Glutamato monosódico y suprasistema neuroendocrinoinmune murino

Introducción: El glutamato monosódico se emplea en humanos desde el pasado siglo como potenciador del sabor. Su inoculación parenteral en murinos durante el período neonatal causa lesiones en varios núcleos hipotalámicos. Objetivo: Describir los efectos del glutamato monosódico sobre el sistema neuroendocrinoinmune en murinos. Metodos: Se realizó una revisión de artículos de libre acceso en las bases de datos PubMed y SciELO entre enero de 2013 y julio de 2020. También se examinó el texto básico de la asignatura Sangre y Sistema Inmune de la carrera de medicina. Desarrollo: Con independencia de su efecto adictivo, varios estudios defienden la inocuidad del glutamato monosódico. Sin embargo, este compuesto puede atravesar la barrera hematoencefálica de neonatos de murinos, y ocasionar trastornos metabólicos, reproductivos y del sistema inmune. Conclusiones: El glutamato monosódico en roedores causa alteraciones en los órganos que integran el suprasistema neuroendocrinoinmune y, por tanto, afecta sus funciones homeostáticas. Los mecanismos patogénicos no se conocen con exactitud.

Introduction: Monosodium glutamate has been used in humans since the last century as a flavor enhancer. Its parenteral inoculation in murine during the neonatal period causes lesions in several hypothalamic nuclei. Objective: To describe the effects of monosodium glutamate on the neuroendocrine immune system in murine samples. Methods: A review of open access articles in the PubMed and SciELO databases was conducted between January 2013 and July 2020. The basic text of the Blood and Immune System course of the medical school was also reviewed. Development: Regardless of its addictive effect, several studies defend the safety of monosodium glutamate. However, this compound can cross the blood-brain barrier of murine neonates, causing metabolic, reproductive and immune system disorders. Conclusions: Monosodium glutamate in rodents causes alterations in the organs that make up the neuroendocrine-immune suprasystem and, therefore, affects their homeostatic functions. The pathogenic mechanisms are not known exactly.

Characterization of group Ⅰ metabotropic glutamate receptors in rat superior cervical ganglion and their changes following chronic intermittent hypoxia / 解剖学报

Objective To observe the expression and localization of group Ⅰ metabotropic glutamate receptors (mGluR1/ 5) in rat superior cervical ganglion (SCG) and the effect of chronic intermittent hypoxia (CIH) on mGluR1/ 5 protein level. Methods Twelve male SD rats were randomly divided into control group(Ctrl)and CIH group(CIH), 6 rats in each group. After 6 weeks of modeling, the effect of CIH on mGluR1/ 5 protein level was detected by Western blotting, the expression and distribution of mGluR1/ 5 in SCG were detected by immunohistochemistry and double-immunofluorescent staining. Results mGluR1/ 5 was expressed in rat SCG. mGluR1 was distributed in neurons and small intensely fluorescent (SIF) cells, but not in satellite glial cells (SGCs), nerve fibers and blood vessels, whereas mGluR5 was mainly distributed in nerve fibers and a little in neurons, but not in SGCs, SIF cells and blood vessels. CIH increased the protein levels of mGluR1/ 5 (P<0. 01) in rat SCG. Conclusion Both mGluR1 and mGluR5 are expressed in the rat SCG, but their distribution are different, and the increased protein levels of both may be involved in CIH-induced hypertension.

Advances of pathogenesis and drug development in amyotrophic lateral sclerosis / 中国药理学通报

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons. ALS patients develop progressive muscle atrophy, muscle weak and paralysis, finally died of respiratory failure. ALS is characterized by fast aggression and high mortality. What' s more, the disease is highly heterogeneous with unclear pathogenesis and lacks effective drugs for therapy. In this review, we summarize the main pathological mechanisms and the current drugs under development for ALS, which may provide a reference for the drug discovery in the future.

Protective Role of Pomegranate on kidney of Albino Rat Treated with Monosodium Glutamate

Background: Sodium mono glutamate (MSG), the sodium salt of glutamic acid, is a food flavoring agent that is widely used in many countries. Pomegranate is used as a traditional medication in numerous countries, it is planted in Asian countries, Mediterranean countries and the U.S.A. Aim of the work: The present study aimed to detect structural and functional changes in adult rat kidney tissue treated with sodium mono glutamate, and the possible protective effect of pomegranate on the kidney treated with MSG. Materials and Methods: This study was done by using 60 adult Wistar Albino rats of both sexes were divided into three equal groups: Group I (control group), Group II (sodium mono glutamate treated group), and Group III (combined MSG and pomegranate treated group) Doses were given once daily for 8 weeks every day. At the end of the treatment period, blood samples collected from each rat were used for measuring the values of urea and creatinine. Also animals of the different groups were sacrificed at the end of the experiment, quickly dissected and the kidneys were removed and stained with hematoxylin and eosin (H&E) for the histological examination by light microscopy, other tissue sections were evaluated using a transmission electron microscope. Both were used to examine the effect of sodium mono glutamate on cortex of the kidneys of albino rats ,compared with control group and the combined MSG and pomegranate group. Results: There was a major rise in blood urea level and blood creatinine level in sodium mono glutamate treated group in contrast to the control group. There was a significant reduction in blood urea level and blood creatinine level in combined sodium mono glutamate and pomegranate treated group in comparison to MSG treated group. Examination of kidney tissue of rats treated with sodium mono glutamate (Group. II) showed damaging changes of its structure. The glomerulus had markedly widened blood capillaries with thickened filtration membrane. The epithelial tubular cells had marked degenerative changes. Examination of rats kidney tissue treated with sodium mono glutamate and pomegranate (Group III) revealed improvement of the lesions in the glomeruli and renal tubules. Conclusion: Pomegranate protected the kidneys and restricted the histological and functional alterations caused by sodium mono glutamate, and thus, there is an advantage of usage of pomegranate with sodium mono glutamate.

Variaciones morfológicas de la glándula submandibular en ratas obesas por acción de glutamato monosódico / Morphological variations of the submandibular gland in obese rats by the action of monosodium glutamate

Este estudio tuvo como objetivo demostrar la existencia de variaciones morfológicas en el tejido conectivo de la glándula submandibular de ratas obesas expuestas a glutamato monosódico (GMS). Se utilizaron 12 ratas Sprague Dawley machos recién nacidas (6 ratas para el grupo 1, control; 6 ratas para el grupo 2 (GMS), 4 mg/g de glutamato monosódico de peso (5 dosis) mantenidas por 16 semanas respectivamente con una dieta y agua ad libitum. En el estudio se realizó un análisis estereológico e histológico, demostrándose una variación en el tejido conectivo presentando una disminución del volúmen glandular, mayor fibrosis, y disminución de adipocitos a nivel periférico siendo reemplazado por tejido rico en colágeno. Los vasos sanguíneos observados a nivel estereológico no presentan mayores cambios en cuanto a volumen, superficie y área.

SUMMARY: This study aims to demonstrate the existence of morphological variations in the connective tissue of the submandibular gland of obese rats exposed to MSG. Twelve male newborn Sprague Dawley rats were used (6 rats for group 1, control; 6 rats for group 2 (MSG), 4 mg/g of monosodium glutamate of weight (5 doses) maintained for 16 weeks respectively with a diet and water ad libitum. In the study, a stereological and histological analysis was carried out, demonstrating a variation in the connective tissue, presenting a decrease in the glandular volume, greater fibrosis, and a decrease in adipocytes at the peripheral level, being replaced by tissue rich in collagen. Blood cells observed at the stereological level do not present major changes in terms of volume, surface and area, but in the histological study greater vascularization is observed.

Subchronic Administration of High-dose Monosodium Glutamate Causes Spatial Memory Dysfunction and Structural Deficits of Rat Hippocampus

@#Introduction: The toxicity of high concentration monosodium glutamate (MSG) has become a controversial issue because of its inconsistent results in human and animal studies. This present study aims to evaluate the effect of subchronic high-doses oral administration of MSG on spatial memory performance and hippocampal pyramidal cells number. Methods: This study involved twenty-eight male Wistar rats, which were divided into a control group of NaCl 0.9% and three intervention groups of MSG 1.0 mg/g bodyweight (M1), 2.0 mg/g bodyweight (M2), and 4.0 mg/g bodyweight (M3) for 30 days. Statistical analysis used a One-way ANOVA test. Results: The result showed significant differences in spatial memory on the Morris Water Maze (MWM) test, including path length (p = 0.020) and escape latency (p = 0.011) according to general linear model repeated measurement analysis. The mean difference of estimated hippocampal pyramidal cells total number among the groups showed volume (p = 0.001), numerical density (p = 0.590), and cells number (p = 0.004). Furthermore, Post-Hoc analysis in both spatial memory and hippocampal pyramidal cells showed that the increasing MSG dose from 1.0 to 4.0 mg/g bodyweight led to a decrease in the results of spatial memory performance on the MWM test and a decrease in hippocampal cells. Conclusion: The present study has provided novel quantitative data that subchronic administration of high-dose MSG caused deleterious effects on the spatial memory function and the volume and number of hippocampal pyramidal cells.

Effects of Yudian Decoction （愈癫汤） on the Metabolic Balance of Glu/GABA in the Brain Tissue of Schizophrenia Model Rats / 中医杂志

ObjectiveTo explore the possible mechanism of Yudian Decoction （愈癫汤） in the treatment of schizophrenia. MethodTwenty male offspring from 5 normal female 17-day-pregnant SD rats were selected as blank group. Fifteen female 17-day-pregnant SD rats were injected intraperitoneally with methyl azomethine acetate （MAM） 25 mg/kg， and the male offspring simulated the neurodevelopmental abnormality to establish a rat model of schizophrenia. Sixty successfully-modeled rats were randomly divided into 20 rats in the model group， 20 rats in the Yudian Decoction group and 20 risperidone group. After 3 days of adaptive cage feeding， the rats in the Yudian Decoction group were gavaged with 1.54 g/（kg·d） of Yudian Decoction， the risperidone group was gavaged with 0.24 mg/（kg·d） of risperidone capsule， while the blank group and the model group were gavaged with 6.7 ml/（kg·d） of distilled water， once a day， for 14 consecutive days. Sample was collected on the day after the last gavage. The expression of glutamate receptor （GluR） and γ-aminobutyric acid receptor subunit α1 （GABAARα1）-positive neurons in the hippocampus and prefrontal cortex were detected by immunofluorescence， and the positive rate was calculated； the expression of small clear proteins （PVs） in the hippocampal CA1 region and the medial prefrontal cortex was detected by immunohistochemistry； The expression of glutamic acid decarboxylase 65 （GAD65） and glutamic acid decarboxylase 67 （GAD67） proteins and mRNAs in the hippocampus and prefrontal cortex were detected by immunoblotting and reverse transcription PCR. ResultCompared with the blank group， the positive rate of GluR in hippocampal area and prefrontal cortex of rats in the model group increased， the positive rate of GABAARα1 in hippocampal area decreased， the PV optical density value in hippocampal CA1 area and medial prefrontal cortex decreased， and the expression of GAD65， GAD67 proteins and mRNA in hippocampal area and prefrontal cortex decreased （P＜0.05 or P＜0.01）. Compared with the model group， GluR positivity rate in hippocampus and prefrontal cortex of risperidone group and Yudian Decoction decreased， GABAARα1 positivity rate in hippocampus increased， PV optical density value in hippocampus CA1 area and medial prefrontal cortex increased， and GAD65， GAD67 proteins and mRNA expression in hippocampus and prefrontal cortex increased （P＜0.05 or P＜0.01）. Compared with the risperidone group， the positive rate of GluR in hippocampus and prefrontal cortex and GABAARα1 in hippocampus in the Yudian Decoction group was reduced， the PV optical density value of hippocampal CA1 area was increased， the protein and mRNA expression of GAD67 in hippocampus area was elevated， and the protein expression of GAD65 in prefrontal cortex was reduced （P＜0.05）. ConclusionYudian Decoction may improve the pathological process of schizophrenia by regulating key regulators of glutamate/γ-aminobutyric acid （Glu/GABA） metabolic balance in the hippocampus and prefrontal cortex and maintaining the balance between neuronal excitation and inhibition.

Progressive encephalomyelitis with rigidity and myoclonus: a case report / 中华神经科杂志

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a specific subtype of the stiff-person syndrome, which is rare and difficult to diagnose clinically. A case of PERM in a 66-year-old female with a fluctuating progressive course was reported in this article. She had increased facial muscle tone, pruritus and sensory hypersensitivity mainly in the head and neck, medullary involvement syndrome and bilateral lower limb rigidity as the main clinical manifestations, and a previous history of pulmonary malignancy, thymoma, typeⅠ diabetes and Hashimoto′s thyroiditis. The patient′s serum and cerebrospinal fluid were positive for anti-glutamic acid decarboxylase antibody. The electromyogram showed a large number of motor unit potentials in the trunk and proximal extremities in the quiet state, which were significantly enhanced during spastic episodes, consistent with the electromyographic manifestations of stiff-person syndrome. The final diagnosis was PERM, and immunotherapy including gamma globulin and hormone responded well. PERM is a rare neurological autoimmune disease with atypical early symptoms, which can be easily misdiagnosed, and it requires attention to avoid delaying the diagnosis.

Role of activation of VGLUT2 neurons in vagal nodose ganglion in dexmedetomidine-caused bradycardia in mice / 中华麻醉学杂志

Objective:To evaluate the role of activation of vesicular glutamate transporter 2 (VGLUT2) neurons in vagal nodose ganglion in dexmedetomidine-caused bradycardia in mice.Methods:Ninety-six SPF healthy male VGLUT2-cre mice, aged 10 weeks, weighing 20-25 g, were divided into 6 groups ( n=16 each) by the random number table method: normal saline control group (NS group), dexmedetomidine group (Dex group), viral control + chemogenetic control + dexmedetomidine group (eGFP-NS+ Dex group), viral transfection + chemogenetic control + dexmedetomidine group (hM4Di-NS+ Dex group), viral control + chemogenetic inhibition + dexmedetomidine group (eGFP-CNO+ Dex group) and viral transfection + chemogenetic inhibition + dexmedetomidine group (hM4Di-CNO+ Dex group). Dexmedetomidine 100 μg/kg was intraperitoneally injected in Dex group. The equal volume of normal saline was intraperitoneally injected in NS group. AAV2/9-hSyn-DIO-hM4Di-eGFP was injected in the right nodose ganglion in hM4Di-NS+ Dex group and hM4Di-CNO+ Dex group, and AAV2/9-hSyn-DIO-eGFP was injected in the right nodose ganglion in eGFP-NS+ Dex group and eGFP-CNO+ Dex group, allowing the virus expression for 21 days. On the 22nd day after virus injection, clozapine-n-oxide (CNO) 5 mg/kg was intraperitoneally injected in hM4Di-CNO+ Dex group and eGFP-CNO+ Dex group, the equal volume of normal saline was intraperitoneally injected in hM4Di-NS+ Dex group and eGFP-NS+ Dex group, 1 h later the efficacy of CNO reached the peak, and then dexmedetomidine 100 μg/kg was intraperitoneally injected. The respiratory rate, heart rate, SpO 2 and discharge frequency of the right vagal nodose ganglion were synchronously measured by multi-channel electrophysiology in vivo. The expression of phosphorylated extracellular signal-regulated kinase (pERK) and VGLUT2 and co-expression of pERK and VGLUT2 in the right vagal nodose ganglion were detected by immunofluorescence assay. Results:Compared with NS group, the percentage of heart rate variation and neuron firing frequency after administration were significantly increased, and pERK expression was up-regulated in the other five groups ( P<0.05). Compared with Dex group, the percentage of heart rate variation and neuron firing frequency after administration were significantly decreased, and pERK expression was down-regulated in hM4Di-CNO+ Dex group, and no significant change was found in the parameters mentioned above in hM4Di-NS+ Dex group, eGFP-NS+ Dex group and eGFP-CNO+ Dex group ( P>0.05). Compared with hM4Di-CNO+ Dex group, the percentage of heart rate variation and neuron firing frequency after administration were significantly increased, and pERK expression was up-regulated in eGFP-CNO+ Dex group ( P<0.05). There was no significant difference in the percentage of respiratory variation and SpO 2 among the six groups ( P>0.05). The expression of VGLUT2-positive neurons was abundant in nodose ganglia, and the co-expression rate of pERK and VGLUT2 was nearly 90%. The co-expression rate of pERK and VGLUT2 decreased to about 30% after inhibition of VGLUT2 neurons in ganglion. Conclusions:The mechanism by which dexmedetomidine causes bradycardia is associated with activation of VGLUT2 neurons in vagal nodose ganglia in mice.

Role of Homer1a/mGluR5 signaling pathway in cognitive dysfunction induced by sleep deprivation in aged rats / 中华麻醉学杂志

Objective:To evaluate the role of Homer1a/metabotropic glutamate receptor 5 (mGluR5) signaling pathway in sleep deprivation-induced cognitive dysfunction in aged rats.Methods:One hundred and four SPF healthy male Sprague-Dawley rats, aged 22-24 months, weighing 320-360 g, were divided into 4 groups ( n=26 each) using a random number table method: normal control group (group Control), sleep deprivation+ vehicle group (group SD+ Vehicle), sleep deprivation+ mGluR5 forward allosteric agent CDPPB group (group SD+ CDPPB), and sleep deprivation+ mGluR5 antagonist MPEP group (group SD+ MPEP). A 48-h sleep deprivation model was developed by sleep-deprived rod method. At the beginning of developing the model and 24 h after developing the model, CDPPB 10 mg/kg, MPEP 10 mg/kg and the equal volume of 1% Tween 80 were intraperitoneally injected in group SD+ CDPPB, group SD+ MPEP and group SD+ Vehicle, respectively.Morris water maze and novel object recognition tests were conducted to evaluate cognitive function after development of the model. The expression of Homer1a and mGluR5 in the hippocampus was detected by Western blot, the dendritic spine density in the hippocampal CA1 region was detected by Golgi staining, and the field excitatory postsynaptic potential (fEPSP) slope in the hippocampal CA1 region was detected by isolated electrophysiology. Results:Compared with Control group, the number of crossing the original platform, time of staying at the target quadrant, and novel object recognition index at 1 and 24 h after training were significantly decreased, the expression of Homer1a in the hippocampus was up-regulated, the expression of mGluR5 in the hippocampus was down-regulated, and the density of dendritic spine and fEPSP slope in the hippocampal CA1 region were decreased in group SD+ Vehicle ( P<0.05). Compared with group SD+ Vehicle, the number of crossing the original platform, time of staying at target quadrant, and novel object recognition index at 1 and 24 h after training were significantly increased, the expression of mGluR5 in hippocampus was up-regulated, and the density of dendritic spines and fEPSP slope in the hippocampal CA1 region were increased in group SD+ MPEP( P<0.05), and no statistically significant change was found in the parameters mentioned above in group SD+ CDPPB ( P>0.05). Conclusions:Sleep deprivation impairs the synaptic plasticity of hippocampal neurons by regulating Homer1a/mGluR5 signaling pathway, and thus mediating the process of cognitive dysfunction in aged rats.

Caudate nucleus and thalamus in untreated patients with obsessive-compulsive disorder: a magnetic resonance spectroscopy study / 中华行为医学与脑科学杂志

Objective:To investigate the neurobiochemical metabolites of caudate nucleus and thalamus in patients with obsessive-compulsive disorder and their relationship with obsessive-compulsive symptoms.Methods:From April 2019 to January 2022 in Beijing Anding Hospital, totally 25 untreated patients with obsessive-compulsive disorder were recruited, and 20 healthy controls matched with gender, age and educational background were recruited for the study.The maps of neurobiochemical metabolites of patients and normal controls were collected by hydrogen proton magnetic resonance spectroscopy.With bilateral caudate nucleus and thalamus as brain regions of interest.The relative concentrations of N-acetylaspartic acid (NAA), glutamic acid (Glu) and γ-aminobutyric acid (GABA) were fitted by LCModel software.At the same time, the clinical symptoms of patients were evaluated with Yale-Brown obsessive-compulsive scale (Y-BOCS) and Hamilton anxiety scale (HAMA). SPSS 20.0 software was used for statistical analysis.Independent double sample t-test was used to compare the differences of different nerve biochemical metabolite concentrations between patients with obsessive-compulsive disorders and healthy controls.Pearson correlation analysis was used to explore the correlation between biochemical metabolite concentrations and clinical symptoms. Results:The Glu concentration in the left thalamus of patients with obsessive-compulsive disorder (3.97±0.41) was higher than that of the control group (3.66±0.55)( t=-2.11, P<0.05), while the NAA concentration was (4.87±0.47)lower than that of the control group (5.15±0.44)( t=2.05, P<0.05). The GABA concentrations in the right caudate nucleus (0.50±0.18) and thalamus (0.80±0.19) were lower than those in the control group ((0.63±0.23), (0.96±0.24))( t=2.08, 2.36, both P<0.05). Pearson correlation analysis showed that the Glu concentration in the left caudate nucleus of patients with obsessive-compulsive disorder was positively correlated with the total score of Y-BOCS( r=0.46, P<0.05). Spearman correlation analysis showed that Glu concentration in the right caudate nucleus was positively correlated with the total score of HAMA in patients with obsessive-compulsive disorder ( r=0.46, P<0.05). Conclusion:NAA, Glu and GABA metabolism in caudate nucleus and thalamus are abnormal in patients with obsessive-compulsive disorder, and Glu concentration is positively correlated with the severity of obsessive-compulsive and anxiety symptoms.

Mechanism of Dihuang Yinzi in Improving Astrocyte Injury and Regulating Synaptic Structure and Function in AD Mice / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of Dihuang Yinzi in improving astrocyte injury and protecting synaptic structure and function in the brain of Alzheimer's disease （AD） mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. The mice in the control + Dihuang Yinzi group and the model + Dihuang Yinzi group were administered with Dihuang Yinzi by gavage， and those in the control group and the model group received an equal volume of sterilized normal saline， once a day for 150 days. The learning and memory ability of mice was tested by the light-dark box test and Y-maze spontaneous alternation test. The content of glutamate （Glu） and glutamine （Gln） was measured by liquid chromatography-tandem mass spectrometry （LC-MS）. Long-term potentiation （LTP） assay was used to detect synaptic plasticity in brain tissues. The protein expression levels of excitatory amino acid transporter 2 （EAAT2）， postsynaptic density protein95 （PSD95）， and synaptophysin （SYN） in brain tissues were measured by Western blot. Immunofluorescence was used to assess the localization and expression of EAAT2. Colorimetry was performed to detect Na+-K+ ATPase activity in mouse brain tissues. ResultAs compared with the control group， the model group showed shortened residence latency （P<0.01）， increased number of errors （P<0.01） in the light-dark box test， reduced spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， down-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， blunted activity of Na+-K+ ATPase （P<0.01）， up-regulated Glu level （P<0.01）， down-regulated Gln level （P<0.01）， and reduced relative population spike （PS） amplitude and the slope of excitatory postsynaptic potential （EPSP） （P<0.05， P<0.01）， while the above experimental indexes were not significantly different in the control + Dihuang Yinzi group. Compared with the model group， the model + Dihuang Yinzi group displayed prolonged residence latency （P<0.05）， decreased number of errors （P<0.01） in the light-dark box test， increased spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， up-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， potentiated activity of Na+-K+ ATPase （P<0.01）， reduced Glu level （P<0.01）， up-regulated Gln level （P<0.01）， and increased PS amplitude and EPSP slope （P<0.01）. ConclusionDihuang Yinzi can improve cognitive dysfunction in AD mice by protecting astrocytes， increasing Glu uptake to reduce its abnormal accumulation， and protecting synaptic structure and function.

Glutamate-releasing BEST1 channel is a new target for neuroprotection against ischemic stroke with wide time window

Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6-72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.

Rational metabolic engineering of Corynebacterium glutamicum for efficient synthesis of L-glutamate / 生物工程学报

L-glutamic acid is the world's largest bulk amino acid product that is widely used in the food, pharmaceutical and chemical industries. Using Corynebacterium glutamicum G01 as the starting strain, the fermentation by-product alanine content was firstly reduced by knocking out the gene encoding alanine aminotransferase (alaT), a major by-product related to alanine synthesis. Secondly, since the α-ketoglutarate node carbon flow plays an important role in glutamate synthesis, the ribosome-binding site (RBS) sequence optimization was used to reduce the activity of α-ketoglutarate dehydrogenase and enhance the glutamate anabolic flow. The endogenous conversion of α-ketoglutarate to glutamate was also enhanced by screening different glutamate dehydrogenase. Subsequently, the glutamate transporter was rationally desgined to improve the glutamate efflux capacity. Finally, the fermentation conditions of the strain constructed using the above strategy were optimized in 5 L fermenters by a gradient temperature increase combined with a batch replenishment strategy. The glutamic acid production reached (135.33±4.68) g/L, which was 41.2% higher than that of the original strain (96.53±2.32) g/L. The yield was 55.8%, which was 11.6% higher than that of the original strain (44.2%). The combined strategy improved the titer and the yield of glutamic acid, which provides a reference for the metabolic modification of glutamic acid producing strains.

Review of research progress on neurotransmitter function and depression / 中国药理学通报

Depression is one of the most common psychiatric disorders with high prevalence, disability and relapse rates, and its etiology and pathogenesis are complex and still not fully understood. Neurotransmitters play a key role in maintaining chemical homeostasis in brain, and many studies have shown a strong link between neurotransmitters and the development and treatment of depression in recent years. Therefore, studying the neurotransmitters associated with depression has the potential to provide research targets and ideas for the pathogenesis and treatment strategies of depression. This paper reviews the recent domestic and foreign research results on neurotransmitter function and the pathogenesis of depression, aiming to analyze the in-depth relationship between neurotransmitter function and the pathogenesis of depression, and provide research ideas for the follow-up ex-ploration of the pathogenesis and diagnosis and treatment strategies of depression.

Yigong Powder regulates CXCL12/CXCR4 signaling to reduce glutamate release and prevent cognitive decline in mouse model of aging / 中国中药杂志

This study aims to explore the effect of preventive administration of Yigong Powder on the learning and memory abilities of the mouse model of aging induced by D-galactose and decipher the underlying mechanism, so as to provide a basis for the application of Yigong Powder in the prevention and treatment of cognitive decline. Forty KM mice were randomized into control, model, donepezil(1.5 mg·kg~(-1)), and high-dose(7.5 g·kg~(-1)) and low-dose(3.75 g·kg~(-1)) Yigong Powder groups. The mice in other groups except the control group were injected with D-galactose(200 g·kg~(-1)) at the back of the neck for the modeling of aging. At the same time, the mice were administrated with corresponding drugs by gavage for one month. Morris water maze was used to examine the learning and memory abilities of the mice. Hematoxylin-eosin staining was employed to observe the pathological and morphological changes of the hippocampus. The immunofluorescence assay was employed to detect the expression of ionized calcium-binding adapter molecule 1(IBA1), glial fibrillary acidic protein(GFAP), chemokine C-X-C-motif ligand 12(CXCL12), chemokine C-X-C-motif receptor 4(CXCR4) in the hippocampus and observe the positional relationship between IBA1, GFAP, and CXCR4. Western blot was employed to determine the protein levels of extracellular regulated kinase(ERK), p-ERK, and tumor necrosis factor receptor 1(TNFR1). Enzyme-linked immunosorbent assay was employed to measure the levels of glutamate and tumor necrosis factor(TNF-α) in the brain tissue and the level of TNF-α in the serum and spleen. Yigong Powder significantly shortened the escape latency, increased the times crossing platforms, and prolonged the cumulative time in quadrants of the aging mice. It alleviated the nerve cell disarrangement, increased intercellular space, and cell degeneration or death in the hippocampus and reduced the pathology score of the damaged nerve. Moreover, Yigong Powder reduced the positive area of IBA1 and GFAP, reduced the levels of TNF-α in the brain tissue, serum, and spleen, and decreased spleen index. Furthermore, Yigong Powder decreased the average fluorescence intensity of CXCL12 and CXCR4, reduced CXCR4-positive astrocytes and microglia, down-regulated the protein levels of p-ERK/ERK and TNFR1, and lowered the level of glutamate in the brain tissue. This study showed that the preventive administration of Yigong Powder can ameliorate the learning and memory decline of the D-galactose-induced aging mice by regulating the immune function of the spleen and the CXCL12/CXCR4 signaling in the brain to reduce glutamate release. However, the mechanism of Yigong San in preventing and treating dementia via regulating spleen and stomach function remains to be studied.

The role of NMDA glutamate receptors in lung injury caused by chronic long-term intermittent hypobaric hypoxia

Chronic intermittent hypoxia (CIH), a component of sleep apnea-hypopnea syndrome, is suggested to cause damage to lung tissue, and the role of glutamate is not well studied. We used a chronic long-term intermittent hypobaric hypoxia (CLTIHH) model of rats to find out if such procedure causes lung injury and the potential effect of N-methyl-D-aspartate receptors (NMDARs) by using receptor antagonist MK-801 (dizocilpine). Thirty-two rats were placed into four groups; a control and three CLTIHH groups where rats were placed into a low-pressure chamber set to 430 mmHg for 5 h/day, 5 days/week, for 5 weeks. Only one group received MK-801 (0.3 mg/kg, ip) daily. We evaluated tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nuclear factor (NF)-kB for the inflammatory process, superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), total antioxidant status (TAS), and total oxidant status (TOS) for oxidative stress, and caspase-9 levels. Blood plasma, bronchoalveolar fluid (BALF), and lung tissue extracts were evaluated. Both oxidant and inflammatory parameters were significantly increased in all the mediums of the CLTIHH groups except the group that received MK-801. Significant evidence was collected on MK-801 alleviating the effect of CLTIHH. Histological evaluations revealed lung damage and fibrotic changes in the CLTIHH groups. It was first shown that the CLTIHH procedure caused chronic lung injury, and that inflammation and oxidant stress were influential in the formation of lung injury. Secondly, NMDAR antagonist MK-801 effectively inhibited the development of lung injury and fibrosis.

Vitamin E suppresses aortic ultrastructural alterations induced by toxic doses of monosodium glutamate / La vitamina E suprime las alteraciones ultraestructurales aórticas inducidas por dosis tóxicas de glutamato monosódico

SUMMARY: An association between certain food additives and chronic diseases is reported. Current study determined whether administering toxic doses of the food additive monosodium glutamate (MSG) into rats can induce aortopathy in association with the oxidative stress and inflammatory biomarkers upregulation and whether the effects of MSG overdose can be inhibited by vitamin E. MSG at a dose of (4 mg/kg; orally) that exceeds the average human daily consumption by 1000x was administered daily for 7 days to the rats in the model group. Whereas, rats treated with vitamin E were divided into two groups and given daily doses of MSG plus 100 mg/ kg vitamin E or MSG plus 300 mg/kg vitamin E. On the eighth day, all rats were culled. Using light and electron microscopy examinations, a profound aortic injury in the model group was observed demonstrated by damaged endothelial layer, degenerated smooth muscle cells (SMC) with vacuoles and condensed nuclei, vacuolated cytoplasm, disrupted plasma membrane, interrupted internal elastic lamina, clumped chromatin, and damaged actin and myosin filaments. Vitamin E significantly protected aorta tissue and cells as well as inhibited MSG-induced tissue malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). The highest used vitamin E dosage was more effective. Additionally, a significant correlation was observed between the aortic injury degree and tissue MDA, TNF-α, IL-6, and superoxide dismutase (SOD) levels (p=0.001). Vitamin E effectively protects against aortopathy induced by toxic doses of MSG in rats and inhibits oxidative stress and inflammation.

RESUMEN: Se reporta una asociación entre ciertos aditivos alimentarios y enfermedades crónicas. El objetivo de este estudio fue determinar si la administración de dosis tóxicas del aditivo alimentario glutamato monosódico (MSG) en ratas puede inducir aortopatía en asociación con el estrés oxidativo y la regulación positiva de los biomarcadores inflamatorios y si el efecto de una sobredosis de MSG se puede inhibir con vitamina E. Se administró MSG diariamente durante 7 días una dosis de (4 g/kg; por vía oral) que excede el consumo diario humano promedio, en 1000x a las ratas del grupo modelo. Mientras que las ratas tratadas con vitamina E se dividieron en dos grupos y se administraron dosis diarias de MSG más 100 mg/kg de vitamina E o MSG más 300 mg/kg de vitamina E. Todas las ratas fueron sacrificadas en el octavo día. Usando exámenes de microscopía óptica y electrónica, se observó una lesión aórtica profunda en el grupo modelo demostrada por una capa endotelial dañada, células musculares lisas degeneradas (SMC) con vacuolas y núcleos condensados, citoplasma vacuolado, membrana plasmática rota, lámina elástica interna interrumpida, cromatina agrupada y filamentos de actina y miosina dañados. La vitamina E protegió significativamente el tejido y las células de la aorta, además de inhibir el malondialdehído tisular (MDA) inducido por MSG, la interleucina-6 (IL-6) y el factor de necrosis tumoral alfa (TNF-α). La dosis más alta de vitamina E utilizada fue más efectiva. Además, se observó una correlación significativa entre el grado de lesión aórtica y los niveles tisulares de MDA, TNF-α, IL-6 y superóxido dismutasa (SOD) (p=0,001). La vitamina E efectivamente protege contra la aortopatía inducida por dosis tóxicas de MSG en ratas e inhibe el estrés oxidativo y la inflamación.

nNav1.5 expression is associated with glutamate level in breast cancer cells

Abstract Background: Glutamate and voltage-gated sodium channels, both have been the target of intense investigation for its involvement in carcinogenesis and progression of malignant disease. Breast cancer with increased level of glutamate often metastasize to other organs (especially bone), whilst re-expression of 'neonatal' Nav1.5, nNav1.5 in breast cancer is known to promote cell invasion in vitro, metastasis in vivo and positive lymph node metastasis in patients. Methods: In this study, the role of nNav1.5 in regulating glutamate level in human breast cancer cells was examined using pharmacological approach (VGSCs specific blocker, TTX, glutamate release inhibitor, riluzole and siRNA-nNav1.5). Effect of these agents were evaluated based on endogenous and exogenous glutamate concentration using glutamate fluorometric assay, mRNA expression of nNav1.5 using qPCR and finally, invasion using 3D culture assay. Results: Endogenous and exogenous glutamate levels were significantly higher in aggressive human breast cancer cells, MDA-MB-231 cells compared to less aggressive human breast cancer cells, MCF-7 and non-cancerous human breast epithelial cells, MCF-10A. Treatment with TTX to MDA-MB-231 cells resulted in significant reduction of endogenous and exogenous glutamate levels corresponded with significant suppression of cell invasion. Subsequently, downregulation of nNav1.5 gene was observed in TTX-treated cells. Conclusions: An interesting link between nNav1.5 expression and glutamate level in aggressive breast cancer cells was detected and requires further investigation.

Research progress of cystine/glutamate antiporter as drug targets / 药学学报

Cystine/glutamate antiporter [system Xc(-)] is a sodium independent amino acid transporter, which is a heterodimer composed of light chain subunit xCT and heavy chain subunit 4F2hc (CD98) through covalent disulfide bond. System Xc(-) typically mediates cystine uptake and glutamate output, helps to maintain the balance of glutamate, cystine and cysteine inside and outside the cell, regulates the level of glutamate inside and outside the membrane and the synthesis of intracellular glutathione, thus affecting oxidative stress and glutamate neurotoxicity. This review expounds the structure and function of system Xc(-), analyzes the role of the transporter in physiology and pathology, discusses the role and mechanism in different diseases, and discusses the specific research progress of system Xc(-) as a drug target. This review summarizes the research status of system Xc(-) and provides theoretical guidance for further research on system Xc(-) and drug discovery.