Gamma-aminobutyric Acid Research Articles

γ-Aminobutyric acid alleviates litchi thaumatin-like protein-induced inflammation and reduces gut microbial translocation

Previous research reported litchi thaumatin-like protein (LcTLP) could lead to inflammation, which is a factor causing the adverse reactions after excessive intake of litchi. As a main amino acid in litchi pulp, γ-aminobutyric acid (GABA) was found with anti-inflammatory effect. Therefore, this study aimed to investigate the effects of GABA on LcTLP-induced inflammation through RAW264.7 macrophages and C57BL mice models. In vitro study showed GABA could effectively regulate the level of inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-10, and prostaglandin E2) and Ca2+ in cells, and inhibit the phosphorylation of p65, IκB, p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). These results indicate GABA alleviated inflammation through nuclear factor-κB and mitogen-activated protein kinase pathways signaling pathways. In vivo experiment was performed to verify the anti-inflammatory effect of GABA, and the results demonstrated that GABA reduced the inflammation and oxidative stress in the liver of LcTLP-treated mice, as it down-regulated the pro-inflammatory cytokines, malondialdehyde, aspartate transferase, and alanine transaminase. The relative expression of phosphorylated p38, JNK and ERK in mice liver with GABA treatment were reduced to 65 %, 39 % and 80 % of the control group, respectively. Furthermore, GABA treatment enriched probiotic bacteria and decreased pathogenic bacteria in mice gut, which reveals GABA could effectively reduce the translocation of gut microbiota.

The Effects of Variation in the GABAA Receptor Gene on Anxious Depression are Mediated by the Functional Connectivity Between the Amygdala and Middle Frontal Gyrus.

γ-aminobutyric acid (GABA) and its main receptor, the GABAA receptor, are implicated in major depressive disorder (MDD). Anxious depression (AD) is deemed to be a primary subtype of MDD. The amygdala and the dorsolateral prefrontal cortex (DLPFC) are key brain regions involved in emotional regulation. These regions contain the most GABAA receptors. Although the GABAergic deficit hypothesis of MDD is generally accepted, few studies have demonstrated how GABAA receptor gene polymorphisms affect the functions of specific brain regions, in particular, the amygdala and the DLPFC. The sample comprised 83 patients with AD, 70 patients with non-anxious depression (NAD), and 62healthy controls (HC).All participants underwent genotyping for polymorphisms of GABAA receptor subunit genes, followed by a resting-state fMRI scan. The HAMD-17 was used to evaluate the severity of MDD. ANOVA was performed to obtain the difference in the imaging data, GABAA receptor multi-locus genetic profile scores (MGPS), and HAMD-17 scores among three groups, then the significant differences between AD and NAD groups were identified. Mediating effect analysis was used to explore the role of functional connectivity (FC) between the amygdala and DLPFC in the association between the GABAA receptor gene MGPS and AD clinical features. Compared with the NAD group, the AD group had a higher GABAA receptor MGPS. AD patients exhibited a negative correlation between the MGPS and FC of the right centromedial (CM) subregion, and the right middle frontal gyrus (MFG). A negative correlation was also observed between the MGPS and anxiety/somatic symptoms. More importantly, the right CM and right MFG connectivity mediated the association between the GABAA receptor MGPS and anxiety/somatic symptoms in patients with AD. The decreased FC between the right MFG and right CM subregion mediates the association between GABAA receptor MGPS and AD.

Sub-nanometer size level regulation of biomimetic channels in porous membrane for high-capacity removal of toxic dye contaminants

Organic dyes are an important chemical with a market demand of millions of tons. However, their massive emissions, especially alkaline dye contaminants, have caused serious disruption of the ecosystem and even cancers. Inspired by bionic mass transfer, several amino acid fragments (carboxylic acid, γ-aminobutyric acid, and glutamic acid) are introduced into the 2.5 nm-pore size cavity through in-situ polymerization. The flexible amino acid chains facilitate the transport of guest molecules into the channels, accelerating their movement within the porous framework. These flexible chains are implanted into a 2.5 nm pore cavity, forming a 0.8–1.5 nano-meter-sized confinement space, bringing about the strong absorption capability for alkaline contaminants. Notably, LNU-74-glutamic acid achieves an ultra-fast absorption rate for toxic dye contaminants (4.74 g g−1h−1), as well as the highest capacity per unit area among all reported porous adsorbents, including porous carbons, metal–organic frameworks, porous polymers. After encapsulation in commercial polymer, the mixed-matrix membrane reveals (LNU-74-glutamic acid@MMM) a rejection rate greater than 98 % in various real water environments at permeation flux of ∼320 L m−2h−1, including strong acid/alkali, river water, and seawater.

Enhanced γ-aminobutyric acid production by Co-culture fermentation with Enterococcus faecium AB157 and Saccharomyces cerevisiae SC125

γ-aminobutyric acid (GABA), a non-protein amino acid, is a major inhibitory neurotransmitter within the human nervous system. Research on enhancing GABA production through the co-culture of yeast and lactic acid bacteria is limited, and the intricacies of their interactions and the mechanisms behind GABA enhancement are not fully elucidated. In this study, five yeast strains from Sichuan Pao Cai were co-cultured with Enterococcus faecium AB157 to increase GABA content, and it was found that combining E. faecium AB157 with Saccharomyces cerevisiae SC125 at a 4:1 ratio, along with 12 g/L MSG, at 35 °C, optimized GABA production to reach levels of 6.57 g/L. Within the co-culture system, there was a notable increase in both glutamate decarboxylase activity (GAD) and medium pH, while the activity of Autoinducer-2 (AI-2) remained stable. Furthermore, the cell-free supernatants (CFS) from S. cerevisiae SC125 were able to enhance GABA production by E. faecium AB157, up to 4.61 g/L. RNA sequencing revealed that the GABA biosynthetic pathways and quorum sensing (QS) in co-fermentation on E. faecium AB157 were upregulated, and the ATP synthesis and arginine deiminase pathway were downregulated compare to the pure culture of E. faecium AB157.

Exploration of potential biomarkers for prurigo nodularis based on plasma-metabolome analysis.

Prurigo nodularis (PN) is a chronic and debilitating skin disease with severe itching that negatively impacts patients' quality of life and mental state. However, the treatment options for PN remain limited. Global metabolomics analysis can offer effective information on energy metabolism, pathogenesis and potential diagnostic biomarkers. No study on metabolomic analysis of PN has been reported. To further understand the mechanisms of PN and analyse the plasma metabolite profiles in patients with PN. Targeted-metabolome analysis of 306 metabolites in plasma from 18 patients with PN and 19 healthy controls was performed using Liquid Chromatography-tandem Mass Spectrometer analysis. We identified 31 differential metabolites. Most acylcarnitines, long-chain fatty acids, alpha-aminobutyric acid, hydroxybutyric acid and lactic acid among these metabolites were up-regulated in patients with PN; in contrast, glucaric acid, suberic acid, bile acid derivatives and most amino acids were down-regulated. Positive correlations exist between glucaric acid and itching severity and acylcarnitines and insomnia. Suberic acid and the Investigator's Global Assessment (IGA) scores correlate negatively. Metabolite variation reflects the dysregulation of energy metabolism and chronic systematic inflammation in PN. Several metabolites, such as glucaric acid, suberic acid and acylcarnitines, merit further study as potential biomarkers of disease severity in PN.

Assessment of sedative activity of fraxin: In vivo approach along with receptor binding affinity and molecular interaction with GABAergic system.

Insomnia is a sleep disorder in which you have trouble falling and/or staying asleep. This research aims to evaluate the sedative effects of fraxin (FX) on sleeping mice induced by thiopental sodium (TS). In addition, a molecular docking study was conducted to investigate the molecular processes underlying these effects. The study used adult male Swiss albino mice and administered FX (10 and 20 mg/kg, i.p.) and diazepam (DZP) (2 mg/kg) either separately or in combination within the different groups to examine their modulatory effects. After a period of 30 min, the mice that had been treated were administered (TS: 20 mg/kg, i.p.) to induce sleep. The onset of sleep for the mice and the length of their sleep were manually recorded. Additionally, a computational analysis was conducted to predict the role of gamma-aminobutyric acid (GABA) receptors in the sleep process and evaluate their pharmacokinetics and toxicity. The outcomes indicated that FX extended the length of sleep and reduced the time it took to fall asleep. When the combined treatment of FX and DZP showed synergistic sedative action. Also, FX had a binding affinity of -7.2 kcal/mol, while DZP showed -8.4 kcal/mol. The pharmacokinetic investigation of FX demonstrated favorable drug-likeness and strong pharmacokinetic characteristics. Ultimately, FX demonstrated a strong sedative impact in the mouse model, likely via interacting with the GABAA receptor pathways.

Role of GABAA receptors of the dorsomedial periaqueductal grey on blood pressure and heart rate in the anesthetized rat.

The midbrain dorsomedial periaqueductal grey column (dmPAG) is involved in the regulation of cardiovascular responses. Due to the presence of Gamma-Aminobutyric acid (GABA) receptors in the dmPAG, this study aimed to investigate the role of GABAA receptors in the dmPAG on cardiovascular parameters and its possible peripheral mechanisms. The left femoral artery was cannulated, and systolic arterial pressure (SAP), mean arterial pressure (MAP) and heart rate (HR) were recorded using a Power lab system. Microinjection of saline, muscimol and bicuculline (BIC) was done using a stereotaxic device. Also, the peripheral mechanisms dependent on GABAA receptors in the dmPAG were evaluated by intravenous (i.v.) injection of hexamethonium (Hexa) and atropine (Atr) 5min before the BIC. Results showed that BIC significantly increased ∆SAP, ∆MAP and ∆HR than the control group, but muscimol had no significant effect. Injection of Hex significantly attenuates the effect of BIC on ∆SAP and ∆MAP. Atr (i.v) significantly increased the ∆HR, and when injected before BIC microinjection, it did not affect the cardiovascular responses induced by BIC. These findings show that GABAA receptors of the dmPAG have inhibitory effects on the cardiovascular system, which are mostly mediated by the sympathetic system.

PSVII-17 The effects of gamma-aminobutyric acid on growth performance, antioxidant capacity, rumen fermentation, and diarrhea in newborn calves before weaning

PSVII-17 The effects of gamma-aminobutyric acid on growth performance, antioxidant capacity, rumen fermentation, and diarrhea in newborn calves before weaning

Use Of Ketamine In Refractory Status Epilepticus With Hemodynamic Instability

The use of benzodiazepines, such as midazolam, as a last-resort treatment for refractory status epilepticus is widely practiced, particularly in patients who are hemodynamically stable. However, as the dosage of this antiepileptic agent is increased, it potentiates γ-aminobutyric acid (GABA) activity, which can lead to hypotension and subsequently necessitate the administration of vasopressor agents, especially in cases involving hemodynamic instability, as illustrated by this case where a young man who arrived at the emergency department with complaints of epileptic seizures and was already on regular anti-epileptic medications. During a seizure episode in the department, he was administered intravenous Lorazepam according to standard protocol to stop the seizure, and then placed on an IV infusion of Midazolam. However, his hemodynamics became unstable due to the side effects of the benzodiazepines administered. To address this instability, the decision was made to initiate an infusion of Ketamine along with a low dose of Midazolam. This combination successfully terminated the epileptic activity and stabilized his hemodynamics. In these instances, either concurrent or standalone administration of N-methyl-D-aspartate (NMDA) receptor antagonists might prove beneficial for managing refractory status epilepticus. For example, ketamine infusion can inhibit the reuptake of catecholamines into the systemic circulation, thereby aiding in the maintenance of blood pressure in hemodynamically unstable patients. The initial application of a combined third-line therapy, which involves blocking NMDA receptors while simultaneously enhancing GABAergic activity, appears promising for the management of refractory status epilepticus

Multi-Omics Integrative Analyses Identified Two Endotypes of Hip Osteoarthritis.

(1) Background: Osteoarthritis (OA) is a heterogeneous disorder, and subgroup classification of OA remains elusive. The aim of our study was to identify endotypes of hip OA and investigate the altered pathways in the different endotypes. (2) Methods: Metabolomic profiling and genome-wide genotyping were performed on fasting blood. Transcriptomic profiling was performed on RNA extracted from cartilage samples. Machine learning methods were used to identify endotypes of hip OA. Pathway analysis was used to identify the altered pathways between hip endotypes and controls. GWAS was performed on each of the identified metabolites. Transcriptomic data was used to examine the expression levels of identified genes in cartilage. (3) Results: 180 hip OA patients and 120 OA-free controls were classified into three clusters based on metabolomic data. The combination of arginine, ornithine, and the average value of 7 lysophosphatidylcholines had an area under the curve (AUC) of 0.97 (95% CI: 0.96-0.99) to discriminate hip OA from controls, and the combination of γ-aminobutyric acid, spermine, aconitic acid, and succinic acid had an AUC of 0.96 (95% CI: 0.94-0.99) to distinguish two hip OA endotypes. GWAS identified 236 SNPs to be associated with identified metabolites at GWAS significance level. Pro-inflammatory cytokine levels were significantly different between two endotypes (all p < 0.05). (4) Conclusions: Hip OA could be classified into two distinct molecular endotypes. The primary differences between the two endotypes involve changes in pro-inflammatory factors and energy metabolism.

Abstract 53: Chronic Angiotensin-(1-7) Treatment May Enhance GABAergic Neurotransmission onto Melanocortin-4 Receptor Neurons in The Hypothalamic Paraventricular Nucleus in a Sex-Specific Manner

Angiotensin (Ang)-(1-7) is a protective hormone of the renin-angiotensin system that lowers blood pressure in animal models of cardiovascular disease; however, the precise mechanisms remain incompletely understood. Recent data from our laboratory suggests that blood pressure lowering effects of Ang-(1-7) may involve the arcuate nucleus of the hypothalamus (ARC). We have shown that Ang-(1-7) activates proopiomelanocortin (POMC)-containing neurons in the ARC. While ARC POMC neuron activation canonically increases blood pressure by stimulating melanocortin-4 receptors (MC4R) in the hypothalamic paraventricular nucleus (PVN), these neurons also release the inhibitory neurotransmitter GABA. Selective activation of these GABAergic POMC neurons could serve as a novel mechanism to lower blood pressure. In this study, we hypothesized that Ang-(1-7) treatment inhibits PVN MC4R neuron activity via enhanced GABAergic function. To test this, male and female MC4R-GFP mice were implanted with osmotic mini pumps at 14 weeks of age and treated chronically with either Ang-(1-7) (400 ng/kg/min) or saline. After six weeks of drug administration, action potential firing of PVN MC4R-expressing neurons was examined using cell attached electrophysiology. To assess GABAergic function, changes in action potential firing frequency following bath application of the GABA A receptor antagonist bicuculline (10 μm) were compared between Ang-(1-7) and saline treated animals (n=4-6 mice/group). While Ang-(1-7) did not alter baseline firing frequency of MC4R PVN neurons in male mice (1.5±0.6 vs. 1.1±0.3 Hz saline; p=0.630, unpaired t-test), it enhanced bicuculline responsiveness as indicated by a greater peak increase in action potential firing frequency (156.9±18.0 vs. 106.2±6.8 % saline; p=0.013). In female mice, Ang-(1-7) increased baseline action potential firing frequency of PVN MC4R neurons (1.5±0.4 vs. 0.3±0.1 Hz saline; p=0.026) but did not alter bicuculline responsiveness (111.0±5.3 vs. 143.2±25.3 % saline; p=0.241). Overall, our data suggest that Ang-(1-7) enhances GABAergic neurotransmission onto PVN MC4R neurons in a sex-specific manner. These data provide new insight into the neural mechanisms of Ang-(1-7), which could have implications for understanding the beneficial cardiovascular effects of this hormone. Additional studies are needed to examine this inhibitory neurocircuit in the context of hypertension as well as precise mechanisms underlying the observed sex differences.

Drug Intoxication Associated with Pregabalin: An Autopsy Case

Pregabalin is a gamma-aminobutyric acid analogue; it has been used clinically as an anticonvulsant and analgesic agent. Few documented reports exist of deaths resulting from pregabalin overdose. This report discusses a case of pregabalin intoxication in a 27-year-old male, who was found unconscious in a prison and later pronounced dead at a local hospital. An autopsy and toxicological analysis revealed the presence of pregabalin, alprazolam, diazepam, escitalopram, fluoxetine, lorazepam, bromazepam, flunitrazepam, zolpidem, and piroxicam. The concentrations of pregabalin and alprazolam were 10.3 mg/L and 0.10 mg/L in heart blood, and 11.4 mg/L and 0.08 mg/L in femoral blood, respectively. The other detected drugs were within therapeutic concentrations. Ethyl alcohol was not detected in the blood. Although the pregabalin concentration was within the therapeutic or toxic range, the concomitant use of other drugs, particularly benzodiazepines and zolpidem, likely enhanced its toxicity. Based on the autopsy findings and toxicological results, the cause of death was determined to be multidrug intoxication, including pregabalin. Although pregabalin is generally considered safe and deaths from its use alone are very rare, it can be fatal at relatively low blood concentrations when combined with opioids or other medications. The rising use of pregabalin in Korea increases the risk of overdose deaths, similar to this case. Therefore, in forensic practice, the possibility of such fatalities should be considered when pregabalin is detected.

Evaluating the dynamic effects of complex probiotics as cellulase replacements during fermentation of apple pomace

Apple pomace, an abundant agricultural by-product with low utilization rates, often leads to environmental pollution if not properly managed. This study aimed to enhance the nutritional value of apple pomace by comparing the effects of solid-state fermentation using complex probiotics and cellulase preparation. Additionally, the study investigated the dynamic changes in various components throughout the fermentation process with complex probiotics. The results of single-strain solid-state fermentation tests indicated that Lactiplantibacillus plantarum DPH, Saccharomyces cerevisiae SC9, and Bacillus subtilis C9 were the optimal strains for fermenting the most effective substrate combination, comprising 73 % apple pomace and 20 % millet bran. The strains (complex probiotics) and a cellulase preparation were used for the solid-state fermentation of the apple pomace mixture for nine days, respectively. The contents of acid detergent fiber, neutral detergent fiber, hemicellulose, and insoluble dietary fiber decreased by up to 9.99 %, 9.59 %, 23.21 %, and 14.34 %, respectively. In contrast, the content of soluble dietary fiber significantly increased by up to 29.74 %. Both methods reduced cellulose crystallinity and modified the substrate's surface structure, resulting in a looser arrangement. Fermentation with complex probiotics for three or six days increased the abundance of lactic acid bacteria, which comprised >87 % of the total microbial population. Concurrently, the abundance of detrimental bacteria, such as Salmonella, Acetobacter, Escherichia, and Pantoea, significantly decreased. Furthermore, fermentation with complex probiotics for six or nine days enhanced antioxidant properties, leading to a significant increase in beneficial metabolites, including amino acids, organic acids, gamma-aminobutyric acid, serotonin. In conclusion, complex probiotics can effectively substitute for cellulase preparation in the solid-state fermentation of apple pomace, with a six-day fermentation period yielding optimal results. This study provides valuable insights into enhancing the value of apple pomace in the feed industry and the effective application of agro-industrial by-products.

New antidepressant mechanism of Yueju Pill: Increasing ghrelin level by inhibiting gastric mTOR/S6K signaling pathway and sensitizing hippocampal GHS-R

Background and aimYueju Pill (YJ) not only has good antidepressant effect but also can effectively treat digestive system diseases. However,it remains unclear whether the mechanism of antidepressant action of YJ is related to the peripheral digestive system. The purpose of this study was to elucidate the antidepressant mechanism of YJ on ghrelin level based on gastric mTOR/S6K signal pathway and sensitized hippocampal Ghrelin/GHS-R system in CUMS mice. Experimental procedureThe depression model was induced by chronic unpredictable mild stress (CUMS) and social isolation. The antidepressant effect of YJ was observed by behavioral experiment and hemodynamic experiments. Ghrelin levels in in hippocampus and blood were measured by Elisa kit, and the mRNA of ghrelin in mice stomach was measured by Real-time Quantitative PCR (RT-qPCR). The activation level of gastric mTOR/S6K signal pathway was detected by Western Blot (WB). Rapamycin (Rapa) and L-Leucine (L-Leu) were used to verify the effects of YJ on the synthesis and release of ghrelin. The activity of GHS-R in hippocampus was observed by immunofluorescence. Hippocampal neuronal damage was evaluated by HE staining and Nissl staining. The level of central neurotransmitter was measured by liquid chromatograph mass spectrometer (LC-MS). Results and conclusionYJ ameliorates CUMS-induced depressive-like behavior by inhibiting the gastric mTOR/S6K signaling pathway and increasing GHR expression in the mouse stomach. However, these effects of YJ could be resisted by L-Leu (a mTOR receptor agonist). Further studies have shown that YJ can sensitize the Ghrelin/GHS-R system in the hippocampus, with significant neuroprotective effects, and is also involved in regulating the levels of key neurotransmitters (5-hydroxytryptamine, Dopamine and γ-aminobutyric acid) in depressive-like states.

Timing of interventions to control neuronal chloride elevation in a model of neonatal seizures after hippocampal injury.

Following hypoxic-ischemic (HI) brain injury, neuronal cytoplasmic chloride concentration ([Cl-]i) increases, potentially contributing to depolarizing γ-aminobutyric acid (GABA) responses, onset of seizures, and the failure of antiepileptic drugs that target inhibitory chloride-permeable GABAA receptors. Post-HI seizures characteristically begin hours after injury, by which time substantial accumulation of [Cl-]i may have already occurred. In immature neurons, a major pathway for Cl- influx is the reversible Na+-K+-2Cl- cotransporter NKCC1. Spontaneous neuronal network, neuronal [Cl-]i, and GABA activity were determined in hippocampal preparations from neonatal Clomeleon and SuperClomeleon/DLX-cre mice to test whether blocking NKCC1 earlier after oxygen-glucose deprivation (OGD) injury would more effectively ameliorate the increase in [Cl-]i, ictallike epileptiform discharges (ILDs), and the failure of the GABAergic anticonvulsant phenobarbital. In vitro, murine intact hippocampi were free of ILDs for 12 h after preparation. Transient OGD resulted in a gradual increase in [Cl-]i, depolarizing action of GABA, and facilitation of neuronal network activity. Spontaneous ILDs began 3-5 h after injury. Blocking NKCC1 with 2-10 μmol·L-1 bumetanide reduced [Cl-]i equally well when applied up to 10 h after injury. Whereas phenobarbital or bumetanide applied separately were less effective when applied later after injury, ILDs were successfully suppressed by the combination of phenobarbital and bumetanide regardless of the number of prior ILDs or delay in application. The present age-specific group studies demonstrate that after OGD, NKCC1 transport activity significantly contributes to progressive [Cl-]i accumulation, depolarizing action of GABA, and delayed onset of ILDs. In this neonatal model of neuronal injury and ILDs, earlier treatment with bumetanide alone more efficiently recovered control baseline [Cl-]i and depressed epileptiform discharges. However, there was no time dependency to the anti-ictal efficacy of the combination of phenobarbital and bumetanide. These invitro results suggest that after perinatal injury, early pre-emptive treatment with phenobarbital plus bumetanide would be as efficacious as late treatment after seizures are manifest.

Inhibitory Actions of Potentiating Neuroactive Steroids in the Human α1β3γ2L γ-Aminobutyric Acid Type A Receptor.

The γ-aminobutyric acid type A (GABAA) receptor is modulated by a number of neuroactive steroids. Sulfated steroids and 3β-hydroxy steroids inhibit, while 3α-hydroxy steroids typically potentiate the receptor. Here, we have investigated inhibition of the α1β3γ2L GABAA receptor by the endogenous neurosteroid 3α-hydroxy-5β-pregnan-20-one (3α5βP) and the synthetic neuroactive steroid 3α-hydroxy-5α-androstane-17β-carbonitrile (ACN). The receptors were expressed in Xenopus oocytes. All experiments were done using two-electrode voltage-clamp electrophysiology. In the presence of low concentrations of GABA, 3α5βP and ACN potentiate the GABAA receptor. To reveal inhibition, we conducted the experiments on receptors activated by the combination of a saturating concentration of GABA and propofol to fully activate the receptors and mask potentiation, or on mutant receptors in which potentiation is ablated. Under these conditions, both steroids inhibited the receptor with IC50s of ∼13 μM and maximal inhibitory effects of 70-90%. Receptor inhibition by 3α5βP was sensitive to substitution of the α1 transmembrane domain (TM) 2-2' residue, previously shown to ablate inhibition by pregnenolone sulfate. However, results of coapplication studies and the apparent lack of state dependence suggest that pregnenolone sulfate and 3α5βP inhibit the GABAA receptor independently and through distinct mechanisms. Mutations to the neurosteroid binding sites in the α1 and β3 subunits statistically significantly, albeit weakly and incompletely, reduced inhibition by 3α5βP and ACN. SIGNIFICANCE STATEMENT: The heteromeric GABAA receptor is inhibited by sulfated steroids and 3β-hydroxy steroids, while 3α-hydroxy steroids are considered to potentiate the receptor. We show here that 3α-hydroxy steroids have inhibitory effects on the α1β3γ2L receptor, which are observed in specific experimental settings and are expected to manifest under different physiological conditions.

Gamma-aminobutyric acid and glutamate/glutamine levels in the dentate nucleus and periaqueductal gray in new daily persistent headache: a magnetic resonance spectroscopy study

BackgroundMagnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence.MethodsTwenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed.ResultsThere were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16).ConclusionsThe results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms.

Increasing germination and antioxidant activity of aged wheat and triticale grains by priming with gamma-aminobutyric acid

During storage, elevated temperature and humidity cause accelerated aging and deterioration of seeds of various plant species, including important cultivated cereals, such as wheat and triticale. Germination of old seeds can be facilitated by seed priming with physiologically active substances that correct the pro/antioxidant balance and reduce the development of oxidative stress. Gamma-aminobutyric acid (GABA) is a regulatory compound with direct and indirect antioxidant effects. However, its effect on the germination of grains of cereals with low germination has not been extensively studied. The objective of this study was to examine the impact of GABA priming on the germination of aged grains of winter bread wheat (Triticum aestivum ‘Scorpion’) and winter triticale (×Triticosecale ‘Raritet’). the extent of oxidative stress and the state of the antioxidant system in seedlings. The results indicated that a three-hour treatment of grains with GABA at the optimal concentration (1 mM) resulted in a significant (18–21%) increase in germination energy and seed germination rate, as well as an increase in the biomass of shoots and roots of seedlings of both species. Concomitantly, the influence of GABA resulted in a reduction in oxidative stress markers, including the generation of superoxide anion radicals, hydrogen peroxide content, and the product of lipid peroxidation malondialdehyde. In wheat seedlings, the total content of phenolic compounds increased, while in triticale seedlings, the content of anthocyanins increased almost twofold. In seedlings derived from GABA-primed grains, catalase activity was also significantly elevated in the absence of notable alterations in superoxide dismutase and peroxidase activity. It was postulated that GABA priming is a promising approach for enhancing the germination of cereal seeds with diminished sowing quality.

Medium Formulation and Optimisation of Fermentation Condition Enhancing γ-aminobutyric Acid (GABA) Biosynthesis by Lactiplantibacillus plantarum B7

Extensive studies on γ-aminobutyric acid (GABA) over decades highlight its significant physiological and pharmacological effects on humans. GABA produced using microbe is favoured compared to enzymatic and chemical methods due to operational ease and reduced harmful pollutant formation. This study focused on increasing γ-aminobutyric acid (GABA) biosynthesis from Lactiplantibacillus plantarum B7, employing a multi-step optimisation strategy. An unoptimised cultivation approach yielded a maximum GABA of 11.68 ± 0.04 g/L and viable cell count of 10.47 ± 0.01 log CFU/mL at 48 h. A nutrient-rich medium was developed through single-parameter optimisation, comprising 1%, 2.5% and 0.0002% of glucose, yeast extract and each trace element (CaCO3, KI, and Tween 80) respectively. Temperature, pH, incubation period, initial concentration of monosodium glutamate (MSG) and pyridoxal-5’-phosphate (PLP) demonstrated significant contributions towards GABA production and cell growth as determined using a two-level factorial design. Steepest ascent identified optimal conditions (36°C, pH 5.5, 370 mM MSG, and 0.7 mM PLP), resulting in 30.50 g/L GABA and 11.51 log CFU/mL at 60 h. Further refinement via a central composite experiment yielded optimal conditions (temperature-35.6°C, pH-5.66, initial MSG concentration-335.61 mM, PLP concentration-0.723 mM) with improved GABA production (32.18 g/L) and cell growth (11.52 log CFU/mL) over 63.66 h. Therefore, this approach utilising lactic acid bacteria capable of GABA synthesis holds promise for mass-produced, enhanced-functional foods.

Faecalibacterium prausnitzii, FOS and GOS loaded synbiotic reverses treatment-resistant depression in rats: Restoration of gut-brain crosstalk

Alterations in commensal gut microbiota, such as butyrate-producing bacteria and its metabolites, have been linked to stress-related brain disorders, including depression. Herein, we investigated the effect of Faecalibacterium prausnitzii (ATCC-27766) administered along with fructooligosaccharides (FOS) and galactooligosaccharides (GOS) in a rat model of treatment-resistant depression (TRD). The behavioral changes related to anxiety-, anhedonia- and despair-like phenotypes were recorded employing elevated plus maze, sucrose-preference test, and forced-swim test, respectively. Rats exposed to unpredictable chronic mild-stress (UCMS) and adrenocorticotropic hormone (ACTH) injections exhibited a TRD-like phenotype. Six-week administration of F. prausnitzii and FOS + GOS ameliorated TRD-like conditions in rats. This synbiotic treatment also restored the decreased levels of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate in the fecal samples of TRD rats. Synbiotic-recipient TRD rats displayed an increased abundance of Lactobacillus helveticus, Lactobacillus hamsteri, and Ruminococcus flavefaciens. Moreover, more mucus-producing goblet cells were seen in the colon of synbiotic-treated rats, suggesting improved gut health. The synbiotic treatment effectively modulated neuroinflammation by reducing proinflammatory cytokines (IFN-γ, TNF-α, CRP, and IL-6). It normalized the altered levels of key neurotransmitters such as serotonin, gamma-aminobutyric acid, noradrenaline, and dopamine in the hippocampus and/or frontal cortex. The enhanced expression of brain-derived neurotrophic factor, tryptophan hydroxylase 1, and serotonin transporter-3 (SERT-3), and reduced levels of indoleamine 2,3-dioxygenase 1 (IDO-1) and kynurenine metabolite were observed in the synbiotic-treated group. We suggest that F. prausnitzii and FOS + GOS-loaded synbiotic may reverse the TRD-like symptoms in rats by positively impacting gut health, neuroinflammation, neurotransmitters, and gut microbial composition.