Cerebrospinal fluid levels of L-glutamate signal central inflammatory neurodegeneration in multiple sclerosis.

Excessive extracellular concentrations of L-glutamate (L-Glu) can be neurotoxic and contribute to neurodegenerative processes in multiple sclerosis (MS). The association between cerebrospinal fluid (CSF) L-Glu levels, clinical features, and inflammatory biomarkers in patients with MS remains unclear. In 179 MS patients (relapsing remitting, RR, N = 157; secondary progressive/primary progressive, SP/PP, N = 22), CSF levels of L-Glu at diagnosis were determined and compared with those obtained in a group of 40 patients with non-inflammatory/non-degenerative disorders. Disability at the time of diagnosis, and after 1 year follow-up, was assessed using the Expanded Disability Status Scale (EDSS). CSF concentrations of lactate and of a large set of pro-inflammatory and anti-inflammatory molecules were explored. CSF levels of L-Glu were slightly reduced in MS patients compared to controls. In RR-MS patients, L-Glu levels correlated with EDSS after 1 year follow-up. Moreover, in MS patients, significant correlations were found between L-Glu and both CSF levels of lactate and the inflammatory molecules interleukin (IL)-2, IL-6, and IL-1 receptor antagonist. Altered expression of L-Glu is associated with disability progression, oxidative stress, and inflammation. These findings identify CSF L-Glu as a candidate neurochemical marker of inflammatory neurodegeneration in MS.

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome.

Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) share many symptoms of fatigue, pain, and cognitive dysfunction that are not relieved by rest. Patterns of serum metabolites in ME/CFS and GWI are different from control groups and suggest potential dysfunction of energy and lipid metabolism. The metabolomics of cerebrospinal fluid was contrasted between ME/CFS, GWI and sedentary controls in 2 sets of subjects who had lumbar punctures after either (a) rest or (b) submaximal exercise stress tests. Postexercise GWI and control subjects were subdivided according to acquired transient postexertional postural tachycardia. Banked cerebrospinal fluid specimens were assayed using Biocrates AbsoluteIDQ® p180 kits for quantitative targeted metabolomics studies of amino acids, amines, acylcarnitines, sphingolipids, lysophospholipids, alkyl and ether phosphocholines. Glutamate was significantly higher in the subgroup of postexercise GWI subjects who did not develop postural tachycardia after exercise compared to nonexercise and other postexercise groups. The only difference between nonexercise groups was higher lysoPC a C28:0 in GWI than ME/CFS suggesting this biochemical or phospholipase activities may have potential as a biomarker to distinguish between the 2 diseases. Exercise effects were suggested by elevation of short chain acylcarnitine C5-OH (C3-DC-M) in postexercise controls compared to nonexercise ME/CFS. Limitations include small subgroup sample sizes and absence of postexercise ME/CFS specimens. Mechanisms of glutamate neuroexcitotoxicity may contribute to neuropathology and "neuroinflammation" in the GWI subset who did not develop postural tachycardia after exercise. Dysfunctional lipid metabolism may distinguish the predominantly female ME/CFS group from predominantly male GWI subjects.

An early increase in glutamate is critical for the development of depression-like behavior in a chronic restraint stress (CRS) model.

Dysfunction in glutamate homeostasis contributes to the pathology of depression-like behavior. Using a chronic restraint stress (CRS) model of depression in C57BL/6 mice, we measured glutamate levels in the cerebrospinal fluid at different restraint time points (CRS 1 d, CRS 3 d, CRS 5 d, CRS 7 d, CRS 14 d, and CRS 21 d). Glutamate levels were increased in the early stage of stress (CRS 1 d and CRS 5 d) but returned to basal levels at the other time points (CRS 7 d-21 d). We hypothesized that glutamate-induced excitotoxicity is critical for the development of depression-like behavior in the CRS model. Treatment with sodium valproate (VPA) or lamotrigine (LTG), two drugs that prevent excitotoxicity in neurons by increasing inhibitory inputs or blocking sodium channels, in the early stage (CRS 1 d-5 d) was sufficient to correct depression-like behavior. In contrast, treatment with the classic antidepressant fluoxetine (FLX) during the same time period was not sufficient to correct depressive behavior. Western blot of two markers of dendritic spines PSD95 and VGluT1 showed that restraining mice for 5 d resulted in the loss of dendritic spines, which was rescued by VPA or LTG. In conclusion, an initial increase in glutamate levels plays an important role in the development of depression-like behavior in the CRS model.

Application of the UV-vis spectrophotometry method for the determination of glutamate in the cerebrospinal fluid of rats.

In experimental nociception models, there is an increase in the glutamate cerebrospinal fluid (CSF) and a decrease in its levels in analgesic treatments. For the determination of glutamate in CSF, an analytical UV spectrophotometric method was developed and validated. The measurements on the UV-vis spectrophotometer were performed after the derivatization reaction of the neurotransmitter, when reading in the ultraviolet (UV) region, at the maximum absorption wavelength of 265 nm. The technique presented excellent linearity, as well as good intraday and interday precision, with coefficients of variation less than 15 %, and a correlation coefficient close to 1.0 (lower dispersion of the experimental set points and lower uncertainty of the estimated regression coefficients). The analytical conditions that were established by the ultraviolet spectrophotometric method demonstrated selectivity, linearity, precision, specificity, robustness, and accuracy. This is suitable for the quantitative determination of glutamate in the CSF. The technique developed by UV-vis spectrophotometry for glutamate dosing was fast, efficient, easy to perform, and more economically accessible when compared to current standard techniques. When comparing the data obtained in this study with the results of the official methodology, in which HPLC and spectrofluorimetry were used, it was observed that the closest values of glutamate release occurred between the spectrofluorimeter and the UV-vis spectrophotometer. The UV-vis spectrophotometry method for the determination of CSF glutamate has been shown to be accurate, reproducible, and satisfactory, making it an extremely advantageous and a viable alternative for the determination of amino acid glutamate.

Selective mGluR1 Negative Allosteric Modulator Reduces Blood-Brain Barrier Permeability and Cerebral Edema After Experimental Subarachnoid Hemorrhage.

The blood-brain barrier (BBB) disruption leads to the vasogenic brain edema and contributes to the early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the mechanisms underlying the BBB damage following SAH are poorly understood. Here we reported that the neurotransmitter glutamate of cerebrospinal fluid (CSF) was dramatically increased in SAH patients with symptoms of cerebral edema. Using the rat SAH model, we found that SAH caused the increase of CSF glutamate level and BBB permeability in EBI, intracerebroventricular injection of exogenous glutamate deteriorated BBB damage and cerebral edema, while intraperitoneally injection of metabotropic glutamate receptor 1(mGluR1) negative allosteric modulator JNJ16259685 significantly attenuated SAH-induced BBB damage and cerebral edema. In an in vitro BBB model, we showed that glutamate increased monolayer permeability of human brain microvascular endothelial cells (HBMEC), whereas JNJ16259685 preserved glutamate-damaged BBB integrity in HBMEC. Mechanically, glutamate downregulated the level and phosphorylation of vasodilator-stimulated phosphoprotein (VASP), decreased the tight junction protein occludin, and increased AQP4 expression at 72 h after SAH. However, JNJ16259685 significantly increased VASP, p-VASP, and occludin, and reduced AQP level at 72 h after SAH. Altogether, our results suggest an important role of glutamate in disruption of BBB function and inhibition of mGluR1 with JNJ16259685 reduced BBB damage and cerebral edema after SAH.

Combined use of alcohol and cigarette increases locomotion and glutamate levels in the cerebrospinal fluid without changes on GABAA or NMDA receptor subunit mRNA expression in the hippocampus of rats.

Interactions on neurotransmitter systems in the reward pathways may explain the high frequency of combined use of alcohol and cigarettes in humans. In this study, we evaluated some behavioral and neurochemical changes promoted by chronic exposure to alcohol and cigarette smoke in rats. Adult rats were administered with 2 g/kg alcohol (v.o.) or/and inhaled the smoke from 6 cigarettes, twice/day, for 30 days. Behavioral tests were performed 3 h after the alcohol administration and 1 h after the last exposure to cigarette smoke in the morning. Cerebrospinal fluid was collected for glutamate determination and the hippocampus was dissected for GABAA and NMDA receptor subunits mRNA expression determination. Results showed that the combined use of alcohol and cigarette smoke (ALTB) in rats increased the locomotor activity and all interventions decreased anxiety-like behaviors. Despite being on a short-term withdrawal, the cigarette smoke exposure decreased the percentage of open arm entries in the elevated plus maze test, which was prevented by combined use with alcohol. Even though GABAA and glutamate receptor subunits expression did not change in the hippocampus, glutamate levels were significantly higher in the cerebrospinal fluid from ALTB rats. Therefore, we showed that the combined use of alcohol and cigarette maintained a psychostimulant effect after a short-term withdrawal that was associated with the elevated glutamatergic activity. The combined use also prevented anxiety-like signs in cigarette smoke exposure rats, decreasing an adverse effect caused by nicotine withdrawal. These results could explain, in part, the elevated frequency of combined use of these two drugs of abuse in humans.

Bioanalytical methodology for determination of glutamate and aspartate for use in pharmacological sciences with application of Integrated Calibration Method.

A new calibration approach based on the adaptation of Integrated Calibration Method (ICM) to consecutive two components analysis in separation science is presented. Consecutive ICM method (C-ICM) was conceptually developed and applied to determination of two excitatory amino acids - glutamate and aspartate in cerebrospinal fluids collected by the use of brain microdialysis from freely-moving animals. Both analytes as a neurotransmitters play an important role in formation of the memory trace, and thus the processes of learning and memory. Due to their low concentration and presence of interferences, considered analytical system - animal brain - was a big challenge. High-performance liquid chromatography (HPLC) with electrochemical detection (ECD) was used in all experimental work. The most important feature of proposed method is integration of interpolative and extrapolative ways to calculate analyte concentration in single calibration procedure, which consequently leads to obtain series of six estimations of analytical result. Comparison of individual estimations with each other allows for a more in-depth analysis of systematic errors. It was proved that C-ICM approach enables diagnosis and compensation of systematic errors induced by occurrence of interference effects and improvement of accuracy of analytical results. Most of all, it was demonstrated that application of this method is efficient and useful analytical tool in analysis of complicated biological samples in pharmacology and neuroscience.

Mass spectrometry-based method for quantification of nimodipine and glutamate in cerebrospinal fluid. Pilot study with patients after aneurysmal subarachnoid haemorrhage.

WHAT IS KNOWN AND OBJECTIVE: Delayed cerebral ischaemia is an important cause of morbidity and mortality after aneurysmal subarachnoid haemorrhage (aSAH). Nimodipine is the only drug approved by the FDA for improving outcome after aSAH. Clinically, however, there are no specific values of this drug in cerebrospinal fluid (CSF) during aSAH treatment that could be associated to outcome improvement. Furthermore, the neurotransmitter glutamate acts as a secondary marker for brain injury. The aim was to establish a method to measure nimodipine and glutamate concentrations simultaneously in CSF of patients after aSAH. METHODS: From June 2017 to June 2018, we prospectively collected clinical data of patients with aSAH admitted to our neurointensive care unit. All included patients received nimodipine orally (60 mg every 4 hours). Patients, who developed clinical vasospasm during their in-hospital stay, underwent intra-arterial application of nimodipine (IAN), followed by angiographic control. A method using high-performance liquid chromatography coupled with mass spectrometric analysis (LC-MS/MS) was established for quantification of both analytes in CSF. RESULTS AND DISCUSSION: In 15 (60%) of 25 patients, nimodipine and glutamate concentrations were measured. After IAN for treatment of vasospasms, CSF nimodipine concentrations were slightly higher than in patients who received nimodipine only orally (0.60 ± 0.27 ng/mL vs 0.48 ± 0.18 ng/mL). Patients developing vasospasm exhibited higher glutamate concentrations than patients without vasospasm (188.84 ng/mL vs136.07 ng/mL). WHAT IS NEW AND CONCLUSION: The developed method allowed the simultaneous quantification of nimodipine and glutamate in CSF. Furthermore, we demonstrated that IAN resulted in higher concentrations in CSF, when compared to oral application only.

Effects of cannabidivarin (CBDV) on brain excitation and inhibition systems in adults with and without Autism Spectrum Disorder (ASD): a single dose trial during magnetic resonance spectroscopy.

Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies - including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites - markers of the brain's primary excitatory and inhibitory system - in both the 'typical' and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the 'shift' in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.

Inhibition of MicroRNA-195 Alleviates Neuropathic Pain by Targeting Patched1 and Inhibiting SHH Signaling Pathway Activation.

Trigeminal neuralgia (TN) is a type of chronic neuropathic pain that is caused by peripheral nerve lesions that result from various conditions, including the compression of vessels, tumors and viral infections. MicroRNAs (miRs) are increasingly recognized as potential regulators of neuropathic pain. Previous evidence has demonstrated that miR-195 is involved in neuropathic pain, but the mechanism remains unclear. To investigate the pathophysiological role of miR-195 and Shh signaling in TN, persistent facial pain was induced by infraorbital nerve chronic constriction injury (CCI-IoN), and facial pain responses were evaluated by Von Frey hairs. qPCR and Western blotting were used to determine the relative expression of miR-195 and Patched1, the major receptor of the Sonic Hedgehog (Shh) signaling pathway, in the caudal brain stem at distinct time points after CCI-IoN. Here, we found that the expression of miR-195 was increased in a rat model of CCI-IoN. In contrast, the expression of Patched1 decreased significantly. Luciferase assays confirmed the binding of miR-195 to Patched1. In addition, the overexpression of miR-195 by an intracerebroventricular (i.c.v) administration of LV-miR-195 aggravated facial pain development, and this was reversed by upregulating the expression of Patched1. These results suggest that miR-195 is involved in the development of TN by targeting Patched1 in the Shh signaling pathway, thus regulating extracellular glutamate.

Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder.

There is increasing interest in the use of cannabis and its major non-intoxicating component cannabidiol (CBD) as a treatment for mental health and neurodevelopmental disorders, such as autism spectrum disorder (ASD). However, before launching large-scale clinical trials, a better understanding of the effects of CBD on brain would be desirable. Preclinical evidence suggests that one aspect of the polypharmacy of CBD is that it modulates brain excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels, including in brain regions linked to ASD, such as the basal ganglia (BG) and the dorsomedial prefrontal cortex (DMPFC). However, differences in glutamate and GABA pathways in ASD mean that the response to CBD in people with and without ASD may be not be the same. To test whether CBD 'shifts' glutamate and GABA levels; and to examine potential differences in this response in ASD, we used magnetic resonance spectroscopy (MRS) to measure glutamate (Glx = glutamate + glutamine) and GABA+ (GABA + macromolecules) levels in 34 healthy men (17 neurotypicals, 17 ASD). Data acquisition commenced 2 h (peak plasma levels) after a single oral dose of 600 mg CBD or placebo. Test sessions were at least 13 days apart. Across groups, CBD increased subcortical, but decreased cortical, Glx. Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant. Thus, CBD modulates glutamate-GABA systems, but prefrontal-GABA systems respond differently in ASD. Our results do not speak to the efficacy of CBD. Future studies should examine the effects of chronic administration on brain and behaviour, and whether acute brain changes predict longer-term response.

Lack of correlation between CSF glutamate levels and PSQI scores in heavy smokers.

OBJECTIVE: Glutamate is an excitatory neurotransmitter in the central nervous system that participates in initiation and maintenance of sleep and wakefulness. The mechanisms involved occur in the brainstem, lateral hypothalamus, and basal forebrain. Our previous study suggested that higher levels of glutamate in cerebrospinal fluid (CSF) contributed to poorer sleep quality. Smoking has been shown to be harmful to sleep quality. In the present study, we recruited non-smokers and heavy smokers and measured the concentration of CSF glutamate in order to investigate the associations among smoking status, sleep quality, and CSF glutamate levels. METHODS: We recruited 147 men (n = 68 non-smokers, 30.31 ± 9.10 years; n = 79 heavy smokers, 34.54 ± 10.71 years). Glutamate concentrations in CSF were measured by spectrophotometry, and subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: PSQI total scores were significantly higher in heavy smokers than that in non-smokers (p < 0.001). Glutamate concentrations in CSF were lower in heavy smokers than that in non-smokers (p < 0.001). CSF glutamate levels positively correlated with PSQI total scores in the non-smokers group (r = 0.313, p = 0.011, effect size = 0.324). No correlation was found between CSF glutamate levels and PSQI total scores in the heavy smokers group (p > 0.05). Multivariable linear regression analysis showed that years of smoking was contributed to the PSQI total scores (p = 0.008), and cigarettes smoked per day contributed to the decreased CSF glutamate levels in heavy smokers (p = 0.001). CONCLUSION: Poorer subjective sleep quality and lower CSF glutamate concentrations were observed in the heavy smokers group than in the non-smokers group. In addition, lack of correlation was observed between CSF glutamate levels and PSQI scores in the heavy smokers.

CSF glutamate level decreases in heavy smokers and negatively correlates with BDI scores.

Glutamate is involved in mental disorders and nicotine addiction. The aim of the present study was to evaluate the relationship between cerebrospinal fluid (CSF) glutamate levels and mental status in Chinese heavy smokers. Participants comprised 41 non-smokers and 77 heavy smokers (n = 118). Cerebrospinal fluid was extracted and glutamate levels were measured. We recorded age, years of education, BMI, the Barratt impulsiveness scale (BIS), the Beck Depression Inventory (BDI) and the Self-Rating Anxiety Scale (SAS). BIS action scores, total scores and BDI scores were significantly different between the groups. Partial correlation analyses with age and education years as covariates found that CSF glutamate levels negatively correlated with BDI scores, but did not correlate with SAS scores in heavy smokers. No correlation was found between CSF glutamate levels and BDI or SAS scores in non-smokers. In conclusion, heavy smokers had more impulsivity had lower levels of CSF glutamate and higher BDI scores. CSF glutamate levels negatively correlated with BDI scores in heavy smokers.

Poor evidence for putative abnormalities in cerebrospinal fluid neurotransmitters in patients with depression versus healthy non-psychiatric individuals: A systematic review and meta-analyses of 23 studies.

BACKGROUND: Although investigated for decades, surprisingly no systematic review has ever been published on monoamines concentrations in cerebrospinal fluid (CSF) in major depressive disorder (MDD) versus healthy individuals (HC). METHODS: We did a systematic review and meta-analyses according to the PRISMA Statement based on comprehensive database searches for studies on CSF biomarkers of monoamines and their precursor and/or metabolites, and glutamine, glutamate and GABA in MDD versus HC. Risk of bias was systematically assessed. RESULTS: A total of 23 studies were included. Statistically significantly decreased levels between MDD and HC were found regarding CSF 5-HIAA (n = 2/13 (15%)), HVA (n = 2/11 (18%)), MHPG (n = 1/8 (13%)), and GABA (n = 2/4 (50%)), while increased levels were reported regarding NE (n = 1/2 (50%)), MHPG (n = 1/8 (13%)) and DOPEG (n = 1/1 (100%)). A majority of the studies found no statistically significant differences between MDD and HC regarding CSF 5-HIAA, HVA, NE, MHPG, glutamine, glutamate and GABA. Meta-analyses showed: 5-HIAA (-3.85, -8.89, 1.19, 0.14), HVA (-18.02, -30.99, -5.04, 0.01), MHPG (0.11, -2.96, 3.17, 0.95) and GABA (-33.20, -51.79, -14.62, 0.00) (mean difference, lower 95% CL, upper 95% CL, p-value). Most studies were influenced by risk of bias mainly due to small sample sizes, and not considering potential confounders as age, gender, severity of depression, body height and position during lumbar puncture, analytics of biomarkers and medication. CONCLUSION: The evidence for CSF 5-HIAA, HVA, NE, MHPG, DOPEG and GABA being related to the pathophysiology of MDD is poor. Future controlled studies of monoamines or metabolites should validate the null i.e., that the concentrations of these compounds are not abnormal in MDD.

Striatal neurometabolite levels in patients with schizophrenia undergoing long-term antipsychotic treatment: A proton magnetic resonance spectroscopy and reliability study.

Previous proton magnetic resonance spectroscopy (1H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla 1H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the 1H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired 1H-MRS acquisitions: average = 90.33; range = 7-306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576-0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naïve first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication.

Increased cerebrospinal fluid levels of GABA, testosterone and estradiol in women with polycystic ovary syndrome.

STUDY QUESTION: Do cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA), testosterone (T) and estradiol (E2) differ in women with polycystic ovary syndrome (PCOS) as compared to eumenorrheic, ovulatory women (EW)? SUMMARY ANSWER: Women with PCOS displayed higher CSF levels of GABA and E2, and possibly T, than EW. WHAT IS KNOWN ALREADY: The chronic anovulation characteristic of PCOS has been attributed to increased central GnRH drive and resulting gonadotropin aberrations. Androgens are thought to regulate GABA, which in turn regulates the neural cascade that modulates GnRH drive. STUDY DESIGN, SIZE, DURATION: This cross-sectional observational study included 15 EW and 12 non-obese women with PCOS who consented to a lumbar puncture in addition to 24 h of serum blood collection at 15-min intervals. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 27 women were studied at a the General Clinical Research Center (GCRC) at the University of Pittsburgh. Serum analytes included T, E2 and androstenedione. CSF analytes included GABA, glutamate, glucose, T and E2. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had higher CSF GABA as compared to EW (9.04 versus 7.04 µmol/L, P < 0.05). CSF glucose and glutamate concentrations were similar between the two groups. CSF T was 52% higher (P = 0.1) and CSF E2 was 30% higher (P < 0.01) in women with PCOS compared to EW. Circulating T was 122% higher (P < 0.01) and circulating E2 was 75% higher (P < 0.01) in women with PCOS than in EW. LIMITATIONS REASONS FOR CAUTION: The study is limited by its small sample size and the technical limitations of measuring CSF analytes that are pulsatile and have short half-lives. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS displayed significantly higher circulating levels of T and E2, significantly higher CSF levels of E2, and higher levels of CSF testosterone, although the latter was not statistically significant. A better understanding of the central milieu informs our understanding of the mechanisms mediating increased the GnRH drive in PCOS and lends a new perspective for understanding the presentation, pathogenesis and potential health consequences of PCOS, including gender identity issues. STUDY FUNDING/COMPETING INTEREST(S): No conflicts of interest. The study was funded by NIH grants to SLB (RO1-MH50748, U54-HD08610) and NIH RR-00056 to the General Clinical Research Center of the University of Pittsburgh. TRIAL REGISTRATION NUMBER: NCT01674426.

The recency ratio is associated with reduced CSF glutamate in late-life depression.

Glutamate is the principal excitatory neurotransmitter in the central nervous system, and is thought to be involved in the process of memory encoding and storage. Glutamate disturbances have also been reported in psychiatric disorders, such as schizophrenia and major depressive disorder (MDD), and in Alzheimer's disease. In this paper, we set out to study the relationship between cerebrospinal fluid (CSF) glutamate levels and memory performance, which we believe has not been reported previously. In particular, we focused on recall performance broken down by serial position. Our prediction was that the recency ratio (Rr), a novel cognitive marker of intellectual impairment, would be linked with CSF glutamate levels. We studied data from a group of cognitively intact elderly individuals, 28 of whom had MDD, while 19 were controls. Study results indicated that Rr levels, but no other memory score, were inversely correlated with CSF glutamate levels, although this was found only in individuals with late-life MDD. For comparison, glutamine or GABA were not correlated with any memory performance measure.

[Protective effects of Ginkgo Terpene Lactones Meglumine Injection on focal cerebral ischemia in rats].

To investigate the protective effects of ginkgo diterpene lactone meglumine injection (GDLMI) on cerebral focal ischemia reperfusion injury induced by middle cerebral artery occlusion (MCAO) in rats, and explore its possible mechanism. One hundred and forty male SD rats were randomly divided into sham operation group, model group, ginkgo biloba extract injection (Ginaton, 1.0 mL•kg⁻¹) group, nimodipine (0.4 mg•kg⁻¹) group, and GDLMI (5.2, 2.6, 1.3 mg•kg⁻¹) groups; All of rats received corresponding drugs by tail vein injection 4 days before operation (normal saline in model group and sham operation group). Except the sham operation group, the cerebral ischemic stroke model was established by MCAO method in right brain of the other rats. After 3 h of ischemia, all the animals received intravenous administration again. The neurobehavioral scores of rats after ischemia-reperfusion were evaluated and the infarct rate of brain tissue was observed by TTC staining. The super oxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and lactic acid (LA) contents in brain tissue homogenate and the concentration of Ca2+, glutamate (Glu) and aspartate (Asp), creatine phosphate kinase (CK-BB) and lactate dehydrogenase (LDH) content changes in cerebrospinal fluid were measured. As compared with the sham operation group, the cerebral infarction rate was increased significantly in the model group; the content of MDA and LA in the homogenate of brain tissue was increased, and the content of GSH and SOD was decreased; in cerebrospinal fluid, Ca2+ concentration was decreased, and the content of Glu and Asp, CK-BB and LDH increased significantly. As compared with the model group, the high and medium dose GDLMI groups can significantly reduce the cerebral infarction rate and improve the symptoms of neurological impairment; increase SOD and GSH activity, reduce MDA and LA content in serum; increase Ca2+ concentration in cerebrospinal fluid and decrease the content of neurotransmitter Glu and Asp as well as CK-BB and LDH. GDLMI could obviously improve neurologic impairment in model rats, and the mechanism may be related to recovering the blood brain barrier, scavenging free radicals, decreasing free Ca2+ inflow into the cells and the content of excitatory amino acid in cerebrospinal fluid to improve its protective effect on cerebral ischemia.

Abnormality in glutamine-glutamate cycle in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder: a 3-year follow-up study.

Major depressive disorder (MDD), common in the elderly, is a risk factor for dementia. Abnormalities in glutamatergic neurotransmission via the N-methyl-D-aspartate receptor (NMDA-R) have a key role in the pathophysiology of depression. This study examined whether depression was associated with cerebrospinal fluid (CSF) levels of NMDA-R neurotransmission-associated amino acids in cognitively intact elderly individuals with MDD and age- and gender-matched healthy controls. CSF was obtained from 47 volunteers (MDD group, N=28; age- and gender-matched comparison group, N=19) at baseline and 3-year follow-up (MDD group, N=19; comparison group, N=17). CSF levels of glutamine, glutamate, glycine, L-serine and D-serine were measured by high-performance liquid chromatography. CSF levels of amino acids did not differ across MDD and comparison groups. However, the ratio of glutamine to glutamate was significantly higher at baseline in subjects with MDD than in controls. The ratio decreased in individuals with MDD over the 3-year follow-up, and this decrease correlated with a decrease in the severity of depression. No correlations between absolute amino-acid levels and clinical variables were observed, nor were correlations between amino acids and other biomarkers (for example, amyloid-ß42, amyloid-ß40, and total and phosphorylated tau protein) detected. These results suggest that abnormalities in the glutamine-glutamate cycle in the communication between glia and neurons may have a role in the pathophysiology of depression in the elderly. Furthermore, the glutamine/glutamate ratio in CSF may be a state biomarker for depression.