Low GABA Levels Research Articles

CsGAT1 modulates GABA metabolism and positively regulates cold resistance in tea plants

Tea plants (Camellia sinensis) are perennial woody economic crops that are often exposed to a range of abiotic stresses, especially low temperatures, during development. γ-Aminobutyric acid (GABA) is a nonprotein amino acid widely distributed in plants that is involved in the low-temperature response of plants. Here, we found that CsGAT1 was upregulated in tea leaves subjected to low-temperature stress according to transcriptomic data. Heterologous expression of CsGAT1 in a yeast mutant revealed that it specifically transports GABA. Subcellular localization assays revealed that CsGAT1 was located on the plasma membrane. The organizational localization experiments revealed that the expression level of CsGAT1 was relatively high in the old leaves and roots and relatively low in the flowers. Testing of different cold-tolerant tea germplasm resources revealed that cultivars with relatively low cold resistance presented relatively low CsGAT1 expression and GABA levels. In addition, Arabidopsis plants overexpressing CsGAT1 presented high levels of GABA accumulation and significant low-temperature resistance. In summary, we believe that CsGAT1 regulates the ability of tea plants to resist low-temperature stress by changing the concentration of GABA inside and outside the cell. This study provides a theoretical basis for breeding new tea cultivars with strong resistance to low-temperature stress during production.

Genetically engineered Lactococcus lactis strain constitutively expresses GABA-producing genes and produces high levels of GABA.

γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter of the central nervous system that impacts physical and mental health. Low GABA levels have been documented in several diseases, including multiple sclerosis and depression, and studies suggest that GABA could improve disease outcomes in those conditions. Probiotic bacteria naturally produce GABA and have been engineered to enhance its synthesis. Strains engineered thus far use inducible expression systems that require the addition of exogenous molecules, which complicates their development as therapeutics. This study aimed to overcome this challenge by engineering Lactococcus lactis with a constitutive GABA synthesis gene cassette. GABA synthesizing and transport genes (gadB and gadC) were cloned onto plasmids downstream of constitutive L. lactis promoters [P2, P5, shortened P8 (P8s)] of different strengths and transformed into L. lactis. Fold increase in gadCB expression conferred by these promoters (P2, P5, and P8s) was 322, 422, and 627, respectively, compared to the unmodified strain (P=0.0325, P8s). GABA synthesis in the highest gadCB expressing strain, L. lactis-P8s-glutamic acid decarboxylase (GAD), was dependent on media supplementation with glutamic acid and significantly higher than the unmodified strain (P<0.0001, 125mM, 200mM glutamic acid). Lactococcus lactis-P8s-GAD is poised for therapeutic testing in animal models of low-GABA-associated disease.

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.

Quantitative GABA magnetic resonance spectroscopy as a measure of motor learning function in the motor cortex after subarachnoid hemorrhage.

The neural mechanisms underlying gross and fine motor dysfunction after subarachnoid hemorrhage (SAH) remain unknown. The γ-aminobutyric acid (GABA) deficit hypothesis proposes that reduced neuronal GABA concentrations and the subsequent lack of GABA-mediated inhibition cause motor impairment after SAH. This study aimed to explore the correlation between GABA levels and a behavioral measure of motor performance in patients with SAH. Motor cortical GABA levels were assessed in 40 patients with SAH and 10 age-matched healthy controls using proton magnetic resonance spectroscopy. The GABA and N-acetylasparate (NAA) ratio was measured in the normal gray matter within the primary motor cortex. The relationship between GABA concentration and hand-motor performance was also evaluated. Results showed significantly lower GABA levels in patients with SAH's left motor cortex than in controls (GABA/NAA ratio: 0.282 ± 0.085 vs. 0.341 ± 0.031, respectively; p = 0.041). Reaction times (RTs), a behavioral measure of motor performance potentially dependent on GABAergic synaptic transmission, were significantly longer in patients than in controls (936.8 ± 303.8 vs. 440.2 ± 67.3 ms, respectively; p < 0.001). Moreover, motor cortical GABA levels and RTs exhibited a significant positive linear correlation among patients (r = 0.572, rs = 0.327, p = 0.0001). Therefore, a decrease in GABA levels in the primary motor cortex after SAH may lead to impaired cortical inhibition of neuronal function and indicates that GABA-mediated synaptic transmission in the motor cortex is critical for RT.

The GABAergic system in Alzheimer's disease: a systematic review with meta-analysis.

The γ-aminobutyric acid (GABA)ergic system is the primary inhibitory neurotransmission system in the mammalian brain. Its dysregulation has been shown in multiple brain conditions, but in Alzheimer's disease (AD) studies have provided contradictory results. Here, we conducted a systematic review with meta-analysis to investigate whether the GABAergic system is altered in AD patients compared to healthy controls (HC), following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 18th, 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABAA, GABAB, and GABAC receptors, GABA transporters (GAT) 1-3 and vesicular GAT in the brain, and GABA levels in the cerebrospinal fluid (CSF) and blood. Heterogeneity was estimated using the I2 index, and the risk of bias was assessed with an adapted questionnaire from the Joanna Briggs Institute Critical Appraisal Tools. The search identified 3631 articles, and 48 met the final inclusion criteria (518 HC, mean age 72.2, and 603 AD patients, mean age 75.6). Random-effects meta-analysis [standardized mean difference (SMD)] revealed that AD patients presented lower GABA levels in the brain (SMD = -0.48 [95% CI = -0.7, -0.27], adjusted p value (adj. p) < 0.001) and in the CSF (-0.41 [-0.72, -0.09], adj. p = 0.042), but not in the blood (-0.63 [-1.35, 0.1], adj. p = 0.176). In addition, GAD65/67 (-0.67 [-1.15, -0.2], adj. p = 0.006), GABAA receptor (-0.51 [-0.7, -0.33], adj. p < 0.001), and GABA transporters (-0.51 [-0.92, -0.09], adj. p = 0.016) were lower in the AD brain. Here, we showed a global reduction of GABAergic system components in the brain and lower GABA levels in the CSF of AD patients. Our findings suggest the GABAergic system is vulnerable to AD pathology and should be considered a potential target for developing pharmacological strategies and novel AD biomarkers.

Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls

There has been little analysis of neurochemical correlates of compulsive behaviour to illuminate its underlying neural mechanisms. We use 7-Tesla proton magnetic resonance spectroscopy (1H-MRS) to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate and GABA levels in anterior cingulate cortex (ACC) and supplementary motor area (SMA) of healthy volunteers and participants with Obsessive-Compulsive Disorder (OCD). Within the SMA, trait and clinical measures of compulsive behaviour are related to glutamate levels, whereas a behavioural index of habitual control correlates with the glutamate:GABA ratio. Participants with OCD also show the latter relationship in the ACC while exhibiting elevated glutamate and lower GABA levels in that region. This study highlights SMA mechanisms of habitual control relevant to compulsive behaviour, common to the healthy sub-clinical and OCD populations. The results also demonstrate additional involvement of anterior cingulate in the balance between goal-directed and habitual responding in OCD.

The presence and severity of epilepsy coincide with reduced γ-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation. Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements. A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p = .001) and lower levels of GABA (p = .002), γ-hydroxybutyrate (GHB; p = .004), and γ-guanidinobutyrate (GBA; p = .003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (p = .04). The cutoff values with the highest discriminative ability to predict seizures were age > 9.2 years (p = .001), GABA < 2.57 μmol·L-1 (p = .002), GHB < 143.6 μmol·L-1 (p = .004), and GBA < .075 μmol·L-1 (p = .007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age and lower plasma GABA, GHB, and GBA (area under the receiver operating characteristic curve of .798, p = .008). Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.

Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms

BackgroundAbnormal neurotransmitter levels have been reported in individuals at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate the onset of clinically relevant symptoms. Our aim was to explore in vivo measures of excitatory/inhibitory balance in 22q11.2 deletion carriers, a population at genetic risk for psychosis. MethodsGlx (glutamate+glutamine) and GABA+ (gamma-aminobutyric acid with macromolecules and homocarnosine) concentrations were estimated in the anterior cingulate cortex, superior temporal cortex, and hippocampus using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and the Gannet toolbox in 52 deletion carriers and 42 control participants. T1-weighted images were acquired longitudinally and processed with FreeSurfer version 6 to extract hippocampal volume. Subgroup analyses were conducted in deletion carriers with psychotic symptoms. ResultsWhile no differences were found in the anterior cingulate cortex, deletion carriers had higher levels of Glx in the hippocampus and superior temporal cortex and lower levels of GABA+ in the hippocampus than control participants. We additionally found a higher Glx concentration in the hippocampus of deletion carriers with psychotic symptoms. Finally, more pronounced hippocampal atrophy was significantly associated with increased Glx levels in deletion carriers. ConclusionsWe provide evidence for an excitatory/inhibitory imbalance in temporal brain structures of deletion carriers, with a further hippocampal Glx increase in individuals with psychotic symptoms that was associated with hippocampal atrophy. These results are in line with theories proposing abnormally enhanced glutamate levels as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia.

S-28-6: URINARY METABOLOMICS, DIETARY SALT INTAKE AND BLOOD PRESSURE: THE AFRICAN-PREDICT STUDY

Objective: Excessive salt intake is the leading dietary risk factor for cardiovascular disease (CVD). This increased risk may be attributed to alterations in the human metabolome. Salt sensitivity is associated with ethnicity, and ethnic differences in the interaction between sodium intake and the metabolome may play an integral part in CVD development. We therefore investigated 1) the urinary metabolomic profiles of Black and White adults according to low, moderate and high dietary salt intake; and 2) explored the relationships of identified metabolites with blood pressure. Design and Methods: This study included data of White (N = 447) and Black (N = 380) adults aged 20 to 30 years from the African-PREDICT study. Estimated salt intake was determined from 24hr urinary sodium. Urinary amino acids and acylcarnitines were measured using liquid chromatography tandem mass spectrometry. Clinic, 24hr and central systolic blood pressure (SBP) were measured. Results: Whites with a high salt intake (&gt; 10 g/day) had higher SBP (clinic, 24hr and central) compared to those with low (&lt; 5 g/day) or moderate (5 to 10 g/day) salt intakes (all p &lt; 0.05). The metabolites GABA (q = 0.020), citrulline (q = 0.020), glutamic acid (q = 0.046), serine (q = 0.054) and proline (q = 0.054) were lower in those with higher salt intake. In stepwise multivariable adjusted regression analyses, we found that clinic SBP of white adults were inversely associated with GABA (Adj. R2 = 0.35; Std. β=-0.123; p = 0.005), serine (Adj. R2 = 0.35; Std. β=-0.099; p = 0.022) and proline (Adj. R2 = 0.35; Std. β=-0.099; p = 0.021), and central SBP with GABA (Adj. R2 = 0.34; Std. β=-0.094; p = 0.036), glutamic acid (Adj. R2 = 0.34; Std. β=-0.090; p = 0.035) and proline (Adj. R2 = 0.034; Std. β=-0.106; p = 0.015). In Black adults, there were no differences in SBP or metabolites between low, moderate or high salt intake groups, with no relationships between SBP and GABA, glutamic acid, citrulline, serine or proline. Conclusion: In White adults, high salt intake was associated with low levels of GABA, glutamic acid, serine and proline, which in turn were related to high SBP. We hypothesise that metabolomic changes are related to salt intake and may contribute to pathophysiological mechanisms associated with increased blood pressure.

Endocytosis of GABA receptor: Signaling in nervous system.

GABA (ᵞ-aminobutyric acid), is the principal neurotransmitter known for its inhibitory role in chemical synapses. Being localized primarily in the central nervous system (CNS) it maintains a balance between excitatory (regulated by another neurotransmitter, glutamate) and inhibitory impulses. GABA acts by binding to their specific receptors GABAA and GABAB when released into the post-synaptic nerve terminal. Both of these receptors are responsible for fast and slow inhibition of neurotransmission, respectively. GABAA is a ligand-gated ionopore receptor which opens the Cl- ion channel and decreases the resting potential of the membrane resulting into inhibition of the synapse. On the other hand, GABAB is a metabotropic receptor which increases the K+ ion levels preventing Ca+ ion release inhibiting the release of other neurotransmitters into the presynaptic membrane. The internalization and trafficking of these receptors is also conducted through distinct pathways and mechanism, discussed in detail in the chapter. Without the desired levels of GABA in the body, the psychological and neurological states of brain get hard to maintain. Various neurodegenerative diseases/disorders have been associated to low levels of GABA, such as anxiety, mood disorders, fear, schizophrenia, hungtington's chorea, seizures, epilepsy, etc. The allosteric sites present on GABA receptors have been proved to be potent drug targets to pacify the pathological states of these brain related disorders to an extent. Further in depth studies focussing on the subtypes of GABA receptors and their comprehensive mechanism are required to explore new drug targets and therapeutic avenues for effectual management of GABA related neurological diseases.

GABAergic system in Alzheimer’s disease: a systematic review with meta‐analysis

AbstractBackgroundCholinergic and glutamatergic dysfunctions have been widely described in Alzheimer’s disease (AD). However, the role of other neurotransmitter systems, such as the GABAergic, remains poorly understood. In fact, studies evaluating GABAergic neurotransmission in AD patients have provided contradictory results, pointing to a need for a consensus in the literature regarding the GABAergic system in AD. Thus, we aimed at examining whether the GABAergic system is altered in AD.MethodWe systematically reviewed and meta‐analyzed the literature following the PRISMA 2020 guidelines (PROSPERO #alz064082). We searched in the PubMed and Web of Science databases for studies reporting quantitative or semi‐quantitative data of GABA, and GABAergic transporters, receptors, and synthesis enzymes. The participants included were AD subjects and age‐matched cognitively unimpaired (CU) individuals. The effect sizes were determined via the standardized mean difference (SMD) using Hedge’s g method with random effects. The percentage of heterogeneity between studies was estimated using I2 test. Data are presented as SMD [95% CI], I2 %.ResultThe search identified 3,223 papers (Figure 1). Forty‐nine records met the inclusion criteria (a total of 667 AD patients, mean age 75.4, and 584 CU subjects, mean age 72.4). Here, we present results obtained in the CSF, blood, and different brain regions in which more than five studies have been meta‐analyzed. GABA levels were decreased in the CSF (‐0.42 [‐0.74, ‐0.1], p&lt;0.0001, 0%), temporal cortex (‐0.97 [‐1.38, ‐0.55], p&lt;0.0001, 54.6%), occipital cortex (‐1.03 [‐1.86, ‐0.2], p=0.015, 78%), and striatum (‐0.58 [‐1.09, ‐0.07], p=0.025, 0%), but not in the blood (‐0.64 [‐1.39, 0.11], p=0.092, 64.2%), frontal cortex (‐0.49 [‐1.06, 0.08], p=0.09, 73.1%), and hippocampus (‐0.39 [‐0.8, 0.03], p=0.068, 24.7%); GABA A receptor availability was decreased in the frontal (‐0.74 [‐1.44, ‐0.05], p=0.037, 50.5%) and temporal cortices (‐0.73 [‐1.15, ‐0.3], p=0.001, 7.4%), but not in the hippocampus (‐0.79 [‐1.64, 0.06], p=0.068, 66.9%). Figure 2 provides a summary of our findings.ConclusionOur results demonstrated a decrease of GABAergic system components in multiple brain regions and low levels of GABA in the CSF of AD subjects compared to age‐matched CU individuals, pointing to an important role played by GABAergic neurotransmission in the pathophysiology of AD.

Glutamine and GABA alterations in cingulate cortex may underlie alcohol drinking in a rat model of co-occurring alcohol use disorder and schizophrenia: an 1H-MRS study

Alcohol use disorder commonly occurs in patients with schizophrenia and significantly worsens the clinical course of the disorder. The neurobiological underpinnings of alcohol drinking are not well understood. Magnetic resonance spectroscopy (MRS) has been used to assess the neurochemical substrates that may be associated with alcohol drinking in patients; however, the causal impact of these findings remains elusive, highlighting the need for studies in animal models. This study performed MRS in the neonatal ventral hippocampal lesioned (NVHL) rat model, a model of co-occurring schizophrenia and substance use disorders. NVHL lesions (or sham surgeries) were performed on post-natal day 7 and animals were given brief exposure to alcohol during adolescence (10% v/v in a 2-bottle choice design). Animals were re-exposed to alcohol during adulthood (20% v/v) until a stable drinking baseline was established, and then forced into abstinence to control for the effects of differential alcohol drinking. Animals were scanned for MRS after one month of abstinence. NVHL rats consumed significantly more alcohol than sham rats and in the cingulate cortex showed significantly higher levels of GABA and glutamine. Significantly lower GABA levels were observed in the nucleus accumbens. No differences between the NVHL and sham animals were observed in the hippocampus. Correlation analysis revealed that GABA and glutamine concentrations in the cingulate cortex significantly correlated with the rats’ alcohol drinking prior to 30 days of forced abstinence. These findings suggest that a potential dysfunction in the glutamate/GABA–glutamine cycle may contribute to alcohol drinking in a rat model of schizophrenia, and this dysfunction could be targeted in future treatment-focused studies.

Glutamatergic pathways in the brains of turtles: A comparative perspective among reptiles, birds, and mammals.

Glutamate acts as the main excitatory neurotransmitter in the brain and plays a vital role in physiological and pathological neuronal functions. In mammals, glutamate can cause detrimental excitotoxic effects under anoxic conditions. In contrast, Trachemys scripta, a freshwater turtle, is one of the most anoxia-tolerant animals, being able to survive up to months without oxygen. Therefore, turtles have been investigated to assess the molecular mechanisms of neuroprotective strategies used by them in anoxic conditions, such as maintaining low levels of glutamate, increasing adenosine and GABA, upregulating heat shock proteins, and downregulating KATP channels. These mechanisms of anoxia tolerance of the turtle brain may be applied to finding therapeutics for human glutamatergic neurological disorders such as brain injury or cerebral stroke due to ischemia. Despite the importance of glutamate as a neurotransmitter and of the turtle as an ideal research model, the glutamatergic circuits in the turtle brain remain less described whereas they have been well studied in mammalian and avian brains. In reptiles, particularly in the turtle brain, glutamatergic neurons have been identified by examining the expression of vesicular glutamate transporters (VGLUTs). In certain areas of the brain, some ionotropic glutamate receptors (GluRs) have been immunohistochemically studied, implying that there are glutamatergic target areas. Based on the expression patterns of these glutamate-related molecules and fiber connection data of the turtle brain that is available in the literature, many candidate glutamatergic circuits could be clarified, such as the olfactory circuit, hippocampal–septal pathway, corticostriatal pathway, visual pathway, auditory pathway, and granule cell–Purkinje cell pathway. This review summarizes the probable glutamatergic pathways and the distribution of glutamatergic neurons in the pallium of the turtle brain and compares them with those of avian and mammalian brains. The integrated knowledge of glutamatergic pathways serves as the fundamental basis for further functional studies in the turtle brain, which would provide insights on physiological and pathological mechanisms of glutamate regulation as well as neural circuits in different species.

P564. Frontostriatal Neurochemical Profiling of the Healthy Human Brain Using Magnetic Resonance Spectroscopy and [18F]-FDOPA Positron Emission Tomography

Dysfunction of prefrontal GABAergic neurons and abnormalities of striatal presynaptic dopamine synthesis are important phenotypes in neuropsychiatric illnesses such as schizophrenia. Recent meta-analyses of magnetic resonance spectroscopy (MRS) studies suggest that lower GABA levels in dorsal anterior cingulate cortex (dACC) may be associated with psychosis. Further, a number of positron emission tomography (PET) studies have found schizophrenia-associated dopamine synthesis excesses in the striatum, although these findings are mixed. Despite illness models highlighting frontostriatal circuit dysfunction, it is unclear whether variability in cortical GABA and striatal dopamine synthesis are related phenomena in humans, which would have implications for findings in clinical populations.

Ergothioneine extract from Aspergillus oryzae prevents lipid oxidation and increases bioactive compounds during the processing of germinated brown rice

This study aimed to evaluate the impact of ergothioniene (ESH) concentrated extract (CE) to lipid anti-oxidation and γ-aminobutyric acid (GABA), γ-oryzanol (GORZ) biosynthesis during germinated brown rice (GBR) processing. To do that 0, 2, 4 and 6% ESH CE was supplemented to soaking stage of brown rice for 6 hr and determined changes about the quality of GBR during processing. The results showed when added 4% of ESH CE to soaking stage, total lipid was stable during four stages of GBR processing as 1.96, 1.87, 1.77, and 1.67 g/100 g corresponding to less increasing peroxide and thiobarbituric acid–reactive substances (TBARs) as 0.53, 0.54, 0.55, and 0.55 meq/kg lipid and 0.21, 0.23, 0.25, and 0.26 µmol TBARs/g while GABA and GORZ increased considerably to 2378.63 mg/kg and 222 mg/kg, respectively. The results indicated that ESH CE helps to increase GABA, GORZ and prevent lipid oxidation that contributes to improving the quality of GBR. Novelty impact statement GBR contains various bioactive compounds such as GABA, GORZ, which have positive effects for human health. So, it becomes one of the value-added products from rice. However, in GBR processing, there are still some problems that impact negatively on the quality of GBR such as low levels of GABA, GORZ and high levels of peroxide and TBAR values that may occur during processing. To address these problems, this study used ESH, a powerful antioxidant compound, which was biosynthesized from Aspergillus oryzae applying to GBR processing. The results show that ESH CE not only inhibits fat oxidation during GBR processing but also increases significantly GABA, GORZ level. So, this study contributed one of great solutions for improving the quality of GBR products.

Neurotransmitter Dysfunction in Irritable Bowel Syndrome: Emerging Approaches for Management.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose aetiology is still unknown. Most hypotheses point out the gut-brain axis as a key factor for IBS. The axis is composed of different anatomic and functional structures intercommunicated through neurotransmitters. However, the implications of key neurotransmitters such as norepinephrine, serotonin, glutamate, GABA or acetylcholine in IBS are poorly studied. The aim of this review is to evaluate the current evidence about neurotransmitter dysfunction in IBS and explore the potential therapeutic approaches. IBS patients with altered colorectal motility show augmented norepinephrine and acetylcholine levels in plasma and an increased sensitivity of central serotonin receptors. A decrease of colonic mucosal serotonin transporter and a downregulation of α2 adrenoceptors are also correlated with visceral hypersensitivity and an increase of 5-hydroxyindole acetic acid levels, enhanced expression of high affinity choline transporter and lower levels of GABA. Given these neurotransmitter dysfunctions, novel pharmacological approaches such as 5-HT3 receptor antagonists and 5-HT4 receptor agonists are being explored for IBS management, for their antiemetic and prokinetic effects. GABA-analogous medications are being considered to reduce visceral pain. Moreover, agonists and antagonists of muscarinic receptors are under clinical trials. Targeting neurotransmitter dysfunction could provide promising new approaches for IBS management.

Age-related parietal GABA alterations in children with autism spectrum disorder.

GABA is the primary inhibitory neurotransmitter in the brain, and is essential to the balance of cortical excitation and inhibition. Reductions in GABA are proposed to result in an overly excitatory cortex that may cause, or contribute to, symptoms of autism spectrum disorder (ASD). This study employed a cross-sectional design to explore GABA+ differences in ASD and the impact of age, comparing 4-12 year olds with ASD (N=24) to typically developing children (N=35). GABA+ concentration was measured using edited magnetic resonance spectroscopy in the left parietal lobe. This study used a mixed model to investigate group differences between children with ASD and typically developing children. There was a significant difference in GABA+ levels between the groups, a significant effect of age and interaction between age and diagnostic group. The ASD group showed an association between GABA+ and age, with GABA+ levels gradually increasing with age (r=0.59, p=0.003). Typically developing children did not show age-related change in GABA+ concentration (r=0.09, p =0.60). By the age of 9, children with ASD showed GABA+ levels that were comparable to their typically developing peers. This study suggests that children with ASD have initially lower levels of GABA+ in the left parietal lobe compared to typically developing children, and that these initially lower levels of GABA+ increase with age in ASD within this region. It is suggested that this developmental shift of GABA+ levels within the left parietal lobe provides a possible explanation for the previously found reductions in childhood that does not persist in adults. LAY SUMMARY: This study measured levels of GABA in the left parietal lobe using magnetic resonance spectroscopy in children with ASD and typically developing children. GABA levels were initially lower in the ASD group, and increased with age, while GABA did not change with age in the typically developing group. This suggests that alterations in GABA signaling may be associated with ASD in childhood. Autism Res 2021, 14: 859-872. © 2021 International Society for Autism Research, Wiley Periodicals LLC.

Selenium Nanoparticles Pre-Treatment Reverse Behavioral, Oxidative Damage, Neuronal Loss and Neurochemical Alterations in Pentylenetetrazole-Induced Epileptic Seizures in Mice.

IntroductionEpilepsy is a chronic neurological condition characterized by behavioral, molecular, and neurochemical alterations. Current antiepileptic drugs are associated with various adverse impacts. The main goal of the current study is to investigate the possible anticonvulsant effect of selenium nanoparticles (SeNPs) against pentylenetetrazole (PTZ)-mediated epileptic seizures in mice hippocampus. Sodium valproate (VPA) was used as a standard anti-epileptic drug.MethodsMice were assigned into five groups (n=15): control, SeNPs (5 mg/kg, orally), PTZ (60 mg/kg, intraperitoneally), SeNPs+PTZ and VPA (200 mg/kg)+PTZ. All groups were treated for 10 days.ResultsPTZ injection triggered a state of oxidative stress in the hippocampal tissue as represented by the elevated lipoperoxidation, heat shock protein 70 level, and nitric oxide formation while decreased glutathione level and antioxidant enzymes activity. Additionally, the blotting analysis showed downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the epileptic mice. A state of neuroinflammation was recorded following the developed seizures represented by the increased pro-inflammatory cytokines. Moreover, neuronal apoptosis was recorded following the development of epileptic convulsions. At the neurochemical level, acetylcholinesterase activity and monoamines content were decreased in the epileptic mice, accompanied by high glutamate and low GABA levels in the hippocampal tissue. However, SeNP supplementation was found to delay the onset and decreased the duration of tonic, myoclonic, and generalized seizures following PTZ injection. Moreover, SeNPs were found to provide neuroprotection through preventing the development of oxidative challenge via the upregulation of Nrf2 and HO-1, inhibiting the inflammatory response and apoptotic cascade. Additionally, SeNPs reversed the changes in the activity and levels of neuromodulators following the development of epileptic seizures.ConclusionThe obtained results suggest that SeNPs could be used as a promising anticonvulsant drug due to its potent antioxidant, anti-inflammatory, and neuromodulatory activities.

GABA and glutamate in pediatric migraine.

Migraine is one of the top 5 most prevalent childhood diseases; however, effective treatment strategies for pediatric migraine are limited. For example, standard adult pharmaceutical therapies are less effective in children and can carry undesirable side effects. To develop more effective treatments, improved knowledge of the biology underlying pediatric migraine is necessary. One theory is that migraine results from an imbalance in cortical excitability. Magnetic resonance spectroscopy (MRS) studies show changes in GABA and glutamate levels (the primary inhibitory and excitatory neurotransmitters in the brain, respectively) in multiple brain regions in adults with migraine; however, they have yet to be assessed in children with migraine. Using MRS and GABA-edited MRS, we show that children (7-13 years) with migraine and aura had significantly lower glutamate levels in the visual cortex compared to controls, the opposite to results seen in adults. In addition, we found significant correlations between metabolite levels and migraine characteristics; higher GABA levels were associated with higher migraine burden. We also found that higher glutamate in the thalamus and higher GABA/Glx ratios in the sensorimotor cortex were associated with duration since diagnosis, i.e., having migraines longer. Lower GABA levels in the sensorimotor cortex were associated with being closer to their next migraine attack. Together, this indicates that GABA and glutamate disturbances occur early in migraine pathophysiology and emphasizes that evidence from adults with migraine cannot be immediately translated to pediatric sufferers. This highlights the need for further mechanistic studies of migraine in children, to aid in development of more effective treatments.

Chronic inhibition of GABA synthesis in the infralimbic cortex facilitates conditioned safety memory and reduces contextual fear

Accurate discrimination between danger and safety cues is essential for survival. Recent findings in humans indicate that patients suffering from anxiety disorders cannot reliably use safety cues in order to inhibit fear responses. However, the neuroanatomical pathways of conditioned safety are still unclear. Aim of the present study was to investigate whether chronic inhibition of GABA synthesis in the infralimbic (IL) cortex, a critical region for fear inhibition, would lead to enhanced conditioned safety memory. Male Sprague Dawley rats were equipped with osmotic mini-pumps attached to an infusion cannula aimed at the IL. Mini-pumps were either filled with the glutamate decarboxylase (GAD) inhibitor l-allylglycine (l-AG) or the inactive enantiomer d-allylglycine (d-AG). Previous studies demonstrated that chronic infusions of l-AG lead to lower GABA levels and overall enhanced neural activity. The effect of IL disinhibition on conditioned safety was investigated utilizing the acoustic startle response. Chronic disinhibition of the IL facilitated conditioned safety memory, along with reduced contextual fear and lower corticosterone levels. The present findings suggest that the IL is a key brain region for conditioned safety memory. Because anxiety disorder patients are often not capable to use safety cues to inhibit unnecessary fear responses, the present findings are of clinical relevance and could potentially contribute to therapy optimization.