTRACT FROM AUTHOR]

Simple Summary: Insects have special receptors called RDL that regulate the effects of a neurotransmitter GABA in their nervous system. Interestingly, these receptors are also the main targets of many insecticides used to control pests. We used fruit flies with different variants of the Rdl gene and tested four new types of meta-diamide and isoxazoline insecticides. The results showed that some mutations made the flies less sensitive to certain insecticides, while another mutation made the flies super resistant to all of the insecticides tested. Using computer simulations, we explored how these mutations might be affecting the insecticides' ability to attach. We found that specific areas between parts of the receptor seem to be important for these new insecticides to work. This helps us understand how insects can resist these insecticides and might lead to better ways to control pests in the future. Ionotropic γ-aminobutyric acid (GABA) receptors in insects, specifically those composed of the RDL (resistant to dieldrin) subunit, serve as important targets for commonly used synthetic insecticides. These insecticides belong to various chemical classes, such as phenylpyrazoles, cyclodienes, meta-diamides, and isoxazolines, with the latter two potentially binding to the transmembrane inter-subunit pocket. However, the specific amino acid residues that contribute to the high sensitivity of insect RDL receptors to these novel insecticides remain elusive. In this study, we investigated the susceptibility of seven distinct Drosophila melanogaster Rdl point mutants against four meta-diamide and isoxazoline insecticides: isocycloseram, fluxametamide, fluralaner, and broflanilide. Our findings indicate that, despite exhibiting increased sensitivity to fluralaner in vitro, the RdlI276C mutant showed resistance to isocycloseram and fluxametamide. Similarly, the double-points mutant RdlI276F+G279S also showed decreased sensitivity to the tested isoxazolines. On the other hand, the RdlG335M mutant displayed high levels of resistance to all tested insecticides. Molecular modeling and docking simulations further supported these findings, highlighting similar binding poses for these insecticides. In summary, our research provides robust in vivo evidence supporting the idea that the inter-subunit amino acids within transmembrane M1 and M3 domains form the binding site crucial for meta-diamide and isoxazoline insecticide interactions. This study highlights the complex interplay between mutations and insecticide susceptibility, paving the way for more targeted pest control strategies. [ABSTRACT FROM AUTHOR]

γ-aminobutyric acid (GABA), recognized as a primary inhibitory neurotransmitter within the brain, serves a crucial role in the aging process and in neurodegenerative conditions such as Alzheimer's disease. Research has demonstrated the beneficial effects of GABA, particularly for elderly individuals. Given that elderly individuals often encounter challenges with swallowing food, beverages designed to address dysphagia represent a preferable option for this demographic. Among the different processing techniques, the germination process triggers biochemical changes, leading to an increase in certain nutrients and bioactive compounds (e.g., GABA). Therefore, we attempted to develop a novel functional beverage utilizing germinated brown rice enriched with GABA and studied its nutritional and bio-functional characterization. The optimal conditions (X1, X2, X3 and X4.) were determined: powdered sugar (40 g), chocolate powder (20 g), sodium carboxymethyl cellulose (0.5 g), GBR (220 g), and water (440 mL). The results of storage studies indicated that the germinated-brown-rice-based beverage exhibited favorable nutritional attributes, including increased γ-oryzanol (52.73 ± 1.56%), total phenolic content (26.68 ± 1.56 mg GAE/100 g), niacin (5.17 ± 0.14%), and GABA (42.12 ± 0.63 mg/100 g) levels. Additionally, the beverage demonstrated notable antioxidant activity (74.23 ± 2.37 µmol TE/100 g), suggesting potential health-promoting effects. Sensory evaluation revealed satisfactory acceptability among consumers, highlighting its palatability. Overall, this study elucidates the development of a novel functional beverage utilizing germinated brown rice enriched with GABA, offering promising nutritional and bio-functional characteristics for health-conscious consumers. [ABSTRACT FROM AUTHOR]

[Display omitted] • BDNF from microglia drives neuropathic pain. • Peripheral BDNF drives chronic inflammatory pain. • BDNF does not drive pain in females. In males but not in females, brain derived neurotrophic factor (BDNF) plays an obligatory role in the onset and maintenance of neuropathic pain. Afferent terminals of injured peripheral nerves release colony stimulating factor (CSF-1) and other mediators into the dorsal horn. These transform the phenotype of dorsal horn microglia such that they express P2X4 purinoceptors. Activation of these receptors by neuron-derived ATP promotes BDNF release. This microglial-derived BDNF increases synaptic activation of excitatory dorsal horn neurons and decreases that of inhibitory neurons. It also alters the neuronal chloride gradient such the normal inhibitory effect of GABA is converted to excitation. By as yet undefined processes, this attenuated inhibition increases NMDA receptor function. BDNF also promotes the release of pro-inflammatory cytokines from astrocytes. All of these actions culminate in the increase dorsal horn excitability that underlies many forms of neuropathic pain. Peripheral nerve injury also alters excitability of structures in the thalamus, cortex and mesolimbic system that are responsible for pain perception and for the generation of co-morbidities such as anxiety and depression. The weight of evidence from male rodents suggests that this preferential modulation of excitably of supra-spinal pain processing structures also involves the action of microglial-derived BDNF. Possible mechanisms promoting the preferential release of BDNF in pain signaling structures are discussed. In females, invading T-lymphocytes increase dorsal horn excitability but it remains to be determined whether similar processes operate in supra-spinal structures. Despite its ubiquitous role in pain aetiology neither BDNF nor TrkB receptors represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Dopamine D2 receptor (D2R) is expressed in striatopallidal neurons and decreases forskolin‐stimulated cyclic adenine monophosphate (cAMP) accumulation and gamma‐aminobutyric acid (GABA) release. Dopamine D3 receptor (D3R) mRNA is expressed in a population of striatal D2R‐expressing neurons. Also, D3R protein and binding have been reported in the neuropil of globus pallidus. We explore whether D2R and D3R colocalize in striatopallidal terminals and whether D3R modulates the D2R effect on forskolin‐stimulated [3H]cAMP accumulation in pallidal synaptosomes and high K+ stimulated‐[3H]GABA release in pallidal slices. Previous reports in heterologous systems indicate that calmodulin (CaM) and CaMKII modulate D2R and D3R functions; thus, we study whether this system regulates its functional interaction. D2R immunoprecipitates with CaM, and pretreatment with ophiobolin A or depolarization of synaptosomes with 15 mM of K+ decreases it. Both treatments increase the D2R inhibition of forskolin‐stimulated [3H]cAMP accumulation when activated with quinpirole, indicating a negative modulation of CaM on D2R function. Quinpirole also activates D3R, potentiating D2R inhibition of cAMP accumulation in the ophiobolin A‐treated synaptosomes. D2R and D3R immunoprecipitate in pallidal synaptosomes and decrease after the kainic acid striatal lesion, indicating the striatal origin of the presynaptic receptors. CaM‐kinase II alfa (CaMKIIα) immunoprecipitates with D3R and increases after high K+ depolarization. In the presence of KN62, a CaMKIIα blocker, D3R potentiates D2R effects on cAMP accumulation in depolarized synaptosomes and GABA release in pallidal slices, indicating D3R function regulation by CaMKIIα. Our data indicate that D3R potentiates the D2R effect on cAMP accumulation and GABA release at pallidal terminals, an interaction regulated by the CaM–CaMKIIα system. [ABSTRACT FROM AUTHOR]

The article focuses on the dangers posed by unregulated psychotropic products like kratom, tianeptine, and phenibut, highlighting their availability in retail settings despite lacking FDA approval, which poses significant public health risks such as addiction and overdose. Topics include advocating for stricter regulation, enhancing public awareness, and promoting collaborative research efforts among healthcare organizations to address these hazards effectively.

Ulcerative colitis (UC) is linked with inflammation of the large intestine due to an overactive response of the colon-immune system. UC is associated with weight loss, rectal bleeding, diarrhea, and abdominal pain. Given that c-amino butyric acid (GABA) suppresses immune cell activity and the excitability of colonic afferents, and that there is a decrease in colonic GABA during UC, we hypothesized that UC pain is due to a decrease in the inhibition of colonic afferents. Thus, restoring GABA in the colon will attenuate inflammatory hypersensitivity. We tested this hypothesis in a mouse model of colitis. Colon inflammation was induced with seven days of dextran sodium sulfate (DSS, 3%) in the drinking water. GABA (40 mg/kg) was administered orally for the same period as DSS, and body weight, colon length, colon permeability, clinical progression of colitis (disease activity index or DAI), and colon histological score (HS) were assessed to determine the effects of GABA on colitis. A day after the end of GABA treatment, visceral sensitivity was assessed with balloon distention (of the colon)-evoked visceromotor response and colon samples were collected for the measurement of GABA and cytokines. Treatment with GABA reduced the DSS-induced increase in the colon permeability, DAI, HS, and decrease in body weight and colon length. Furthermore, GABA inhibited the DSS-induced increase in the proinflammatory cytokines tumor necrosis factor-a (TNF-a), interferon-c (IFN-c), interleukin-12 (IL-12), and increased the expression of the anti-inflammatory cytokine IL-10 in the colon tissue. Importantly, GABA reduced DSS-induced visceral hypersensitivity. These data suggest that increasing gastrointestinal levels of GABA may be useful for the treatment of colitis. [ABSTRACT FROM AUTHOR]

The occurrence, inhibitory modulation, and trophic effects of GABA have been identified in the peripheral sympathetic nervous system. We have demonstrated that GABA and acetylcholine (ACh) may colocalize in the same axonal varicosities or be segregated into separate ones in the rat superior cervical ganglia (SCG). Neurotransmitter segregation varies with age and the presence of neurotrophic factors. Here, we explored age-dependent changes in the occurrence and segregation of GABA and ACh in rats ranging from 2 weeks old (wo) to 12 months old or older. Using immunohistochemistry, we characterized the expression of L-glutamic acid decarboxylase of 67 kDa (GAD67) and vesicular acetylcholine transporter (VAChT) in the rat SCG at 2, 4, 8, 12 wo and 12 months old or older. Our findings revealed that GAD67 was greater at 2 wo compared with the other ages, whereas VAChT levels were greater at 4 wo than at 12 wo and 12 months old or older. The segregation of these neurotransmitters was more pronounced at 2 and 4 wo. We observed a caudo-rostral gradient of segregation degree at 8 and 12 wo. Data point out that the occurrence and segregation of GABA and ACh exhibit developmental adaptative changes throughout the lifetime of rats. We hypothesize that during the early postnatal period, the increase in GABA and GABA-ACh segregation promotes the release of GABA alone which might play a role in trophic actions. [ABSTRACT FROM AUTHOR]

Those studying neural systems within the brain have historically assumed that lower-level processes in the spinal cord act in a mechanical manner, to relay afferent signals and execute motor commands. From this view, abstracting temporal and environmental relations is the province of the brain. Here we review work conducted over the last 50 years that challenges this perspective, demonstrating that mechanisms within the spinal cord can organize coordinated behavior (stepping), induce a lasting change in how pain (nociceptive) signals are processed, abstract stimulus-stimulus (Pavlovian) and response-outcome (instrumental) relations, and infer whether stimuli occur in a random or regular manner. The mechanisms that underlie these processes depend upon signal pathways (e.g., NMDA receptor mediated plasticity) analogous to those implicated in brain-dependent learning and memory. New data show that spinal cord injury (SCI) can enable plasticity within the spinal cord by reducing the inhibitory effect of GABA. It is suggested that the signals relayed to the brain may contain information about environmental relations and that spinal cord systems can coordinate action in response to descending signals from the brain. We further suggest that the study of stimulus processing, learning, memory, and cognitive-like processing in the spinal cord can inform our views of brain function, providing an attractive model system. Most importantly, the work has revealed new avenues of treatment for those that have suffered a SCI. [ABSTRACT FROM AUTHOR]

Electroencephalograms (EEGs) display a mixture of rhythmic and broadband fluctuations, the latter manifesting as an apparent 1/f spectral trend. While network oscillations are known to generate rhythmic EEG, the neural basis of broadband EEG remains unexplained. Here, we use biophysical modelling to show that aperiodic neural activity can generate detectable scalp potentials and shape broadband EEG features, but that these aperiodic signals do not significantly perturb brain rhythm quantification. Further model analysis demonstrated that rhythmic EEG signals are profoundly corrupted by shifts in synapse properties. To examine this scenario, we recorded EEGs of human subjects being administered propofol, a general anesthetic and GABA receptor agonist. Drug administration caused broadband EEG changes that quantitatively matched propofol's known effects on GABA receptors. We used our model to correct for these confounding broadband changes, which revealed that delta power, uniquely, increased within seconds of individuals losing consciousness. Altogether, this work details how EEG signals are shaped by neurophysiological factors other than brain rhythms and elucidates how these signals can undermine traditional EEG interpretation. The neural mechanisms that give rise to aperiodic EEG signals remains unclear. Here the authors characterize EEG signals generated by neural processes other than brain rhythms, demonstrating that certain drugs alter EEG signals in ways that confound traditional interpretation. [ABSTRACT FROM AUTHOR]

The systemic administration of sodium oxybate (SXB), the sodium salt of gamma‐hydroxybutyric acid, promotes slow wave activity (SWA, 0.5–4 Hz EEG power) and increases non‐rapid eye movement (NREM) sleep. These effects are mediated by the widely expressed GABAb receptors, and thus, the brain areas targeted by SXB remain unclear. Because slow waves are mainly a cortical phenomenon, we tested here whether systemic SXB promotes SWA by acting directly on the cortex. Moreover, because somatostatin (SOM) + cortical interneurons play a key role in SWA generation, we also assessed their contribution to the effects of SXB. In adult SOM‐Cre mice, the injection of SXB in left secondary motor cortex increased SWA during NREM sleep in the first 30 min post‐injection (11 mice: either sex). SWA, the amplitude and frequency of the slow waves, and the frequency of the OFF periods increased ipsilaterally and contralaterally to the SXB injection in frontal and parietal cortex. All these changes disappeared when the intracortical injection of SXB was preceded by the chemogenetic inhibition of the SOM+ cells. Thus, SXB may promote the slow waves of NREM sleep, at least in part, by acting directly on the cortex, and this effect involves GABAergic SOM+ interneurons. Our working hypothesis is that SXB potentiates the ability of these cells to inhibit all other cortical cell types via a GABAb mechanism, thus promoting the transition from ON to OFF periods during NREM sleep. [ABSTRACT FROM AUTHOR]

γ‐Aminobutyric acid (GABA), as the primary inhibitory neurotransmitter, is extremely important for maintaining healthy brain function, and deviations from GABA homeostasis are related to various brain diseases. Short‐echo‐time (short‐TE) proton MR spectroscopy (1H‐MRS) has been employed to measure GABA concentration from various human brain regions at high magnetic fields. The aim of this study was to investigate the effect of spectral linewidth on GABA quantification and explore the application of an optimized basis‐set preparation approach using a spectral‐linewidth‐matched (LM) basis set in LCModel to improve the reproducibility of GABA quantification from short‐TE 1H‐MRS. In contrast to the fixed‐linewidth basis‐set approach, the LM basis‐set preparation approach, where all metabolite basis spectra were simulated with a linewidth 4 Hz narrower than that of water, showed a smaller standard deviation of estimated GABA concentration from synthetic spectra with varying linewidths and lineshapes. The test–retest reproducibility was assessed by the mean within‐subject coefficient of variation, which improved from 19.2% to 12.0% in the thalamus, from 27.9% to 14.9% in the motor cortex, and from 9.7% to 2.8% in the medial prefrontal cortex using LM basis sets at 7 T. We conclude that spectral linewidth has a large effect on GABA quantification from short‐TE 1H‐MRS data and that using LM basis sets in LCModel can improve the reproducibility of GABA quantification. [ABSTRACT FROM AUTHOR]

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 GABAB receptors on tonic inhibition, which causes changes (due to disinhibition) in network dynamics, leading to synchronous functional oscillations. [ABSTRACT FROM AUTHOR]

Obesity is the excessive accumulation of body fat resulting from impairment in energy balance mechanisms. In this study, we aimed to investigate the mechanism whereby GABA (γ-aminobutyric acid) prevents high-fat diet-induced obesity, and whether it induces lipolysis and browning in white adipose tissue (WAT), using high-fat diet (HFD)-fed obese mice and 3T3-L1 adipocytes. We demonstrated that GABA substantially inhibits the body mass gain of mice by suppressing adipogenesis and lipogenesis. Consistent with this result, histological analysis of WAT demonstrated that GABA decreases adipocyte size. Moreover, we show that GABA administration decreases fasting blood glucose and improves serum lipid profiles and hepatic lipogenesis in HFD-fed obese mice. Furthermore, Western blot and immunofluorescence analyses showed that GABA activates protein kinase A (PKA) signaling pathways that increase lipolysis and promote uncoupling protein 1 (UCP1)-mediated WAT browning. Overall, these results suggest that GABA exerts an anti-obesity effect via the regulation of lipid metabolism. [ABSTRACT FROM AUTHOR]

γ-Aminobutyric acid (GABA) plays important roles in plant development, including the maintenance of fruit quality when applied as postharvest treatment. However, little information is available about the effects of preharvest GABA treatments. Thus, GABA (10, 50 and 100 mM) was applied as foliar spray at key points of fruit development in three sweet cherry cultivars and over two years. The results show that quality parameters, such as total soluble solid content, titratable acidity and firmness were higher in the fruit from GABA-treated trees than in the controls, either at harvest or during four weeks of cold storage. In addition, the total phenolic and total and individual anthocyanin concentrations were also enhanced by GABA treatments and the fruit color was improved. The activities of the antioxidant enzymes catalase, ascorbate peroxidase and peroxidase were also enhanced by the GABA treatments. The most effective concentration was 50 mM, which led to extending the storage period of sweet cherries with high quality traits to up to four weeks, while for the controls this was two weeks. Thus, GABA treatment had a clear effect on delaying the postharvest ripening and senescence processes in sweet cherries, with an additional effect on enhancing the content of bioactive compounds, such as phenolics and anthocyanins, with antioxidant properties and health benefits. [ABSTRACT FROM AUTHOR]

The basolateral amygdala (BLA) regulates mood and associative learning and has been linked to the development and persistence of alcohol use disorder. The GABA B R (gamma-aminobutyric acid B receptor) is a promising therapeutic target for alcohol use disorder, and previous work suggests that exposure to ethanol and other drugs can alter neuronal GABA B R-dependent signaling. The effect of ethanol on GABA B R-dependent signaling in the BLA is unknown. GABA B R-dependent signaling in the mouse BLA was examined using slice electrophysiology following repeated ethanol exposure. Neuron-specific viral genetic manipulations were then used to understand the relevance of ethanol-induced neuroadaptations in the basal amygdala subregion (BA) to mood-related behavior. The somatodendritic inhibitory effect of GABA B R activation on principal neurons in the basal but not the lateral subregion of the BLA was diminished following ethanol exposure. This adaptation was attributable to the suppression of GIRK (G protein–gated inwardly rectifying K+) channel activity and was mirrored by a redistribution of GABA B R and GIRK channels from the surface membrane to internal sites. While GIRK1 and GIRK2 subunits are critical for GIRK channel formation in BA principal neurons, GIRK3 is necessary for the ethanol-induced neuroadaptation. Viral suppression of GIRK channel activity in BA principal neurons from ethanol-naïve mice recapitulated some mood-related behaviors observed in C57BL/6J mice during ethanol withdrawal. The ethanol-induced suppression of GIRK-dependent signaling in BA principal neurons contributes to some of the mood-related behaviors associated with ethanol withdrawal in mice. Approaches designed to prevent this neuroadaptation and/or strengthen GIRK-dependent signaling may prove useful for the treatment of alcohol use disorder. [ABSTRACT FROM AUTHOR]

Loss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging. [ABSTRACT FROM AUTHOR]

Emerging evidence has demonstrated that using a new manufacturing technology to produce γ-aminobutyric acid (GABA)-fortified oolong (GO) tea could relieve human stress and exert versatile physiological benefits. The purpose of this human study was to investigate the therapeutic effects of daily GO tea consumption on improvements in blood pressure, relaxation-related brain waves, and quality of life (QOL) over a period of 28 consecutive days. Total polyphenols, major catechins, and free amino acids were analyzed via an HPLC assay. Changes in heart rate, blood pressure, α brain waves (index of relaxation), and the eight-item QOL score were investigated on days 0, 7, 14, 21, and 28. The chemical analysis results showed that GO tea contained the most abundant amino acids and GABA, contributing to the relaxation activity. Among all study participants, the daily consumption of GO tea could reduce systolic blood pressure on day 21 and diastolic blood pressure on day 28 (p < 0.05 for both). For participants with pre-hypertension, GO tea could effectively reduce heart rate and systolic and diastolic blood pressure on day 28 (p < 0.05). At the end of the study, incremental changes in alpha brain waves and QOL scores were also demonstrated (p < 0.05 for both). This study suggests that GO tea might potentially serve as a natural source for alternative therapy to improve blood pressure, stress relief, and QOL. [ABSTRACT FROM AUTHOR]

Neonatal distribution of the GABAA receptor-associated protein GABARAP and the tubulin βIII isoform (β-III-tubulin) was studied immunohistochemically across the layers of the neocortical somatosensory area in Wistar rats exposed to perinatal hypoxia. The study used a model of human incomplete pregnancy. Newborn rat pups were exposed to hypoxia on day 2 after birth (P2) in a special chamber containing 7.8% O2 in the respiratory mixture. The neocortex was examined at P5 and P10. In P10 control (unexposed) rats, GABARAP content, as assessed by immunostaining density, increased significantly 2-fold in upper neocortical layers II–III and 4-fold in deeper layers IV–V compared to P5 rats. β-III-tubulin was evenly distributed throughout neocortical layers. Rats that survived hypoxic exposure at P2 exhibited a significant increase in GABARAP and β-III-tubulin content in layers II–III at P10 compared to P5. These changes were paralleled by a significant decrease in the content of GABAA receptor subtype (previous data). GABARAP and β-III-tubulin, as well as the GABAA receptor, compose a complex of elements mediating GABA transmission in the neocortex. Hypoxia causes a change in the content of these proteins in the neocortex, leading presumably to a disruption of the inhibitory GABA effects. [ABSTRACT FROM AUTHOR]

Lotilaner ophthalmic solution 0.25% (XDEMVY™), a gamma-aminobutyric acid-gated chloride channel (GABA-Cl) inhibitor selective for mites, is being developed by Tarsus Pharmaceuticals for the treatment of Demodex blepharitis and meibomian gland dysfunction in patients with Demodex lid infestation (Demodex-induced meibomianitis). On 24 July 2023, lotilaner ophthalmic solution 0.25% received its first approval in the USA for the treatment of Demodex blepharitis. The agent is also currently in phase 3 development for Demodex blepharitis in China and phase 2 development for Demodex-induced meibomianitis in the USA. This article summarizes the milestones in the development of lotilaner ophthalmic solution 0.25% leading to this first approval for the treatment of Demodex blepharitis in the USA. [ABSTRACT FROM AUTHOR]

It is well-established that the hypothalamic–pituitary–gonadal (HPG) axis is suppressed due to negative energy balance. However, less information is available on whether kisspeptin neuronal activity contributes to fasting-induced responses. In the present study, female and male mice were fasted for 24 hours or provided food ad libitum (fed group) to determine whether acute fasting is sufficient to modulate kisspeptin neuronal activity. In female mice, fasting attenuated luteinizing hormone (LH) and prolactin (PRL) serum levels and increased follicle-stimulating hormone levels compared with the fed group. In contrast, fasting did not affect gonadotropin or PRL secretion in male mice. By measuring genes related to LH pulse generation in micropunches obtained from the arcuate nucleus of the hypothalamus (ARH), we observed that fasting reduced Kiss1 mRNA levels in female and male mice. In contrast, Pdyn expression was upregulated only in fasted female mice, whereas no changes in the Tac2 mRNA levels were observed in both sexes. Interestingly, the frequency and amplitude of the GABAergic postsynaptic currents recorded from ARH kisspeptin neurons (ARHKisspeptin) were reduced in 24-hour fasted female mice but not in males. Additionally, neuropeptide Y induced a hyperpolarization in the resting membrane potential of ARHKisspeptin neurons of fed female mice but not in males. Thus, the response of ARHKisspeptin neurons to fasting is sexually dependent with a female bias, associated with changes in gonadotropins and PRL secretion. Our findings suggest that GABAergic transmission to ARHKisspeptin neurons modulates the activity of the HPG axis during situations of negative energy balance. [ABSTRACT FROM AUTHOR]

Alchemilla kiwuensis Engl. (Rosaceae) (A. kiwuensis) is an herbaceous plant traditionally used by Cameroonians to treat epilepsy and other central nervous system disorders. The present study evaluated the antiepileptogenic and antiepileptic effects of A. kiwuensis (40 mg/kg, 80 mg/kg) following Pentylenetetrazole (PTZ)-induced kindling as well as its sub-chronic toxicity. Following an initial i.p administration of a challenge dose (70 mg/kg), Wistar rats of both sexes received sub convulsive doses (35 mg/kg) of PTZ every other day, one hour after the oral gavage of animals with treatments, until two consecutive stage 4, in all animals of negative control. Seizure progression, latency, duration, and repetition were noted. Twenty-four hours later, animals were dissected to extract their hippocampi. The resulting homogenates were used to evaluate Malondialdehyde, reduced glutathione, catalase activity, GABA, GABA-Transaminase, glutamate, glutamate transporter 2, IL-1β and TGF-1 β. Sub-chronic toxicity was conducted according to OECD 407 guidelines. The lyophilisate of A. kiwuensis significantly increased the latency of seizure appearance, delayed seizure progression and decreased seizure repetition and duration. Biochemical analysis revealed that the lyophilisate significantly increased the catalase activity, reduced glutathione, GABA, glutamate transporter 2 and TGF-1B levels. The lyophilisate equally caused a significant decreased in the GABA-Transaminase activity, malondialdehyde, and IL-1 β levels. There was no noticeable sign of toxicity. A. kiwuensis possesses antiepileptic and antiepiletogenic effects by enhancing GABAergic neurotransmission and antioxidant properties, coupled to modulation of glutamatergic and neuroinflammatory pathways and is innocuous in a sub-chronic model. These justifies its local use for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Background and Purpose: GABAA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate. Experimental Approach: New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C‐21 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABAA receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulations. Key Results: All seven analogues retained a negative allosteric modulatory capability whilst exhibiting diverse potencies. Interestingly, we observed differential effects on GABA current decay by compounds incorporating either a six‐ (compound 5) or five‐membered heterocyclic ring (compound 6) on C‐21, which was independent of their potencies as inhibitors. We propose that differences in molecular charges, and the targeted binding of analogues to specific states of the GABAA receptor, are the most likely cause of the distinctive functional profiles. Conclusions and Implications: Our findings reveal that heterocyclic addition to inhibitory neurosteroids not only affected their potency and macroscopic efficacy but also affected innate receptor mechanisms that underlie desensitisation. Acute modulation of macroscopic desensitisation will determine the degree and duration of GABA inhibition, which are vital for the integration of neural circuit activity. Discovery of this form of modulation could present an opportunity for next‐generation GABAA receptor drug design and development. [ABSTRACT FROM AUTHOR]

Objectives: Our previous clinical trial showed that etomidate requirements to reach an appropriate level of anesthesia in patients with obstructive jaundice were reduced, which means that these patients are more sensitive to etomidate. However, the mechanism is still not completely clear. The present study was aimed to investigate the mechanism by which bilirubin facilitates etomidate induced sedation. Methods: A bile duct ligation (BDL) rat model was used to simulate obstructive jaundice. Anesthesia sensitivity to etomidate was determined by the time to loss of righting reflex (LORR). Intrathecal injection of bilirubin was used to test the effects of bilirubin on etomidate induced sedation. The modulating effects of bilirubin on GABA responses were studied using the whole-cell patch clamp technique. Results: The time to LORR induced by etomidate was significantly decreased in the BDL groups (p < 0.05), and unconjugated bilirubin in serum and cerebrospinal fluid (CSF) were markedly increased (p < 0.05). The time to LORR induced by etomidate was decreased after intrathecal injection of bilirubin (p < 0.05). A bilirubin concentration of 1.0 μM increased the GABA-induced currents of rat cortical pyramidal neurons (p < 0.05). Furthermore, 1.0 μM bilirubin enhanced GABA-induced currents modulated by etomidate (p < 0.05). Conclusions: Our results demonstrated that pathologic bilirubin in CSF could enhance etomidate induced sedation. The mechanism may be that bilirubin increase the GABA-induced currents of rat pyramidal neurons. [ABSTRACT FROM AUTHOR]

GABA is an amino acid widely found in vertebrates, plants and microorganisms, which is also an important inhibitory neurotransmitter in the central nervous system. Dietary addition of GABA can regulate feed intake, antioxidant performance and immune level of livestock and poultry, and relieve heat stress of animals. The paper reviews the biological function and mechanism of GABA, summarizes the application effect of GABA as feed additive in cow production, in order to provide reference for reasonable application of GABA in ruminant production. [ABSTRACT FROM AUTHOR]

The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin‐4 (AQP4) expressed on the perivascular astrocytic end‐feet. Various factors, such as noradrenaline levels related to the arousal state, influence clearance efficiency, highlighting the possibility that other neurotransmitters additionally modulate this process. To date, the specific role of γ‐aminobutyric acid (GABA) in the glymphatic system remains unknown. We used C57BL/6J mice to observe the regulatory effect of GABA on glymphatic pathway by administering a cerebrospinal fluid tracer containing GABA or its GABAA receptor (GABAAR) antagonist through cisterna magna injection. Then, we employed an AQP4 knockout mouse model to explore the regulatory effects of GABA on glymphatic drainage and further study whether transcranial magnetic stimulation‐continuous theta burst stimulation (cTBS) could regulate the glymphatic pathway through the GABA system. Our data showed that GABA promotes glymphatic clearance in an AQP4‐dependent manner by activating the GABAAR. Furthermore, cTBS was found to modulate the glymphatic pathway by activating the GABA system. Accordingly, we propose that regulating the GABA system by cTBS could modulate glymphatic clearance and provide new insight for clinical prevention and treatment of abnormal protein deposition‐related diseases. [ABSTRACT FROM AUTHOR]

Fluoroquinolones (FQs) are widely used drugs around the world. This is a result of their broad spectrum of antibacterial activity, high bioavailability, and known efficacy. Since they appeared on the market, their prescribing frequency has gradually increased. In 2011, FQs became the third most prescribed class of antibiotics in the US. Widespread use of these drugs resulted in an increasing number of reported side effects. In 2016, the FDA warned about significant side effects, including mental disorders in the form of anxiety, psychotic symptoms, insomnia, and depression. Psychiatric adverse reactions to FQs occur with a frequency of 1 to 4.4% and the mechanism of their formation is not entirely clear. It is believed that the antagonistic effect of FQs on the GABA receptor or interaction with the main receptor for the glutamatergic system—NMDA—is responsible for this. The paper is a structured review of 68 selected publications and the latest summary of CNS adverse effects that occur during FQ use. Prescribers should be aware of the risk factors for FQ toxicity, including elderly patients with underlying medical conditions or receiving concomitant medication; however, these adverse events may also occur in other groups of patients. [ABSTRACT FROM AUTHOR]

The opioid crisis remains a major public health concern, causing significant morbidity and mortality worldwide. Pain is frequently observed among individuals with opioid use disorder (OUD), and the current opioid agonist therapies (OAT) have limited efficacy in addressing the pain needs of this population. We reviewed the most promising non-opioid analgesic therapies for opioid-dependent individuals synthesising data from randomised controlled trials in the Medline database from December 2022 to March 2023. Ketamine, gabapentin, serotoninergic antidepressants, and GABAergic drugs were found to be the most extensively studied non-opioid analgesics with positive results. Additionally, we explored the potential of cannabinoids, glial activation inhibitors, psychedelics, cholecystokinin antagonists, alpha-2 adrenergic agonists, and cholinergic drugs. Methodological improvements are required to advance the development of novel analgesic strategies and establish their safety profile for opioid-dependent populations. We highlight the need for greater integration of experimental pain methods and abuse liability assessments, more granular assessments of prior opioid exposure, greater uniformity of pain types within study samples, and a particular focus on individuals with OUD receiving OAT. Finally, future research should investigate pharmacokinetic interactions between OAT and various non-opioid analgesics and perform reverse translation basic experiments, particularly with methadone and buprenorphine, which remain the standard OUD treatment. [ABSTRACT FROM AUTHOR]

Unconsciousness maintained by GABAergic anesthetics, such as propofol and sevoflurane, is characterized by slow-delta oscillations (0.3 to 4 Hz) and alpha oscillations (8 to 14 Hz) that are readily visible in the electroencephalogram. At higher doses, these slow-delta–alpha (SDA) oscillations transition into burst suppression. This is a marker of a state of profound brain inactivation during which isoelectric (flatline) periods alternate with periods of the SDA patterns present at lower doses. While the SDA and burst suppression patterns have been analyzed separately, the transition from one to the other has not. Using state–space methods, we characterize the dynamic evolution of brain activity from SDA to burst suppression and back during unconsciousness maintained with propofol or sevoflurane in volunteer subjects and surgical patients. We uncover two dynamical processes that continuously modulate the SDA oscillations: alpha-wave amplitude and slow-wave frequency modulation. We present an alpha modulation index and a slow modulation index which characterize how these processes track the transition from SDA oscillations to burst suppression and back to SDA oscillations as a function of increasing and decreasing anesthetic doses, respectively. Our biophysical model reveals that these dynamics track the combined evolution of the neurophysiological and metabolic effects of a GABAergic anesthetic on brain circuits. Our characterization of the modulatory dynamics mediated by GABAergic anesthetics offers insights into the mechanisms of these agents and strategies for monitoring and precisely controlling the level of unconsciousness in patients under general anesthesia. [ABSTRACT FROM AUTHOR]

The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent find- ings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotrans- mitter corelease in implementing behaviorally relevant computations. [ABSTRACT FROM AUTHOR]

Origanum vulgare L., a medicinal and aromatic herb, has been used for hundreds of years. This plant contains valuable chemical compounds that can be used as medicine for treatment. On the other hand, a gradual increase in the planet's average temperature could negatively affect the growth and the composition of the O. vulgare. For this reason, in this study, the effect of two protective compounds, namely salicylic acid (SA) and gamma-aminobutyric acid (GABA), on temperature and salinity stress conditions was investigated. Oregano plants were grown at 23/12°C temperature as control and 27/16°C heat stress in the greenhouse (16/8 h photoperiod) for one months. The plants were treated with GABA and SA and subjected to salt stress for 30 days. Subsequently, the plant's physiological, biochemical, and phytochemical characteristics were examined. The results showed that all studied traits (in control and treated samples) were significantly different at 27°C, from 23°C. In addition, the highest amount of thymol and carvacrol were detected from plants grown at 27°C. In regards to salinity, stressed- plants had less damage to membrane stability and H2O2 level, when treated with GABA or SA. This study revealed that both SA and GABA compounds had an exellent protective effect on temperature and salt stress on O. vulgare. Based on enzyme-pigment evaluations and secondary metabolites, SA showed a better protective effect on temperature effects and GABA in a saline environment. In general, using these compounds can provide better conditions for the growth and preservation of O. vulgare chemical compounds. However, it certainly requires more experiments to find the signal pathways involved in these processes. [ABSTRACT FROM AUTHOR]

Introduction There is a need for novel anxiolytics with improved side effect profiles compared to benzodiazepines. A promising candidate with alternative pharmacodynamics is the translocator protein ligand, etifoxine. Methods To get further insight into its mechanisms of action and side effects compared to the benzodiazepine alprazolam, we performed a double-blind, placebo-controlled, repeated-measures study in 36 healthy male subjects. Participants were examined for trait anxiety and side effects and underwent repeated transcranial magnetic stimulation (TMS) assessments, including motor evoked potentials (MEP), short intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP). Results We observed attenuation of MEPs by alprazolam but not by etifoxine. SICI was not significantly affected by alprazolam or etifoxine. However, the response pattern indicated a lowered SICI threshold after the administration of etifoxine and alprazolam compared to the placebo. ICF and CSP were influenced by neither medication. Alprazolam led to higher sedation and subjective impairment of concentration compared to etifoxine. Individual anxiety trait scores did not affect TMS parameters. Discussion This study indicated a favorable side effect profile of etifoxine in healthy volunteers. Moreover, it revealed differential GABA-related effects on neuromuscular function by means of TMS. The side effects and TMS profile of etifoxine are compatible with the involvement of neurosteroidogenesis and a predominant α3 subunit modulation compared to alprazolam. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA) transaminase—also called GABA aminotransferase (GABA-AT)—deficiency is a rare autosomal recessive disorder characterized by a severe neonatal-infantile epileptic encephalopathy with symptoms such as seizures, hypotonia, hyperreflexia, developmental delay, and growth acceleration. GABA transaminase deficiency is caused by mutations in GABA-AT, the enzyme responsible for the catabolism of GABA. Mutations in multiple locations on GABA-AT have been reported and their locations have been shown to influence the onset of the disease and the severity of symptoms. We examined how GABA-AT mutations influence the structural stability of the enzyme and GABA-binding affinity using computational methodologies such as molecular dynamics simulation and binding free energy calculation to understand the underlying mechanism through which GABA-AT mutations cause GABA-AT deficiency. GABA-AT 3D model depiction was carried out together with seven individual mutated models of GABA-AT. The structural stability of all the predicted models was analyzed using several tools and web servers. All models were evaluated based on their phytochemical values. Additionally, 100 ns MD simulation was carried out and the mutated models were evaluated using RMSD, RMSF, Rg, and SASA. gmxMMPBSA free energy calculation was carried out. Moreover, RMSD and free energy calculations were also compared with those obtained using online web servers. Our study demonstrates that P152S, Q296H, and R92Q play a more critical role in the structural instability of GABA-AT compared with the other mutated models: G465R, L211F, L478P, and R220K. [ABSTRACT FROM AUTHOR]

Background: Artemisinin (ART) is a compound synthesized from the plant Artemisia annua. This compound has various therapeutic effects and is widely used against malaria. However, ART is known to have modulating effects on GABA (gamma-aminobutyric acid) receptors, which are thought to be responsible for epileptic seizures. This study aimed to evaluate the effects of ART on anti-convulsant, antioxidant, and cholinesterase enzyme activities in Pentylenetetrazole (PTZ)-induced kindling model in mice. Materials and Methods: In the experiment, 6 groups were formed, with seven mice in each group. Mice received a total of 11 intraperitoneal injections of PTZ (35 mg/kg). On the last day of the study, a threat dose of PTZ (75 mg/kg) was administered. In addition, behavioral analysis tests (Locomotor activity and rotarod) and biochemical measurements were performed. Results: Compared with the PTZ group, ART attenuated the severity of the kindling, decreasing the seizure score. ART and VPA reversed increased oxidative stress. Decreased cholinesterase enzymes in PTZ-induced brain increased with ART treatment. While the PTZ application impaired locomotor activity in mice, the ART application provided improvement in locomotor activity. However, no significant difference was found between the groups in the motor performance of the mice. Conclusion: The findings show that ART may have the potential to prevent PTZ-induced oxidative stress, neurochemical changes, behavioral disorders, and seizures. [ABSTRACT FROM AUTHOR]