Changes in brain amino acid content induced by hyposmolar stress and energy deprivation

The changes in endogenous amino acids in brain extracellular and intracellular compartments evoked by hyposmotic stress and energy deprivation were compared. Tissue content and release of ten amino acids were measured simultaneously in rat hippocampal slices by means of high performance liquid chromatography Hyposmotic stress induced a large release of taurine (25568 pmol mg-7 protein), and a smaller release of glutamate, accompanied by an inverse change in tissue content. Adding mannitol to correct osmolarity blocked these changes. Energy deprivation caused an increase in the release of all amino acids except glutamine. The release was particularly large for glutamate and GABA (31141 and 13282 pmol mg^–1 respectively). The intracellular concentrations were generally reduced, but the total amount of the released amino acids increased. In contrast to the effect seen during hyposmolar stress, mannitol enhanced the changes due to energy deprivation. The results show that hyposmolar stress and energy deprivation cause different content and release profiles, suggesting that the mechanisms involved in the two situations are either different, or modulated in different ways. The intracellular amino acid depletion seen during energy deprivation shows that increased outward transport is probably a primary eventL, and increased amino acid formation likely secondary to this release. [Neurol Res 1995; 17: 402–408]     

Reduced sense of agency in chronic schizophrenia with predominant negative symptoms

Self-disturbances in schizophrenia have been regarded as a fundamental vulnerability marker for this disease, and have begun to be studied from the standpoint of an abnormal “sense of agency (SoA)” in cognitive neuroscience. To clarify the nature of aberrant SoA in schizophrenia, it needs to be investigated in various clinical subtypes and stages. The residual type of chronic schizophrenia with predominant negative symptoms (NS) has never been investigated for SoA. Accordingly, we investigated SoA by an original agency attribution task in NS-predominant schizophrenia, and evaluated the dynamic interplay between the predictive and postdictive components of SoA in the optimal cue integration framework. We studied 20 patients with NS-predominant schizophrenia, and compared with 30 patients with paranoid-type schizophrenia and 35 normal volunteers. NS-predominant schizophrenia showed markedly diminished SoA compared to normal controls and paranoid-type schizophrenia, indicating a completely opposite direction in agency attribution compared with excessive SoA demonstrated in paranoid-type schizophrenia. Reduced SoA was detected in experimental studies of schizophrenia for the first time. According to the optimal cue integration framework, these results indicate that there was no increase in compensatory contributions of the postdictive processes despite the existence of inadequate predictions, contrary to the exaggerated postdictive component in paranoid-type schizophrenia.     

谷氨酸在维持或损害记忆中的双向调节作用

背景 适当激动谷氨酸受体(glutamate receptor,GluR)是学习记忆所必须的,然而过度激动GluR则会在海马区域内产生病理性的长时程增强效应,严重者会出现兴奋性毒性(excitotoxicity,EAA)反应,诱发神经元损伤,导致认知障碍.目的 探讨谷氨酸(glutamate,Glu)对记忆的双向调节作用.内容 综述Glu的含量、生理和调节机制、GluR的种类和结构特点、Glu维持记忆的机制及其参与EAA反应进而损害记忆的过程.趋向 神经系统正常运作需要Glu的浓度和GluR活性均处于适宜水平.     

Study pharmacologic of the GABAergic and glutamatergic drugs on seizures and status epilepticus induced by pilocarpine in adult Wistar rats

This work was designed to study the influence of drugs during seizures and status epilepticus (SE) induced by pilocarpine and mortality in adult rats. Glutamate (10 and 20 mg/kg), N-methyl-d-aspartate (NMDA, 5 and 10 mg/kg), ketamine (1.5 and 2.0 mg/kg), gabapentin (200 and 250 mg/kg), phenobarbital (50 and 100 mg/kg) and vigabatrin (250 and 500 mg/kg) were administered intraperitoneally, 30 min prior to pilocarpine (400 mg/kg, i.p.). The animals were observed (24 h) to determine: number of peripheral cholinergic signs, tremors, stereotyped movements, seizures, SE, latency to first seizure and number of deaths after pilocarpine treatment. NMDA and glutamate had pro-convulsive effects in both doses tested. Smaller and higher doses of these drugs no protected and increased pilocarpine-induced seizures and/or mortality. Gabapentin, vigabatrin, phenobarbital and ketamine protected against seizures and increased the latency to first seizure. Thus, these results suggest that caution should be taken in the selection of pharmacotherapy and dosages for patients with seizures and SE because of the possibility of facility the convulsive process toxicity, SE and the mortality of adult animals in this seizures model that is similar temporal lobo epilepsy in humans.     

Neuroprotective effects of safflor yellow B on brain ischemic injury

The present study was conducted to investigate whether safflor yellow B (SYB) had a protective effect on cerebral ischemic injury and to determine the possible mechanisms in vivo and in vitro. In vivo, Male Wistar–Kyoto (WKY) rats were used to make the model of middle cerebral artery occlusion (MCAO). The behavioral test was used to measure neurological deficit scores for evaluation of the ischemic damage of brain. The infarction area of brain was assessed in brain slices stained with 2% solution of 2,3,5-triphenyl tetrazolium chloride (TTC). Spectrophotometric assay was used to determine the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx), contents of malondialdehyde (MDA) and adenosine triphosphate (ATP) of the brain. Furthermore, the respiratory control ratio (RCR = state 3/state 4) was assessed in the brain mitochondria. In vitro, the effect of SYB was tested in cultured fetal cortical cells exposed to glutamate to identify its neuroprotection against neurons damage. The results in vivo showed that SYB at doses of 3.0 and 6.0 mg kg⁻¹ markedly decreased the neurological deficit scores and the infarction area in MCAO rats. At the same time, SYB significantly improved mitochondrial energy metabolism, decreased MDA content, and increased SOD and GPx activities in ischemic brain. The results in vitro showed that SYB remarkably inhibited neuron damage induced by glutamate in cultured fetal cortical cells. These suggest that SYB might act as a potential neuroprotective agent against the cerebral ischemia-induced injury in rat brain through reducing lipid peroxides, scavenging free radicals, and improving the energy metabolism.     

Glutamatergic systems in the bed nucleus of the stria terminalis,effects on cardiovascular system

The bed nucleus of the stria terminalis (BST) is a part of the limbic system. Two studies have shown that microinjection of l-glutamate in the BST elicited cardiovascular depressive and bradycardic responses, but in one study, both pressor and depressor responses were observed in the chemical stimulation of BST by glutamate in the urethane-anesthetized rats. Also, the roles of glutamate receptor subtypes have not been investigated yet. The aim of this study was to find the effects of glutamate and its receptors on the blood pressure and heart rate in the BST of urethane-anesthetized rats. The drugs (50 nl) were microinjected into the BST of anaesthetized rats. The blood pressure and heart rate were recorded throughout each experiment. The average changes in the mean arterial pressure and heart rate at different intervals were compared both within each case group and between the case and the control groups, using repeated measures ANOVA. Microinjection of l-glutamate (0.25 M) into the BST resulted in the decrease of the mean arterial pressure (−18.85 ± 3.84 mmHg) and heart rate (−18 ± 4 beats/min). Injection of AP5, antagonist of glutamate NMDA receptor (2.5 , 5 mM) and CNQX, antagonist of glutamate AMPA receptor (0.5, 1 mM) had no significant effect on the mean arterial pressure and heart rate. Either Ap5 or CNQX, when co-injected with glutamate, abolished the depressor and bradycardic effects of glutamate, suggesting that simultaneous activation of both glutamate receptors is necessary for the effect of glutamate system to emerge.     

Striatal structure and its association with N-Acetylaspartate and glutamate in autism spectrum disorder and obsessive compulsive disorder

Autism spectrum disorders (ASD) and obsessive compulsive disorder (OCD) are often comorbid and are associated with changes in striatal volumes and N-Acetylaspartate (NAA) and glutamate levels. Here, we investigated the relation between dorsal striatal volume and NAA and glutamate levels. We additionally compared striatal volume and shape between ASD, OCD and controls. T1-weighted magnetic resonance (MR) images, proton spectra (1H-MRS) in the left striatum, and phenotypic information were collected from 54 children with ASD, 32 with OCD, and 56 controls (aged 8–13 years) in a four-site study. Dorsal striatal volume and shape were determined using the FMRIB integrated registration and segmentation tool (FIRST). Spectra were processed with Linear Combination Model. The relationship of left striatal volume with NAA and glutamate was investigated, and group comparisons were performed for NAA levels and for bilateral striatal volume and shape. NAA levels were lower in subjects with ASD compared with controls (t=2.86, p=0.005) and were associated with striatal volume (β=0.37, t=2.78, p=0.008). Glutamate levels were also associated with volume in the ASD group (β=0.38, t=2.46, p=0.018). No group differences were found for striatal volume or shape, but a post-hoc diagnosis-by-hemisphere interaction (F_(2,129)=3.86, p=0.024) revealed greater asymmetry (right>left) in striatal volume for the disorder-groups compared with controls. Our findings show involvement of NAA and glutamate in striatal volume in ASD and suggest greater asymmetry in paediatric ASD and OCD compared with controls, pointing to overlapping subcortical abnormalities. The lower NAA in ASD reflects reduced neuronal integrity or impaired neuronal functioning.     

Increased cortical neuronal responses to NMDA and improved attentional set-shifting performance in rats following prebiotic (B-GOS®) ingestion

We have previously shown that prebiotics (dietary fibres that augment the growth of indigenous beneficial gut bacteria) such as Bimuno^? galacto-oligosaccharides (B-GOS^®), increased N-methyl-D-aspartate (NMDA) receptor levels in the rat brain. The current investigation examined the functional correlates of these changes in B-GOS^®-fed rats by measuring cortical neuronal responses to NMDA using in vivo NMDA micro-iontophoresis electrophysiology, and performance in the attentional set-shifting task. Adult male rats were supplemented with B-GOS^® in the drinking water 3 weeks prior to in vivo iontophoresis or behavioural testing. Cortical neuronal responses to NMDA iontophoresis, were greater (+30%) in B-GOS^® administered rats compared to non-supplemented controls. The intake of B-GOS^® also partially hindered the reduction of NMDA responses by the glycine site antagonist, HA-966. In the attentional set-shifting task, B-GOS^® -fed rats shifted from an intra-dimensional to an extra-dimensional set in fewer trials than controls, thereby indicating greater cognitive flexibility. An initial exploration into the mechanisms revealed that rats ingesting B-GOS^® had increased levels of plasma acetate, and cortical GluN2B subunits and Acetyl Co-A Carboxylase mRNA. These changes were also observed in rats fed daily for 3 weeks with glyceryl triacetate, though unlike B-GOS^®, cortical histone deacetylase (HDAC1, HDAC2) mRNAs were also increased which suggested an additional epigenetic action of direct acetate supplementation. Our data demonstrate that a pro-cognitive effect of B-GOS^® intake in rats is associated with an increase in cortical NMDA receptor function, but the role of circulating acetate derived from gut bacterial fermentation of this prebiotic requires further investigation.     

乳果糖口服溶液联合谷氨酸钾注射液治疗肝性脑病的疗效观察

目的探讨乳果糖口服溶液联合谷氨酸钾注射液治疗肝性脑病的临床疗效。方法选取2014年4月—2017年4月在天门市第一人民医院治疗的肝性脑病患者114例为研究对象,将所有患者随机分为对照组和治疗组,每组各57例。对照组静脉滴注谷氨酸钾注射液,60 mL加入到生理盐水500 mL中,1次/d。治疗组在对照组的基础上口服乳果糖口服溶液,30 mL/次,3次/d。两组患者均连续治疗7 d。观察两组的临床疗效,比较两组的生化学指标和Child-Pugh评分。结果治疗后,对照组和治疗组的总有效率分别为75.44%、92.98%,两组比较差异具有统计学意义(P0.05)。治疗后,两组血氨、总胆红素(TBil)、丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转氨酶(AST)水平均显著下降,同组治疗前后比较差异具有统计学意义(P0.05);且治疗组这些生化学指标明显低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组Child-Pugh评分均显著下降,同组治疗前后比较差异具有统计学意义(P0.05);且治疗组Child-Pugh评分明显低于对照组,两组比较差异具有统计学意义(P0.05)。结论乳果糖口服溶液联合谷氨酸钾注射液治疗肝性脑病具有较好的临床疗效,能改善精神状况,降低血氨水平,改善肝脏功能,安全性较好,具有一定的临床推广应用价值。     

Amitriptyline preserves morphine's antinociceptive effect by regulating the glutamate transporter GLAST and GLT-1 trafficking and excitatory amino acids concentration in morphine-tolerant rats

The present study was undertaken to examine the effect of amitriptyline on the antinociceptive effect of morphine and its underlying mechanisms in regulating glutamate transporters trafficking in morphine-tolerant rats. Long-term morphine infusion induced antinociceptive tolerance and down-regulation of glutamate transporters (GTs), GLAST, GLT-1, and EAAC1, expression in the rat spinal cord dorsal horn. Acute amitriptyline treatment potentiated morphine’s antinociceptive effect, with a 5.3-fold leftward shift of morphine’s dose–response curve in morphine-tolerant rats, and this was associated with GLAST and GLT-1 trafficking onto the cell surface. Similar to our previous studies, morphine challenge (10 μg/10 μl, i.t.) significant by increased the excitatory amino acids (EAAs) aspartate and glutamate level in the CSF dialysates of morphine-tolerant rats. Acute amitriptyline treatment not only suppressed this morphine-evoked EAA release, but further reduced the EAA concentration than baseline level. Furthermore, long-term morphine infusion up-regulated PKA and PKC protein expression in the spinal cord dorsal horn, while amitriptyline inhibited the increase in expression of phospho-PKA, PKCα, PKCβII, and PKCγ. In morphine-tolerant rats, acute treatment with PKA inhibitor H89 and PKC inhibitor Gö6805 attenuated morphine tolerance and the morphine-induced CSF glutamate and aspartate elevation, and induced trafficking of GLAST and GLT-1 from cytosol onto the cell surface. These results show that acute amitriptyline treatment preserved morphine’s antinociceptive effect in morphine-tolerant rats; the mechanisms may be involved in inhibition of phospho-PKA and PKC expression, and thus inducing the GLAST and GLT-1 trafficking onto glial cell surface which enhances the EAA uptake from the synaptic cleft and reduces EAA concentration in the spinal CSF.