Gamma-aminobutyric Acid Levels Research Articles

Anthocyanin Extract From Purple Sweet Potato Improving Neurotransmitter and Locomotor in Chronic Stressed-mice

Background: Prolonged stress plays an essential role in depression disorder through brain inflammation and neurotransmitter imbalances. The natural plant antioxidant is promising to resist the negative impact of stress. Objectives: This study aimed to analyze the effect of total anthocyanin (ANC) extracts from purple sweet potatoes (PSP) on brain neurotransmitters, inflammation, and locomotor behavior in the chronic-stressed mice model. Methods: Twenty male adult BALB/c mice were assigned to control, stress (STR), STR+ANC (10 mg/kg body weight [BW]), STR+ANC (20 mg/kg BW), and STR+ANC (40 mg/kg BW). Restraint stress was applied 2 h/d for 14 days. The enzyme-linked immunosorbent assay (ELISA) was performed to measure brain dopamine, gamma-aminobutyric acid (GABA), and corticosterone levels. The locomotor behavior was analyzed using an open field test before and after ANC treatment. In silico, molecular docking was carried out between ANC and monoamine oxidase-B (MAO-B) enzyme. Results: Administration of ANC decreased brain corticosterone levels. The dopamine neurotransmitter decreased in the stress-induced group and increased following ANC treatment. Increased GABA levels were observed in the stressed and treated groups. Locomotor analysis showed reduced total distance movement and velocity after ANC treatment. Molecular prediction showed that ANC can inhibit the MAO-B enzymes. Conclusion: The ANC extracted from PSP relieved brain inflammation and modified the neurotransmitters of dopamine and GABA, affecting the locomotor function of chronically stressed-induced mice. Furthermore, in vivo studies are necessary to evaluate the molecular mechanism of ANC from PSP in chronic stress exposure, particularly on MAO enzyme regulation.

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Acupuncture modulation of the ACE/Ang II/AT1R and ACE2/Ang(1-7)/MasR pathways in the rostral ventrolateral medulla reduces sympathetic output and prevents cardiac injury caused by SHR hypertension.

Acupuncture can reduce blood pressure, heart rate (HR), and ameliorate cardiac damage by modulating the excitability of the sympathetic nervous system, but the exact mechanism of this effect remains unclear. This study investigated the potential mechanisms of acupuncture in the treatment of cardiac damage in hypertension. Spontaneously hypertensive rats (SHR) were used as the hypertension model with Wistar-Kyoto rats as the control. Manual acupuncture, electroacupuncture, and metoprolol were used as interventions. Systolic and diastolic blood pressure (SBP, DBP) plus HR were monitored with cardiac structure determined using Masson staining. Angiotensin II (Ang II) and norepinephrine in myocardium were detected with ELISA as was Ang(1-7) and gamma aminobutyric acid (GABA) in the rostral ventrolateral medulla (RVLM). Expression of mRNA for collagen type I (Col-I), Col-III, actin α1 (ACTA1), and thrombospondin 4 (THBS4) in myocardium was detected using real-time PCR. Expression of angiotensin converting enzyme (ACE), Ang II, angiotensin II type 1 receptor (AT1R), ACE2, and Mas receptor (MasR) proteins in RVLM was monitored using western blot. After manual acupuncture and electroacupuncture treatment, SHRs showed decreased SBP, DBP and HR, reduced myocardial damage. There was decreased expression of the ACE/Ang II/AT1R axis, and increased expression of the ACE2/Ang(1-7)/MasR axis within the RVLM. GABA levels were increased within the RVLM and norepinephrine levels were decreased in myocardial tissue. Metoprolol was more effective than either manual acupuncture or electroacupuncture. Acupuncture directed against hypertensive cardiac damage may be associated with regulation of ACE/Ang II/AT1R and the ACE2/Ang(1-7)/MasR pathway within the RLVM to reduce cardiac sympathetic excitability.

Mulberry leaf extract exhibits multiple anti-diabetic activities and alleviates dysglycemia, systemic inflammation, hepatic steatosis, and xenobiotic metabolism abnormalities in type 2 diabetic mice

Mulberry leaves can be processed into a tea rich in polyphenols and gamma-aminobutyric acid (GABA) with health benefits. This study aimed to investigate the anti-diabetic effects of mulberry leaf extracts. Potential hypoglycemic and anti-glycation activities were evaluated in vitro. The in vivo therapeutic efficacy was assessed in type 2 diabetic mice, with GABA and exendin-4 serving as reference anti-diabetic agents. The ethanol extract of mulberry leaves was found to contain higher levels of GABA and polyphenols than the water extract. Both extracts exhibited multiple anti-diabetic biological activities. Regarding in vivo therapeutic effects, incorporating 3% (g/g) mulberry leaf extract into the diet for 8 weeks improved glycemic control, insulin sensitivity, serum glucagon like peptide-1 levels, hepatic steatosis and xenobiotic metabolism abnormalities. Additionally, the ethanol extract had a more pronounced effect on immunity. In conclusion, mulberry leaves could be considered a sustainable dietary material to alleviate symptoms of type 2 diabetes.

Differential strain sensitivity to low-dose anxiolytic diazepam in anxiety-related behaviour in male Wistar and Wistar-Kyoto, a rat model of endogenous depression

Objectives: Treatment resistant depression (TRD) prevails among individuals with major depressive disorder (MDD) with comorbid anxiety. The Wistar Kyoto (WKY) rat strain, which demonstrates exaggerated vulnerability to anxiety, has recently been suggested as a model for TRD with similar pathophysiology to MDD, non-responsiveness to antidepressants but responsive to deep brain stimulation and ketamine. At the clinical level, TRD is associated with reduced occipital cortical levels of Gamma-AminoButyric Acid (GABA), with a reduction in spontaneous GABAergic synaptic activity reported in WKY. Diazepam (DZP), a GABA agonist, is a widely used anxiolytic, so the present study was carried out to evaluate its efficacy through a low dose, oral administration in male WKY rats, with the progenitor strain Wistar, serving as vehicular control. Materials and Methods: Adult Wistar and WKY rats were treated with 1 mg/kg body weight DZP administered per os (p. o.) for 10 days. From the 6th day, rats were exposed to a comprehensive battery of behavioural paradigms, including novelty-based open field (OPF), anxiogenic elevated plus maze (EPM), light-dark box (LDB) and the stress coping behaviour assessing forced swim test (FST). Results: DZP reversed the EPM-induced anxiety in Wistars by increasing open-arm duration (P &lt; 0.05), entries (P &lt; 0.05) and exploratory behaviour (P &lt; 0.01) while concomitantly decreasing closed-arm duration (P &lt; 0.05) and entries (P &lt; 0.05), with no effect in WKY. DZP also reduced latency to the dark zone (P &lt; 0.05) in LDB and increased swimming behaviour in FST (P &lt; 0.05) in Wistars, with no effect in WKY. Baseline strain differences were observed with reduced exploratory behaviour in OPF (P &lt; 0.01), open arm entries (P &lt; 0.01) and head dips (P &lt; 0.01) in EPM and swimming (P &lt; 0.05) in FST in WKY as compared to Wistars. Strain differences persisted also in the DZP-treated groups where, as compared to matched Wistars, WKY demonstrated reduced open arm duration (P &lt; 0.05), entries (P &lt; 0.001) and head dips (P &lt; 0.001) and increased closed arm duration (P &lt; 0.001) and entries (P &lt; 0.001) in the EPM. WKY also showed reduced time spent (P &lt; 0.05) and entries (P &lt; 0.01) into the light zone and increased time spent in the dark zone (P &lt; 0.05) of LDB. Further, WKY showed increased immobility (P &lt; 0.05) during habituation and reduced swimming behaviour (P &lt; 0.001) during the test. Conclusion: Strain-specific differences and increased baseline anxiety levels in WKY, as compared to Wistars, induced differential effects of DZP with drug-induced effects observed in Wistars but not in WKY, furthering the treatment resistant aspect of this model. DZP efficacy, therefore, varies in different rat strains and manifests in differential strain-specific responses emanating from exaggerated vulnerability to stress. Results also indicated differential sensitivity of tested paradigms to the anxiolytic activity of DZP and stressed the use of a battery of tests that enable a teasing out of anxiety and depression. However, further studies are needed that would unravel GABAergic differences at the receptor level, such as differential receptor binding affinities, underlying gene polymorphisms and the implications thereof for this TRD model.

Optimisation of fermentation conditions for the production of gamma-aminobutyric acid (GABA)-rich soy sauce

This study addresses the challenge of enhancing gamma-aminobutyric acid (GABA) content in soy sauce through optimized fermentation condition. Using a multiple starter culture, consisting of Aspergillus oryzae strain NSK, Bacillus cereus strain KBC and Tetragenococcus halophilus strain KBC, the incubation conditions including the percentage of bacterial inoculum (10, 15 and 20 %), pH (3, 5 and 7) and agitation speed (100, 150 and 200 rpm) were optimized through Response Surface Methodology (RSM). Under the optimal conditions (20 % inoculum, pH 7 and stirring at 100 rpm), the multiple starter culture generated 128.69 mg/L of GABA after 7 days and produced 239.08 mg/L of GABA after 4 weeks of fermentation, which is 36 % higher than under non-optimized conditions (153.48 mg/L). Furthermore, sensory analysis revealed high consumer acceptance of the fermented soy sauce than the control (soy sauce without any treatment and additional bacteria) and commercial soy sauce. Consumers indicated that the starter culture offered an improved umami taste and reduced bitter, sour and salty flavours compared to the commercial product. Under optimal fermentation conditions determined by RSM statistical analysis, the multiple starter culture is able to produce high levels of GABA and is more likely to be accepted by consumers. The findings of this research have the potential to impact the food sector by offering a functional soy sauce with added health benefits and also being well-received by consumers.

Whole-genome analysis, evaluation and regulation of in vitro and in vivo GABA production from Levilactobacillus brevis YSJ3

Gamma-aminobutyric acid (GABA) produced by lactic acid bacteria (LAB) is safe and has several health benefits. Levilactobacillus brevis YSJ3 was selected from 110 LAB. It exhibited the highest in vitro GABA production level of 970.10 μg/mL. Whole-genome analysis revealed that L. brevis YSJ3 contained gadR, gadC, gadB and gadA. Furthermore, the Luedeking–Piret model was fitted, which indicated that GABA production was divided into three stages. The gadR 0079, gadC 0080, and gadB 0081 were confirmed to promote GABA synthesis. Moreover, 55 metabolites, particularly those involved in arginine metabolism, were significantly different at 6 and 20 h of cultivation. Notably, L. brevis YSJ3 significantly improved sleep in mice and increased GABA levels in the mice's gut compared with the control group. This suggests that the oral administration of L. brevis YSJ3 improves sleep quality, probably by increasing intestinal GABA levels. Overall, L. brevis YSJ3 was confirmed as a GABA-producing strain in vitro and in vivo, making it a promising probiotic candidate for its application in food and medicine.

Region-specific changes in brain glutamate and gamma-aminobutyric acid across the migraine attack in children and adolescents.

In patients with migraine, an excitation-inhibition imbalance that fluctuates relative to attack onset has been proposed to contribute to the underlying pathophysiology of migraine, but this has yet to be explored in children and adolescents. This prospective, observational, cohort study examined glutamate and gamma-aminobutyric acid (GABA) levels across the phases of a migraine attack and interictally in children and adolescents using magnetic resonance spectroscopy. Macromolecule-suppressed GABA (sensorimotor cortex and thalamus) and glutamate (occipital cortex, sensorimotor cortex, and thalamus) were measured in children and adolescents (10-17 years) with a migraine diagnosis with or without aura 4 times over 2 weeks. Linear mixed-effects models examined changes in glutamate and GABA during the 72 hours leading up to, and after the onset of an attack. We found significant region-specific changes in glutamate and GABA. Specifically, sensorimotor GABA significantly increased leading up to the headache phase, whereas glutamate significantly decreased following the headache onset in the occipital cortex and the thalamus. Post hoc analyses examined the 24 hours leading up to or following the onset of the headache phase. In the 24 hours before the headache onset, sensorimotor glutamate, occipital glutamate, and thalamic GABA decreased. In the 24 hours post headache onset, sensorimotor glutamate continued to decrease. Our results suggest changes in glutamate and GABA that are consistent with the thalamocortical dysrhythmia hypothesis. These findings provide insight into developmental migraine pathophysiology and may open future avenues for treatment targets specific to children and adolescents.

Regulation of gut microbiota and serum neurotransmitters in mice by Streptococcus thermophilus GA8- and Lacticaseibacillus rhamnosus HAO9-fermented milk containing high levels of gamma-aminobutyric acid.

Gamma-aminobutyric acid (GABA) is an important neurotransmitter in the human body, with several negative emotions reported as being associated with GABA dysregulation. This study investigates the safety and modulatory effects of GABA-enriched milk, fermented by Streptococcus thermophilus GA8 and Lacticasebacillus rhamnosus HAO9, on the gut microbiota and neurotransmitter profiles in mice. Through rigorous culturing and fermentation processes, we achieved consistent GABA production in milk, with concentrations reaching 4.6 and 8.5 g L-1 for GA8-fermented and co-fermented milk, respectively, after 48 h. Using SPF male C57BL/6J mice, we administered either mono-culture or combined-culture milk treatments and monitored physiological impacts. The treatments did not affect mouse body weight but induced significant changes in gut microbiota composition. Beta diversity analysis revealed distinct microbial profiles between treatment groups, highlighting fermentation-specific microbial shifts, such as an increase in Verrucomicrobia for the GA8 group and a modulation in Saccharibacteria_genera_incertae_sedis for the GA8 + HAO9 group. Serum neurotransmitter levels were elevated in both treatment groups, with significant increases in l-glutamine, l-tryptophan and, notably, serotonin hydrochloride in the GA8 + HAO9 group. Correlation analysis identified a positive association between specific bacterial genera and neurotransmitter levels, suggesting a probiotic effect on neuroactive substances. These findings suggest that fermented milk has potential as a probiotic supplement for mood improvement and stress relief, highlighting its role in modulating the gut-brain axis. © 2024 Society of Chemical Industry.

Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.

The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far. This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status. We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability. The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.

Evaluation of Gamma-Aminobutyric Acid (GABA) as a Functional Feed Ingredient on Growth Performance, Immune Enhancement, and Disease Resistance in Olive Flounder (Paralichthys olivaceus) under High Stocking Density.

Gamma-aminobutyric acid (GABA) is a non-protein amino acid that is found in the brain and central nervous system of animals as an inhibitory neurotransmitter. It has been shown to have a variety of physiological functions, including stress reduction and immune enhancement. This study investigated the effects of dietary supplementation with GABA on growth, serum biochemistry, innate immunity, and disease resistance in juvenile olive flounders (Paralichthys olivaceus) challenged with Edwardsiella tarda under high-stocking density. A control diet and three experimental diets were prepared, with 150 mg/kg (GABA150), 200 mg/kg (GABA200), and 250 mg/kg (GABA250) of GABA added to each diet, respectively. Each experimental diet was fed to olive flounders in triplicate with an initial weight of 12.75 g ± 0.3 g in 40 L tanks at two stocking densities: normal density (20 fish/tank) and high density (40 fish/tank). After 8 weeks of the feeding trial, growth, feed utilization, whole-body proximate compositions, blood analyses, and non-specific immune responses were measured, and challenge tests were performed. There were no significant differences in the weight gain (WG) and specific growth rate (SGR) among fish fed the GABA-supplemented diets at the two stocking densities. However, the normal-density groups showed significantly higher WG and SGR than the high-density groups (p < 0.05). There was no significant difference in feed efficiency and protein efficiency ratio among all groups. Moreover, there was no significant difference in the whole-body proximate composition analysis (p > 0.05). There were no significant differences in cortisol levels in fish fed the GABA at both densities, but the high-density group showed a significantly higher cortisol than the low-density group. Blood GABA significantly increased in a dose-dependent manner regardless of the density groups (p < 0.05). Superoxide dismutase activity showed significantly higher levels than the control group, but there was no significant effect of the stocking densities in fish fed the GABA diets (p < 0.05). Myeloperoxidase activities in fish fed the GABA200 and GABA250 diets showed significantly higher levels at both of the stocking densities (p < 0.05). Lysozyme activity was significantly higher in the GABA150 group than in the CON, GABA200, and GABA250 groups (p < 0.05). After 15 days of challenge tests with Edwardsiella tarda, the cumulative survival rates of the GABA150, GABA200, and GABA250 groups were significantly higher than that of the CON group (p < 0.05). The results suggested that the optimal dietary GABA level for juvenile olive flounder culture is 150 mg/kg, regardless of rearing density, to enhance growth, immunity, and disease resistance.

Increasing Ambient GABA Levels in the Hippocampus to Improve Cognition in a Mouse Model of Schizophrenia: A Research Protocol

Introduction: Schizophrenia is a complex psychiatric disorder characterized by cognitive, positive, and negative symptoms, with cognitive impairments significantly affecting learning, memory, and executive functions. The hippocampus, particularly the CA1 region, is a critical area of interest due to its role in learning and memory and its dysfunction in schizophrenia. This protocol explores the effects of increasing ambient Gamma-Aminobutyric Acid (GABA) levels in the CA1 region on cognitive functions in a Methylazoxymethanol Acetate (MAM) model of schizophrenia. Methods: Utilizing a two-by-two factorial design, male Sprague-Dawley rats undergo either a sham or MAM treatment, followed by a control or GABA modulation intervention. The study will employ GABA transporter inhibitor Tiagabine to increase ambient GABA levels and assess its impact on neuronal excitability and cognitive function. Behavioural assessments will include the Morris water maze and the Attentional set-shifting test to evaluate spatial memory and cognitive flexibility. Histological examinations and electrophysiological measurements will provide insights into structural and functional changes in the hippocampus. Results: The results are expected to demonstrate neurodevelopmental disruptions in MAM-treated offspring and improvements in cognitive performance following GABA modulation. Enhanced spatial memory and cognitive flexibility are anticipated in MAM-treated rats with GABA modulation, as evidenced by performance in the Morris water maze and Attentional set-shifting test. Electrophysiological recordings are likely to show increased tonic inhibition in the CA1 region. Discussion: This study aims to extend the understanding of tonic inhibition in schizophrenia treatment. By focusing on ambient GABA modulation, the research could offer novel insights into therapeutic strategies for schizophrenia, especially in enhancing cognitive functions. However, the translational applicability of intracerebral administration of uptake inhibitors like Tiagabine poses a significant challenge, highlighting the need for future research in more clinically viable methods of GABA modulation. Conclusion: This study was designed to contribute to schizophrenia research, particularly in understanding cognitive impairments and developing potential therapeutic strategies targeting the GABAergic system. The proposed findings could pave the way for novel treatments, improving the quality of life for individuals with schizophrenia.

High-Caloric Diets in Adolescence Impair Specific GABAergic Subpopulations, Neurogenesis, and Alter Astrocyte Morphology

We compared the effects of two different high-caloric diets administered to 4-week-old rats for 12 weeks: a diet rich in sugar (30% sucrose) and a cafeteria diet rich in sugar and high-fat foods. We focused on the hippocampus, particularly on the gamma-aminobutyric acid (GABA)ergic system, including the Ca2+-binding proteins parvalbumin (PV), calretinin (CR), calbindin (CB), and the neuropeptides somatostatin (SST) and neuropeptide Y (NPY). We also analyzed the density of cholinergic varicosities, brain-derived neurotrophic factor (BDNF), reelin (RELN), and cyclin-dependent kinase-5 (CDK-5) mRNA levels, and glial fibrillary acidic protein (GFAP) expression. The cafeteria diet reduced PV-positive neurons in the granular layer, hilus, and CA1, as well as NPY-positive neurons in the hilus, without altering other GABAergic populations or overall GABA levels. The high-sugar diet induced a decrease in the number of PV-positive cells in CA3 and an increase in CB-positive cells in the hilus and CA1. No alterations were observed in the cholinergic varicosities. The cafeteria diet also reduced the relative mRNA expression of RELN without significant changes in BDNF and CDK5 levels. The cafeteria diet increased the number but reduced the length of the astrocyte processes. These data highlight the significance of determining the mechanisms mediating the observed effects of these diets and imply that the cognitive impairments previously found might be related to both the neuroinflammation process and the reduction in PV, NPY, and RELN expression in the hippocampal formation.

Aberrant auditory metabolite levels and topological properties are associated with cognitive decline in presbycusis patients.

Presbycusis has been reported as related to cognitive decline, but its underlying neurophysiological mechanism is still unclear. This study aimed to investigate the relationship between metabolite levels, cognitive function, and node characteristics in presbycusis based on graph theory methods. Eighty-four elderly individuals with presbycusis and 63 age-matched normal hearing controls underwent magnetic resonance spectroscopy, functional magnetic resonance imaging scans, audiological assessment, and cognitive assessment. Compared with the normal hearing group, presbycusis patients exhibited reduced gamma-aminobutyric acid and glutamate levels in the auditory region, increased nodal characteristics in the temporal lobe and precuneus, as well as decreased nodal characteristics in the superior occipital gyrus and medial orbital. The right gamma-aminobutyric acid levels were negatively correlated with the degree centrality in the right precuneus and the executive function. Degree centrality in the right precuneus exhibited significant correlations with information processing speed and executive function, while degree centrality in the left medial orbital demonstrated a negative association with speech recognition ability. The degree centrality and node efficiency in the superior occipital gyrus exhibited a negative association with hearing loss and speech recognition ability, respectively. These observed changes indicate alterations in metabolite levels and reorganization patterns at the brain network level after auditory deprivation.

Green supported of silver nanoparticles on the surface of reduced graphene oxide: Investigation of its anti-epileptic activity on experimental models of epilepsy in mice

This research demonstrated a novel, simple and environmentally safe process for the fabrication of graphene/silver composite using Malva sylvestris flower extract as a capping and reducing agent. Initially, the Malva sylvestris flower was used to make modified reduced graphene oxide that was coated by extract. The phytochemical groups of extract that have poylphenolic function can act as the green reducing agent for capping and reducing Ag ions on the surface of rGO (Reduced Graphene Oxide) to make the desired rGO/M.S./Ag NPs nanocomposite. The FT-IR, TEM, FE-SEM-EDX and XRD results confirmed the successful fabrication of the desired nanocomposite. The efficacy of the rGO/M.S./Ag NPs was first tested using the 6-Hz-induced seizure model. Subsequently, its effectiveness was assessed against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Additionally, the impact of the potent rGO/M.S./Ag NPs nanocomposite on Gamma amino butyric acid (GABA) levels in the brain was investigated to elucidate its potential mechanism of action. Furthermore, the effective rGO/M.S./Ag NPs nanocomposite underwent an actophotometer test to evaluate its potential to induce deficits in locomotor activity. During the 6-Hz seizure test, the rGO/M.S./Ag NPs nanocomposite demonstrated a significant and dose-dependent reduction in 6-Hz-induced seizures at doses of 30 and 90 µg/kg. Subsequently, the rGO/M.S./Ag NPs nanocomposite was assessed in MES and PTZ models. Interestingly, rGO/M.S./Ag NPs provided substantial and dose-dependent protection against MES (P < 0.01) and PTZ-induced (P < 0.01) seizures in mice. The rGO/M.S./Ag NPs nanocomposite exhibited a notable increase in brain GABA levels (P < 0.01) compared to the control, while showing no significant change in locomotor activity across all tested doses. Notably, a higher dose of rGO/M.S./Ag NPs nanocomposite (90 µg/kg, p.o.) and Diazepam (5 mg/mg, p.o.) completely prevented convulsions in all anticonvulsant tests. These results indicate that the rGO/M.S./Ag NPs nanocomposite possesses significant anticonvulsant properties, with one potential mechanism being the enhancement of GABA levels in the brain.

GABA and Executive functions in ASD

Gamma-aminobutyric acid (GABA) is a neurotransmitter critically involved in various psychological and behavioral processes. This review highlights the impact of GABAergic dysfunction within specific brain regions on a range of mental disorders, executive processes, self-control, and behavioral regulation.Reductions in GABAergic neurotransmission within distinct brain regions have been consistently associated with several mental health conditions. Within the context of anxiety disorders, depression, and post-traumatic stress disorder (PTSD), alterations in GABAergic function contribute to symptomatology. GABA plays a pivotal role in anxiety and mood regulation, with its impairment linked to symptoms of depression and mood disorders. Dysfunctional GABAergic transmission also contributes to fear dysregulation and features of PTSD. In terms of executive functions, GABAergic neurotransmission affects working memory, attentional control, and inhibitory regulation. Changes in GABA levels have been linked to decision-making abilities, impulsivity, and attention deficits, especially in conditions like attention deficit hyperactivity disorder (ADHD). GABA further plays a crucial role in self-control mechanisms by regulating impulsivity and prefrontal cortex functionality. Substance use disorders, often accompanied by impaired self-control, are significantly influenced by GABAergic system changes. Additionally, GABA's involvement in anxiety and emotional management affects the control of emotional responses. Behavioral control is modulated by GABAergic action in motor circuitry, where GABA provides inhibitory control for motor actions. Spontaneity, aggression, and stress are influenced by GABAergic dysfunction, impacting behavioral control. In the realm of attentional control, GABAergic neurotransmission influences selective attention and sensory salience, maintaining a balance between neural stimulation and inhibition. The study also explores executive function deficits in individuals with Autism Spectrum Disorder (ASD) in relation to GABA levels within specific brain regions. Moreover, GABA and its network connectivity contribute to individual variations in sensory responsiveness, emphasizing the dynamic role of GABA in the phenotypic heterogeneity of ASD. In summary, this research underscores the critical role of GABAergic neurotransmission within specific brain regions in various psychological disorders, executive functions, self-control, behavioral regulation, and attentional processes. Understanding the directional influence of GABAergic changes on behavior and mental health conditions can pave the way for more targeted interventions in neuropsychiatric disorders.

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia

Schizophrenia (SCZ) is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. The etiology behind the disorder remains elusive although it is hypothesized to be associated with the aberrant response to neurotransmitters, such as dopamine and glutamate. Therefore, investigating the link between dysregulated metabolites and distorted neurodevelopment holds promise to offer valuable insights into the underlying mechanism of this complex disorder. In this study, we aimed to explore a presumed correlation between the transcriptome and the metabolome in a SCZ model based on patient-derived induced pluripotent stem cells (iPSCs). For this, iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at various developmental stages, reflecting neuroepithelial-like cells, radial glia, young and mature neurons. The samples were analyzed by both RNA-sequencing and targeted metabolomics and the two modalities were used to construct integrative networks in silico. This multi-omics analysis revealed significant perturbations in the polyamine and gamma-aminobutyric acid (GABA) biosynthetic pathways during rosette maturation in SCZ lines. We particularly observed the downregulation of the glutamate decarboxylase encoding genes GAD1 and GAD2, as well as their protein product GAD65/67 and their biochemical product GABA in SCZ samples. Inhibition of ornithine decarboxylase resulted in further decrease of GABA levels suggesting a compensatory activation of the ornithine/putrescine pathway as an alternative route for GABA production. These findings indicate an imbalance of cortical excitatory/inhibitory dynamics occurring during early neurodevelopmental stages in SCZ. Our study supports the hypothesis of disruption of inhibitory circuits to be causative for SCZ and establishes a novel in silico approach that enables for integrative correlation of metabolic and transcriptomic data of psychiatric disease models.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Acorus calamus Linn.: A novel neuroprotective approach for traumatic brain injury in Drosophila melanogaster

BackgroundTraumatic brain injury (TBI) causes substantial mortality and morbidity globally. Current treatments only alleviate symptoms and do not halt secondary injury progression. ObjectivesEvaluate the neuroprotective potential of Acorus calamus Linn. (AC) in a Drosophila melanogaster model of high-impact TBI. MethodsFruit flies (Drosophila melanogaster) of the Oregon R + strain were administered hydroalcoholic extracts of Acorus calamus Linn. (HAEAC) at concentrations of 25 and 50 µg/mL, 24 h and continuously for 72 h, respectively, following TBI induction. Mortality rate, locomotor function, neurotransmitter levels, and oxidative stress markers were assessed at 24 and 72 h post-injury as outcomemeasures. ResultsAC significantly reduced post-TBI mortality and improved locomotor function in a dose-dependent manner. Additionally, AC increased acetylcholinesterase, gamma-aminobutyric acid, serotonin, and dopamine levels while reducing glutamate. It also boosted antioxidant activity (superoxide dismutase, glutathione, and catalase) and lowered markers of oxidative damage (malondialdehyde, nitrite). ConclusionsAC mitigated behavioral deficits, oxidative damage, and neurotransmitter imbalance in fruit flies after TBI. These findings indicate AC may be more effective than individual drugs for TBI therapy. Further research into its neuroprotective phytochemicals is warranted.

Effect of Oxygen-Glucose Deprivation of Microglia-Derived Exosomes on Hippocampal Neurons: A Study on miR-124 and Inflammatory Cytokines.

Stroke is a cerebrovascular disease that threatens human health. Developing safe and effective drugs and finding therapeutic targets has become an urgent scientific problem. The aim of this study was to investigate the effect of oxygen-glucose deprivation of the microglia-derived exosome on hippocampal neurons and its relationship to miR-124 in the exosome. We incubated hippocampal neurons with exosomes secreted by oxygen-glucose deprivation/ reoxygenation (OGD/R) microglia. The levels of glutamic acid (GLU) and gamma-aminobutyric acid (GABA) in the culture supernatant were detected by ELISA. CCK-8 was used to measure neuronal survival rates. The mRNA levels of TNF-α and IL-6 were detected by RT-qPCR to evaluate the effect of exosomes on neurons. RT-qPCR was then used to detect miR-124 in microglia and their secreted exosomes. Finally, potential targets of miR-124 were analyzed through database retrieval, gene detection with dual luciferase reporters, and western blotting experiments. The results showed that the contents of GLU, TNF-α and IL-6 mRNA increased in the supernatant of cultured hippocampal neurons, the content of GABA decreased, and the survival rate of neurons decreased. Oxygen-glucose deprivation increases miR-124 levels in microglia and their released exosomes. miR-124 acts as a target gene on cytokine signaling suppressor molecule 1(SOCS1), while miR-124 inhibitors reduce the expression of TNF-α and IL-6 mRNA in neurons. These results suggest that oxygen- and glucose-deprived microglia regulate inflammatory cytokines leading to reduced neuronal survival, which may be achieved by miR-124 using SOCS1 as a potential target.