Aldehyde dehydrogenase 2-associated changes in pharmacokinetics, locomotor function and peripheral glutamic acid and gamma-aminobutyric acid levels during acute alcohol intoxication in male mice.

The insufficiency of human aldehyde dehydrogenase 2 (ALDH2) has been consistently associated with high blood acetaldehyde levels and impaired locomotor function during acute alcohol intoxication. The ALDH2-associated change in peripheral glutamic acid (Glu) and gamma-aminobutyric acid (GABA) levels and its correlation with pharmacokinetics and psychomotor function remain unclear. In this study, ALDH2*2 mice were used to build an acute alcohol intoxication model after intraperitoneal administration. The blood ethanol and acetaldehyde concentrations were analyzed to generate concentration-time curves at two doses of alcohol (2.0 and 4.0 g/kg). The dose of 4.0 g/kg was selected in accordance with the preliminary behavioral evaluation result to perform the following behavioral tests (e.g. the rotarod test, the open field test, and the Y-maze test), so as to assess locomotor activity, anxiety and cognitive ability. Plasma Glu and GABA levels were determined through enzyme-linked immunosorbent assays. The results suggested that the ALDH2*2 mice had highly accumulated acetaldehyde levels, impaired locomotor activity and anxiety-like emotion but unimpaired cognitive function, compared to the wild type (WT) mice. The plasma Glu level and the ratio of Glu/GABA in the alcohol-treated WT and ALDH2*2 groups decreased from 2 to 5 h after intraperitoneal administration, whereas the GABA level did not change significantly. The blood alcohol concentration in the WT and ALDH2*2 mice was positively correlated with plasma Glu level, whereas the blood acetaldehyde level was found as the opposite. We speculate that the decline degree of Glu/GABA ratio could be associated with psychomotor retardation and needs to be further investigated.

GABA Receptor SNPs and Elevated Plasma GABA Levels Affect the Severity of the Indian ASD Probands.

Altered signaling of the chief inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), has been speculated in the etiology of autism spectrum disorder (ASD). We have investigated the association of six GABAA-receptor genetic variants and plasma GABA levels with ASD. Subjects were recruited based on the DSM, and CARS2-ST and ADI-R assessed disease severity. Peripheral blood was collected from the ASD probands (N = 251), their parents, and ethnically matched controls (N = 347). A positive correlation between the CARS2-ST and ADI-R scores was observed; domain scores of ADI-R were higher in the severe group categorized by the CARS2-ST. GABRB3 rs1432007 "A," GABRG3 rs897173 "A," and GABRA5 rs140682 "T" showed significant association with ASD. Trait scores were influenced by rs1432007 "AA" and rs140682 "TT." GABA level was significantly higher in the probands than the age-matched controls. Our findings indicate an influence of GABA in the etiology of ASD in the Indian probands.

Jiaotaiwan increased GABA level in brain and serum, improved sleep via increasing NREM sleep and REM sleep, and its component identification.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiaotaiwan (JTW) is good at communicating the heart and kidney. That meets the main mechanism of insomnia in traditional Chinese medicine. But the mechanism of JTW in promoting sleep is not clear. AIM OF THE STUDY: To investigate the mechanism of JTW in promoting sleep and identify the main components. MATERIALS AND METHODS: In this study, we detected the levels of GABA in serum and brain via LC-MS/MS analysis and investigated the hypnotic effect of JTW and its role in promoting sleep via Sleep monitoring and vigilance state analysis. Further, the identification of the main components was carried out by using LC-MS/MS analysis. RESULTS: JTW could increase the GABA levels in serum, FC and BS of SDM rats. JTW reduced the amount of wakefulness, increased the time of NREM sleep and REM sleep. A total of 25 compounds were identified. CONCLUSIONS: The current work provides valuable information on the hypnotic effects of JTW and its regulatory mechanisms in promoting sleep.

Correlation of Antibodies to Neurotransmitters in the Sera of Women with Alcohol Dependence and Depressive Disorders.

Comparative analysis of blood sera from women with alcohol dependence and depressive disorders or from conditionally healthy women revealed reduced level of antibodies to dopamine, norepinephrine, serotonin, glutamate, and GABA in blood serum in women with dysthymic disorder and a depressive episode and their increased content in women with alcohol dependence in combination with depressive disorders.

Endurance exercise improves avoidance learning and spatial memory, through changes in genes of GABA and relaxin-3, in rats.

Different exercise patterns, neurotransmitters, and some genes have numerous effects on learning and memory. This research aims to investigate the long-term effects of submaximal aerobic exercise on spatial memory (SM), passive avoidance learning (PAL), levels of serum relaxin-3, gamma-aminobutyric acid (GABA), RLN3 gene, and glutamic acid decarboxylase (GAD65/67 genes) in the brainstem of adult male Wistar rats. Fifty male Wistar rats were randomly divided into five groups: aerobic exercise groups, performed on a treadmill running (TR), for 5 weeks (Ex5, n = 10), 10 weeks (Ex10, n = 10), involuntary running wheel group for 5 weeks (IRW5, n = 10), sham (Sh, n = 10) and control (Co, n = 10). Consequently, SM, PAL, serum relaxin-3, GABA, and GAD65/67 and RLN3 genes were measured by ELISA and PCR. Ex5, Ex10 and IRW5 improved significantly SM (p ≤ 0.05), PAL (p ≤ 0.001) and decreased significantly relaxin-3 (p ≤ 0.001). RLN3 in the brain also decreased. However, it was not significant. GABA and GAD65/GAD67 increased significantly (p ≤ 0.05) in Ex5, Ex10 compared to Sh and Co. Aerobic exercise enhanced SM and PAL in Ex compared to Co and Sh. However, duration and type of exercise affected the level of enhancement. The serum relaxin-3 and RLN3 gene displayed reverse functions compared to GABA and GAD65/67 genes in Ex. Therefore, the changes of neurotransmitters in serum relaxin-3, GABA, and their genes: RLN3 and GAD65/67 respectively, influenced learning and memory meaningfully.

Neurobehavioral effects of acute low-dose whole-body irradiation.

Radiation exposure has multiple effects on the brain, behavior and cognitive functions. It has been reported that high-dose (>20 Gy) radiation-induced behavior and cognitive aberration partly associated with severe tissue destruction. Low-dose (<3 Gy) exposure can occur in radiological disasters and cerebral endovascular treatment. However, only a few reports analyzed behavior and cognitive functions after low-dose irradiation. This study was undertaken to assess the relationship between brain neurochemistry and behavioral disruption in irradiated mice. The irradiated mice (0.5 Gy, 1 Gy and 3 Gy) were tested for alteration in their normal behavior over 10 days. A serotonin (5-HT), Dopamine, gamma-Aminobutyric acid (GABA) and cortisol analysis was carried out in blood, hippocampus, amygdala and whole brain tissue. There was a significant decline in the exploratory activity of mice exposed to 3 Gy and 1 Gy radiation in an open field test. We observed a significant short-term memory loss in 3 Gy and 1 Gy irradiated mice in Y-Maze. Mice exposed to 1 Gy and 3 Gy radiation exhibited increased anxiety in an elevated plus maze (EPM). The increased anxiety and memory loss patterns were also seen in 0.5 Gy irradiated mice, but the results were not statistically significant. In this study we observed that neurotransmitters are significantly altered after irradiation, but the neuronal cells in the hippocampus were not significantly affected. This study suggests that the low-dose radiation-induced cognitive impairment may be associated with the neurochemical in low-dose irradiation and unlike the high-dose scenario might not be directly related to the morphological changes in the brain.

Effect of transcranial direct current stimulation on in-vivo assessed neuro-metabolites through magnetic resonance spectroscopy: a systematic review.

OBJECTIVES: Previous studies have examined the effect of transcranial direct current stimulation (tDCS) on the in-vivo concentrations of neuro-metabolites assessed through magnetic resonance spectroscopy (MRS) in neurological and psychiatry disorders. This review aims to systematically evaluate the data on the effect of tDCS on MRS findings and thereby attempt to understand the potential mechanism of tDCS on neuro-metabolites. METHODS: The relevant literature was obtained through PubMed and cross-reference (search till June 2020). Thirty-four studies were reviewed, of which 22 reported results from healthy controls and 12 were from patients with neurological and psychiatric disorders. RESULTS: The evidence converges to highlight that tDCS modulates the neuro-metabolite levels at the site of stimulation, which, in turn, translates into alterations in the behavioural outcome. It also shows that the baseline level of these neuro-metabolites can, to a certain extent, predict the outcome after tDCS. However, even though tDCS has shown promising effects in alleviating symptoms of various psychiatric disorders, there are limited studies that have reported the effect of tDCS on neuro-metabolite levels. CONCLUSIONS: There is a compelling need for more systematic studies examining patients with psychiatric/neurological disorders with larger samples and harmonised tDCS protocols. More studies will potentially help us to understand the tDCS mechanism of action pertinent to neuro-metabolite levels modulation. Further, studies should be conducted in psychiatric patients to understand the neurological changes in this population and potentially unravel the neuro-metabolite × tDCS interaction effect that can be translated into individualised treatment.

Low-Dose Ozone Therapy Improves Sleep Quality in Patients with Insomnia and Coronary Heart Disease by Elevating Serum BDNF and GABA.

We studied the effects of low-dose ozone therapy on the sleep quality of patients with coronary heart disease (CHD) and insomnia by measuring the levels of brain-derived neurotrophic factor (BDNF) and GABA in blood serum. The 3-month course of low-dose ozone therapy significantly elevated serum BDNF and GABA in CHD patients with insomnia and improved parameters of anxiety, depression, and sleep quality according to Hospital Anxiety and Depression Scale (HADS), Pittsburgh Sleep Quality Index (PSQI), and Self-Rating Scale of Sleep (SRSS). Ozone therapy also significantly (p<0.05) improved the total antioxidant status of the body by elevating catalase activity and reducing malondialdehyde and 8-OHdeoxyguanosine in the saliva. The serum levels of BDNF and GABA negatively and closely correlated with PSQI and HADS scores. Low-dose ozone therapy improved sleep quality and reduced PSQI and HADS scores due to up-regulation of BDNF and GABA.

Plasma gamma-aminobutyric acid (GABA) levels and posttraumatic stress disorder symptoms in trauma-exposed women: a preliminary report.

RATIONALE: Aberrations in the stress response are associated with posttraumatic stress disorder (PTSD) symptom development, maintenance, and severity. Gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, may play a key role in stress recovery. OBJECTIVES: In this preliminary study, we examined whether plasma GABA levels differed between women with PTSD and trauma-exposed healthy controls. METHODS: Thirty participants provided plasma samples during two phases of the menstrual cycle: the early follicular phase and the mid-luteal phase. During each phase, blood was drawn after 45 min of rest, and after mild and moderately stressful psychophysiological tasks. Plasma GABA levels were measured using HPLC-mass spectrometry (LC-MS/MS). RESULTS: In analyses using PTSD diagnosis as a categorical group variable, women with and without a diagnosis of PTSD did not differ in plasma GABA levels (ps > .18). However, in analyses examining PTSD symptom severity as a continuous variable, there was a trend-level positive association between more severe PTSD symptoms and higher plasma GABA levels across the four blood draws (p = .06). In analyses examining DSM-IV PTSD symptom clusters separately, dysphoria symptoms were positively and significantly associated with plasma GABA levels (p = .03). Similarly, there was a trend-level positive association between avoidance cluster symptoms and plasma GABA levels (p = .06). Plasma GABA levels were not modulated by experimentally induced stress or menstrual cycle phase. CONCLUSIONS: Dysregulation in GABA may be a neurobiological marker and/or potential treatment target for women with PTSD symptom profiles characterized by prominent dysphoria and avoidance cluster symptoms.

Development and validation of a UPLC-MS/MS method for the simultaneous determination of gamma-aminobutyric acid and glutamic acid in human plasma.

Gamma-aminobutyric acid (GABA) and its precursor glutamic acid are important neurotransmitters. Both are also present in peripheral tissues and the circulation, where abnormal plasma concentrations have been linked to specific mental disorders. In addition to endogenous synthesis, GABA and glutamic acid can be obtained from dietary sources. An increasing number of studies suggest beneficial cardio-metabolic effects of GABA intake, and therefore GABA is being marketed as a food supplement. The need for further research into their health effects merits accurate and sensitive methods to analyze GABA and glutamic acid in plasma. To this end, an ultra-pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of GABA and glutamic acid in human plasma. Samples were prepared by a protein precipitation step and subsequent solid phase extraction using acetonitrile. Chromatographic separation was achieved on an Acquity UPLC HSS reversed phase C18 column using gradient elution. Analytes were detected using electrospray ionization and selective reaction monitoring. Standard curve concentrations for GABA ranged from 3.4 to 2500 ng/mL and for glutamic acid from 30.9 ng/mL to 22,500 ng/mL. Within- and between-day accuracy and precision were <10% in quality control samples at low, medium and high concentrations for both GABA and glutamic acid. GABA and glutamic acid were found to be stable in plasma after freeze-thaw cycles and up to 12 months of storage. The validated method was applied to human plasma from 17 volunteers. The observed concentrations ranged between 11.5 and 20.0 ng/ml and 2269 and 7625 ng/ml for respectively GABA and glutamic acid. The reported method is well suited for the measurement of plasma GABA and glutamic acid in pre-clinical or clinical studies.

GABA synaptopathy promotes the elevation of caspases 3 and 9 as pro-apoptotic markers in Egyptian patients with autism spectrum disorder.

Autism spectrum disorder (ASD) is classified as a neurodevelopmental disorder characterized by reduced social communication as well as repetitive behaviors. Many studies have proved that defective synapses in ASD influence how neurons in the brain connect and communicate with each other. Synaptopathies arise from alterations that affecting the integrity and/or functionality of synapses and can contribute to synaptic pathologies. This study investigated the GABA levels in plasma being an inhibitory neurotransmitter, caspase 3 and 9 as pro-apoptotic proteins in 20 ASD children and 20 neurotypical controls using the ELISA technique. Analysis of receiver-operating characteristic (ROC) of the data that was obtained to evaluate the diagnostic value of the aforementioned evaluated biomarkers. Pearson's correlations and multiple regressions between the measured variables were also done. While GABA level was reduced in ASD patients, levels of caspases 3 and 9 were significantly higher when compared to neurotypical control participants. ROC and predictiveness curves showed that caspases 3, caspases 9, and GABA might be utilized as predictive markers in autism diagnosis. The present study indicates that the presence of GABAergic dysfunction promotes apoptosis in Egyptian ASD children. The obtained GABA synaptopathies and their connection with apoptosis can both relate to neuronal excitation, and imbalance of the inhibition system, which can be used as reliable predictive biomarkers for ASD.

Impact of Lead Exposure on Thyroid Status and IQ Performance among School-age Children Living Nearby a Lead-Zinc Mine in China.

BACKGROUND: Lead exposure is one of the most concerning public health problems worldwide, particularly among children. Yet the impact of chronic lead exposure on the thyroid status and related intelligence quotient performance among school-age children remained elusive. OBJECTIVE: The aim of this study was to evaluate the influence of lead exposure on the thyroid hormones, amino acid neurotransmitters balances, and intelligence quotient (IQ) among school-age children living nearby a lead-zinc mining site. Other factors such as rice lead levels, mothers' smoking behavior, and diet intake were also investigated. METHODS: A total of 255 children aged 7-12 years old were recruited in this study. Blood lead level (BLL), thyroid hormones including free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH), and amino acid neurotransmitters such as glutamate (Glu), glutamine (Gln), and γ-aminobutyric acid (GABA) were measured using graphite furnace atomic absorption spectroscopy (GFAAS), chemiluminescence immunoassay, high performance liquid chromatography (HPLC). Raven's standard progressive matrices (SPM) and the questionnaire were used to determine IQ and collect related influence factors. RESULTS: The average BLL of children was 84.8 µg/L. The occurrence of lead intoxication (defined as the BLL ≥ 100 µg/L) was 31.8%. Serum TSH levels and IQ of lead-intoxicated children were significantly lower than those without lead toxicity. The GABA level of girls with the lead intoxication was higher than those with no lead-exposed group. Correlation analyses revealed that BLL were inversely associated with the serum TSH levels (R= -0.186, p < 0.05), but positively related with IQ grades (R = 0.147, p < 0.05). Moreover, BLL and Glu were inversely correlated with IQ. In addition, this study revealed four factors that may contribute to the incidence of lead intoxication among children, including the frequency of mother smoking (OR = 3.587, p < 0.05) and drinking un-boiled stagnant tap water (OR = 3.716, p < 0.05); eating fresh fruits and vegetables (OR = 0.323, p < 0.05) and soy products regularly (OR = 0.181, p < 0.05) may protect against lead intoxication. CONCLUSION: Lead exposure affects the serum TSH, GABA levels and IQ of school-aged children. Developing good living habits, improving environment, increasing the intake of high-quality protein and fresh vegetable and fruit may improve the condition of lead intoxication.

Polymeric nanoencapsulation of zaleplon into PLGA nanoparticles for enhanced pharmacokinetics and pharmacological activity.

Zaleplon (ZP) is a sedative and hypnotic drug used for the treatment of insomnia. Despite its potent anticonvulsant activity, ZP is not commonly used for the treatment of convulsion since ZP is characterized by its low oral bioavailability as a result of poor solubility and extensive liver metabolism. The following study aimed to formulate specifically controlled release nano-vehicles for oral and parenteral delivery of ZP to enhance its oral bioavailability and biological activity. A modified single emulsification-solvent evaporation method of sonication force was adopted to optimize the inclusion of ZP into biodegradable nanoparticles (NPs) using poly (dl-lactic-co-glycolic acid) (PLGA). The impacts of various formulation variables on the physicochemical characteristics of the ZP-PLGA-NPs and drug release profiles were investigated. Pharmacokinetics and pharmacological activity of ZP-PLGA-NPs were studied using experimental animals and were compared with generic ZP tablets. Assessment of gamma-aminobutyric acid (GABA) level in plasma after oral administration was conducted using enzyme-linked immunosorbent assay. The maximal electroshock-induced seizures model evaluated anticonvulsant activity after the parenteral administration of ZP-loaded NPs. The prepared ZP-PLGA NPs were negatively charged spherical particles with an average size of 120-300 nm. Optimized ZP-PLGA NPs showed higher plasma GABA levels, longer sedative, hypnotic effects, and a 3.42-fold augmentation in oral drug bioavailability in comparison to ZP-marketed products. Moreover, parenteral administration of ZP-NPs showed higher anticonvulsant activity compared to free drug. Oral administration of ZP-PLGA NPs achieved a significant improvement in the drug bioavailability, and parenteral administration showed a pronounced anticonvulsant activity.

Plasma amino acids profile in first-episode psychosis, unaffected siblings and community-based controls.

Investigations of plasma amino acids in early psychosis and their unaffected siblings are rare. We measured plasma amino acids involved in the co-activation of dopaminergic, GABAergic, glutamatergic, and serotoninergic neurotransmitters in first-episode psychosis (FEP) patients (n = 166), unaffected siblings (n = 76), and community-based controls (n = 166) included in a cross-sectional study. Plasma levels of glutamic acid (GLU), glutamine, glycine, proline (PRO), tryptophan (TRP), tyrosine, serine and GABA were quantified by gas-chromatography-mass spectrometry. We used the generalized linear model adjusted by sex, age, and body mass index for group comparison and paired t-test for FEP-Sibling pairs. FEP had reduced GABA plasma levels compared to siblings and controls (p < 0.05 for both). Siblings had lower GLU, Glx and PRO (p < 0.05 for all) but increased TRP compared to patients and controls (p < 0.05 for both). FEP patients with longer duration of pharmacological treatment and medicated only with antipsychotics had increased GLU compared to FEP with shorter periods, or with those treated with a combination of medications (p < 0.05 for both). Finally, FEP patients treated only with antipsychotics presented higher Glx compared to those with mixed medications (p = 0.026). Our study suggests that FEP have low a GABA plasma profile. Unaffected siblings may be a possible risk group for metabolic abnormalities.

The free amino acid profiles and metabolic biomarkers of predicting the chemotherapeutic response in advanced sarcoma patients.

PURPOSE: Metabolomics is an emerging field in cancer research. Plasma free amino acid profiles (PFAAs) have shown different features in various cancers, but the characteristic in advanced sarcoma remains unclear. We aimed to uncover the specific PFAAs in advanced sarcoma and to find the relationship between the altering of PFAAs and response to chemotherapy. PATIENTS AND METHODS: We analyzed the differences in PFAAs between 23 sarcoma patients and 30 healthy subjects basing on liquid chromatography-tandem mass spectrometry (LC-MS/MS). Then, we compared the dynamics of PFAAs after chemotherapy between improvement group and deterioration group. RESULTS: We identified seven biological differential amino acids and four pathways which were perturbed in the sarcoma patients compared with healthy subjects. After one cycle chemotherapy, the levels of γ-aminobutyric acid (GABA) and carnosine (Car) decreased significantly in the improvement group but not in deterioration group. The levels of α-aminobutyric acid (Abu) increased significantly in the deterioration group but not in the improvement group. CONCLUSION: Our study suggests the potential specific PFAAs in sarcoma patients. The unusual amino acids and metabolic pathways may provide ideas for clinical drugs targeting therapy. Three amino acids including Car, GABA and Abu may be metabolic biomarkers playing a role in dynamic monitoring of the therapeutic effect.

Maternal separation in rats induces neurobiological and behavioral changes on the maternal side.

The time after parturition is a sensitive period for mothers where they are prone to develop psychopathological symptoms. Studies investigating dams after separation from their pups (maternal separation, MS) showed that MS induces alterations similar to postpartum depression. This study aims to give further details on affected behavior and neurobiology of dams after MS. MS in rats from postnatal day 2-20 over four hours daily was performed. Upon reunion, maternal behavior, and ultrasonic vocalization (USV) of dams were measured. On the day of weaning, dams were tested for anxiety-like behavior in the elevated-plus-maze and marble burying test. Then Morc1 mRNA in the medial prefrontal cortex and Nr3c1 encoding the glucocorticoid receptor mRNA in the hippocampus were measured using real-time PCR to examine possible neurobiological correlates in psychopathology and social behavior. GABA and glutamate serum levels were analyzed by high-performance liquid chromatography as peripheral markers for stress-induced psychopathology. MS in dams increased maternal care towards pups even though both groups show high levels of maternal behavior even in late lactation. Furthermore, the emission of 50-kHz and 22-kHz USVs increased significantly. No differences in anxiety-like behavior were detected. MS further reduced Morc1 but not Nr3c1 expression. Serum GABA but not glutamate levels were significantly increased in separated dams. This study reinforces the benefit of investigating dams after MS for studying postpartum stress. Subclinical markers mainly connected to depression, namely Morc1 and GABA, proved to be useful allowing for earlier detection of symptoms of critical postpartum stress.

Gender-Related Differences on Polyamine Metabolome in Liquid Biopsies by a Simple and Sensitive Two-Step Liquid-Liquid Extraction and LC-MS/MS.

Polyamines are involved in the regulation of many cellular functions and are promising biomarkers of numerous physiological conditions. Since the concentrations of these compounds in biological fluids are low, sample extraction is one of the most critical steps of their analysis. Here, we developed a comprehensive, sensitive, robust, and high-throughput LC-MS/MS stable-isotope dilution method for the simultaneous determination of 19 metabolites related to polyamine metabolism, including polyamines, acetylated and diacetylated polyamines, precursors, and catabolites from liquid biopsies. The sample extraction was optimized to remove interfering compounds and to reduce matrix effects, thus being useful for large clinical studies. The method consists of two-step liquid-liquid extraction with a Folch extraction and ethyl acetate partitioning combined with dansyl chloride derivatization. The developed method was applied to a small gender-related trial concerning human serum and urine samples from 40 obese subjects. Sex differences were found for cadaverine, putrescine, 1,3-diaminopropane, γ-aminobutyric acid, N8-acetylspermidine, and N-acetylcadaverine in urine; N1-acetylspermine in serum; and spermine in both serum and urine. The results demonstrate that the developed method can be used to analyze biological samples for the study of polyamine metabolism and its association with human diseases.

Lithium and GADL1 regulate glycogen synthase kinase-3 activity to modulate KCTD12 expression.

Potassium channel tetramerization domain containing 12 (KCTD12), the auxiliary GABAB receptor subunit, is identified as a susceptibility gene for bipolar I (BPI) disorder in the Han Chinese population. Moreover, the single-nucleotide polymorphism (SNP) rs17026688 in glutamate decarboxylase-like protein 1 (GADL1) is shown to be associated with lithium response in Han Chinese BPI patients. In this study, we demonstrated for the first time the relationship among lithium, GADL1, and KCTD12. In circulating CD11b+ macrophage cells, BPI patients showed a significantly higher percentage of KCTD12 expression than healthy controls. Among BPI patients, carriers of the 'T' allele (i.e., CT or TT) at site rs17026688 were found to secrete lower amounts of GADL1 but higher amounts of GABA b receptor 2 (GABBR2) in the plasma. In human SH-SY5Y neuroblastoma cells, lithium treatment increased the percentage of KCTD12 expression. Through inhibition of glycogen synthase kinase-3 (GSK-3), lithium induced cyclic AMP-response element binding protein (CREB)-mediated KCTD12 promoter activation. On the other hand, GADL1 overexpression enhanced GSK-3 activation and inhibited KCTD12 expression. We found that lithium induced, whereas GADL1 inhibited, KCTD12 expression. These findings suggested that KCTD12 may be an important gene with respect to neuron excitability and lithium response in BPI patients. Therefore, targeting GSK-3 activity and/or KCTD12 expression may constitute a possible therapeutic strategy for treating patients with BPI disorder.

Effects of Sub-Acute Manganese Exposure on Thyroid Hormone and Glutamine (Gln)/Glutamate (Glu)-γ- Aminobutyric Acid (GABA) Cycle in Serum of Rats.

Excessive manganese (Mn) exposure may adversely affect the central nervous system, and cause an extrapyramidal disorder known as manganism. The glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle and thyroid hormone system may be involved in Mn-induced neurotoxicity. However, the effect of Mn on the Gln/Glu-GABA cycle in the serum has not been reported. Herein, the present study aimed to investigate the effects of sub-acute Mn exposure on the Gln/Glu-GABA cycle and thyroid hormones levels in the serum of rats, as well as their relationship. The results showed that sub-acute Mn exposure increased serum Mn levels with a correlation coefficient of 0.733. Furthermore, interruption of the Glu/Gln-GABA cycle in serum was found in Mn-exposed rats, as well as thyroid hormone disorder in the serum via increasing serum Glu levels, and decreasing serum Gln, GABA, triiodothyronine (T3) and thyroxine (T4) levels. Additionally, results of partial correlation showed that there was a close relationship between serum Mn levels and the detected indicators accompanied with a positive association between GABA and T3 levels, as well as Gln and T4 levels in the serum of Mn-exposed rats. Unexpectedly, there was no significant correlation between serum Glu and the serum T3 and T4 levels. In conclusion, the results demonstrated that both the Glu/Gln-GABA cycle and thyroid hormone system in the serum may play a potential role in Mn-induced neurotoxicity in rats. Thyroid hormone levels, T3 and T4, have a closer relationship with GABA and Gln levels, respectively, in the serum of rats.

Minocycline ameliorates anxiety-related self-grooming behaviors and alters hippocampal neuroinflammation, GABA and serum cholesterol levels in female Sprague-Dawley rats subjected to chronic unpredictable mild stress.

Neuroinflammation induced by stress results in aberrant neurotransmission and dyslipidemia, which can trigger depression- and anxiety-like behaviors. Gamma-aminobutyric acid (GABA) and cholesterol play a crucial role in anxiety-like states, including self-grooming - a common stress-evoked rodent behavior. However, the interaction between neuroinflammation, GABA and cholesterol under stress, and their effects on grooming, remain unclear. Here, we utilize the chronic unpredictable mild stress (CUMS) rat cohort used previously in our Zhang et al. (2019) study, to examine whether CUMS affects grooming behavior, and whether minocycline, a microglia antagonist, can correct these behavioral deficits, accompanied by altering hippocampal neuroinflammation, GABA and serum cholesterol levels. Female Sprague-Dawley rats underwent a 6-week CUMS and received daily minocycline (40 mg/kg, i.p.) during this period, followed by behavioral testing in the open field test. Serum cholesterol, inflammatory cytokines and GABA levels in hippocampus were assayed by ELISA. CUMS significantly decreased locomotion, rearing, central zone entries and time spent in the open field center compared to unstressed controls. CUMS also strongly affected self-grooming behaviors, increasing the frequency of grooming episodes, the number of transitions, interruptions and individual elements of various grooming phases. However, these CUMS-induced behavioral abnormalities were corrected by minocycline. Likewise, CUMS elevated total serum cholesterol and lowered serum high-density lipoprotein cholesterol, whereas minocycline ameliorated these responses. CUMS also lowered hippocampal GABA, whereas minocycline normalized CUMS-induced GABA in the hippocampus. We also found significant correlations between neuroinflammation and GABA, neuroinflammation and cholesterol, GABA and grooming, as well as cholesterol and grooming measures, further implicating stress-evoked neuroinflammation, GABA and cholesterol in the regulation of complex rodent behaviors. In summary, minocycline ameliorated CUMS-induced aberrant self-grooming behaviors in rats by altering hippocampal neuroinflammation, GABA and serum cholesterol levels.