Cerebrospinal Fluid Glutamate Levels Research Articles

Substantially elevated serum glutamate and CSF GOT-1 levels associated with cerebral ischemia and poor neurological outcomes in subarachnoid hemorrhage patients

Brain injury and cerebral vasospasm during the 14 days after the subarachnoid hemorrhage (SAH) are considered the leading causes of poor outcomes. The primary injury induces a cascade of events, including increased intracranial pressure, cerebral vasospasm and ischemia, glutamate excitotoxicity, and neuronal cell death. The objective of this study was to monitor the time course of glutamate, and associated enzymes, such as glutamate–oxaloacetate transaminase (GOT1), glutamate-pyruvate transaminase (GPT) in cerebrospinal fluid (CSF) and serum, shortly after SAH, and to assess their prognostic value. A total of 74 participants participated in this study: 45 participants with SAH and 29 controls. Serum and CSF were sampled up to 14 days after SAH. SAH participants' clinical and neurological status were assessed at hospitalization, at discharge from the hospital, and 3 months after SAH. Furthermore, a logistic regression analysis was carried out to evaluate the ability of GOT1 and glutamate levels to predict neurological outcomes. Our results demonstrated consistently elevated serum and CSF glutamate levels after SAH. Furthermore, serum glutamate level was significantly higher in patients with cerebral ischemia and poor neurological outcome. CSF GOT1 was significantly higher in patients with uncontrolled intracranial hypertension and cerebral ischemia post-SAH, and independently predicted poor neurological outcomes.

Severe systemic inflammation promotes persistent brain metabolic abnormalities

AbstractBackgroundSevere systemic inflammation can spread to the central nervous system, promoting neuronal dysfunction. Individuals who survive to a severe inflammatory episode, have greater chances to develop cognitive impairment. In this context, brain inflammatory changes have been considered a risk factor for Alzheimer’s disease (AD). We previously demonstrated, a significant [18F]FDG hypometabolism 24 h after the induction of severe systemic inflammation by cecal ligation and perforation (CLP), a sepsis model. However, whether severe systemic inflammation causes long‐term effects on brain energy metabolism remains unclear. Here, we aim at Investigating persistent consequences of a severe systemic inflammatory episode on brain energy metabolism. We hypothesized that brain energetic metabolism does not completely recover from a systemic inflammatory episode, which could be a trigger for neurodegeneration.MethodWistar rats (90 days old) were submitted to CLP and, examined in vivo via Micro‐PET [18F]FDG imaging 30 days later. Albumin and cellularity in the cerebrospinal fluid (CSF) were assessed by HPLC and flow cytometry, respectively, as an index of blood brain barrier (BBB) integrity. HPLC was also used for evaluating glutamate levels in CSF and glutamate uptake was evaluated in hippocampal and cortical slices using a radioactive assay.ResultWe found a persistent brain [18F]FDG hypometabolism in the CLP group. A 4‐fold increase in albumin levels was observed, along with a prominent increase in cellularity in the CSF of CLP animals. Additionally, decreased glutamate uptake in cortex (32%) and hippocampus (16%) along with increased levels of glutamate in CSF was found in the CLP group (Figure 1).ConclusionThese results that an episode of severe systemic inflammatory causes persistent brain metabolic disturbances and BBB damage. It is very likely that the long period of BBB disruption, allowing for communication between peripheral mediators/cells and the brain, compromises brain energy metabolism. Together, these findings suggest a link between peripheral inflammation and neurodegeneration.

Cerebrospinal fluid glutamate changes in functional movement disorders

The aim of this study was to assess cerebrospinal fluid (CSF) concentrations of specific amino acids using a high-performance liquid chromatography system in a sample of patients with functional movement disorders (FMDs) and in a sample of controls. CSF levels of glutamate were significantly lower in patients with FMD than in controls. This finding argues in favor of glutamatergic dysfunction in the pathophysiology of FMD.

Early High Cerebrospinal Fluid Glutamate: A Potential Predictor for Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is an important complication after aneurysmal subarachnoid hemorrhage (aSAH). Early identification of cerebrospinal fluid (CSF) markers is helpful for warning of impending DCI. This study assessed whether early high CSF glutamate levels can be observed in aSAH patients who later developed DCI. In this prospective clinical study, patients with normal pressure hydrocephalus or aSAH were enrolled. We found that the early CSF levels of glutamate were significantly elevated in aSAH patients compared to patients with normal pressure hydrocephalus. There was a significant difference in early CSF levels of glutamate between aSAH patients without DCI and with DCI. The early CSF levels of glutamate are significantly related to the Hunt and Hess grade, the World Federation of Neurological Surgeons (WFNS) grade, and the modified Fisher score on admission and occurrence of DCI in aSAH patients. Preliminary evidence of this study suggests that early high CSF glutamate levels are correlated with DCI in aSAH patients.

Memantine mediates astrocytic activity in response to excitotoxicity induced by PP2A inhibition

Reduced activity of protein phosphatase 2 A (PP2A) is a common feature in Alzheimer’s disease (AD) and non-AD tauopathies. The administration of okadaic acid (OKA), a potent PP2A and PP1 inhibitor, is a common research tool for inducing AD-like alterations such as tau hyperphosphorylation and cognitive decline. Recently, we showed that OKA increases cerebrospinal fluid (CSF) glutamate levels, which was strongly correlated with cognitive decline. Also, we demonstrated that memantine (MN), a glutamatergic NMDAR channel blocker, was capable of preventing the increase in CSF glutamate levels and cognitive decline. Here, we aimed to analyze whether the protective effects of MN involve intrinsic astrocytic properties, particularly related to glutamate uptake and astrocytic reactivity – indexed by the expression of S100B and glial fibrillary acidic protein (GFAP). Rats received intraperitoneal injections of MN or saline over 3 consecutive days before receiving intrahippocampal infusion of OKA or saline. Afterward, they were submitted to behavioral tasks and then, euthanatized for neurochemical analysis. Here, we showed that the neuroprotective effects of MN in response to OKA neurotoxicity involve astrocytic activation. MN decreased glutamate uptake in the hippocampus and increased the release of S100B protein in the CSF in response to OKA neurotoxicity, which indicates a possible neurons-astrocyte coupling protective mechanism. These findings shed light on astrocytes as potential targets for treating neurological disorders associated with decreased PP2A activity.

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.

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

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. We recruited 147 men (n = 68 non-smokers, 30.31 ± 9.10years; n = 79 heavy smokers, 34.54 ± 10.71years). Glutamate concentrations in CSF were measured by spectrophotometry, and subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). 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). 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.

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.

Serum and cerebrospinal fluid excitatory amino acid, nitric oxide and cerebrospinal fluid malondialdehyde levels in West syndrome

West syndrome (WS) is an epileptic syndrome of early childhood. There have been a limited numbers of studies of cerebrospinal fluid (CSF) excitatory amino acid (EAA), nitric oxide (NO), and malondialdehyde (MDA) levels, as well as plasma levels of EAA, and NO, in WS. In this article, CSF EAA, NO, and MDA levels and plasma EAA, NO status, and a determination of the effects of antiepileptic drug therapy on these values were investigated in children with WS. Evaluation of CSF and serum EAA, NO, and MDA levels and of serum EAA and NO levels after 3 mo of antiepileptic drug therapy revealed a statistically significant decrease in CSF aspartate, glutamate, NO and MDA levels. In conclusion, the decrease in CSF MDA levels in this study is the result of both the decrease in glutamate activity and neuronal damage after controlling seizures with antiepileptic drugs.

Chronic Treatment with a Clinically Relevant Dose of Methylphenidate Increases Glutamate Levels in Cerebrospinal Fluid and Impairs Glutamatergic Homeostasis in Prefrontal Cortex of Juvenile Rats.

The understanding of the consequences of chronic treatment with methylphenidate is very important since this psychostimulant is extensively prescribed to preschool age children, and little is known about the mechanisms underlying the persistent changes in behavior and neuronal function related with the use of methylphenidate. In this study, we initially investigate the effect of early chronic treatment with methylphenidate on amino acids profile in cerebrospinal fluid and prefrontal cortex of juvenile rats, as well as on glutamatergic homeostasis, Na(+),K(+)-ATPase function, and balance redox in prefrontal cortex of rats. Wistar rats at early age received intraperitoneal injections of methylphenidate (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 45th day of age. Twenty-four hours after the last injection, the animals were decapitated and the cerebrospinal fluid and prefrontal cortex were obtained. Results showed that methylphenidate altered amino acid profile in cerebrospinal fluid, increasing the levels of glutamate. Glutamate uptake was decreased by methylphenidate administration, but GLAST and GLT-1 were not altered by this treatment. In addition, the astrocyte marker GFAP was not altered by MPH. The activity and immunocontent of catalytic subunits (α1, α2, and α3) of Na(+),K(+)-ATPase were decreased in prefrontal cortex of rats subjected to methylphenidate treatment, as well as changes in α1 and α2 gene expression of catalytic α subunits of Na(+),K(+)-ATPase were also observed. CAT activity was increased and SOD/CAT ratio and sulfhydryl content were decreased in rat prefrontal cortex. Taken together, our results suggest that chronic treatment with methylphenidate at early age induces excitotoxicity, at least in part, due to inhibition of glutamate uptake probably caused by disturbances in the Na(+),K(+)-ATPase function and/or in protein damage observed in the prefrontal cortex.

HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal-appearing white matter

The hypothalamus-pituitary-adrenal (HPA) axis is activated in most, but not all multiple sclerosis (MS) patients and is implicated in disease progression and comorbid mood disorders. In this post-mortem study, we investigated how HPA axis activity in MS is related to disease severity, neurodegeneration, depression, lesion pathology and gene expression in normal-appearing white matter (NAWM). In 42 MS patients, HPA axis activity was determined by measuring cortisol in cerebrospinal fluid (CSF) and counting hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons. Degree of neurodegeneration was based on levels of glutamate, tau and neurofilament in CSF. Duration of MS and time to EDSS 6 served as indicators of disease severity. Glutamate levels correlated with numbers of CRH-expressing neurons, most prominently in primary progressive MS patients, suggesting that neurodegeneration is a strong determinant of HPA axis activity. High cortisol levels were associated with slower disease progression, especially in females with secondary progressive MS. Patients with low cortisol levels had greater numbers of active lesions and tended towards having less remyelinated plaques than patients with high cortisol levels. Interestingly, NAWM of patients with high cortisol levels displayed elevated expression of glucocorticoid-responsive genes, such as CD163, and decreased expression of pro-inflammatory genes, such as tumor necrosis factor-α. Thus, HPA axis hyperactivity in MS coincides with low inflammation and/or high neurodegeneration, and may impact on lesion pathology and molecular mechanisms in NAWM and thereby be of great importance for suppression of disease activity.

Cerebrospinal fluid glutamate concentration correlates with impulsive aggression in human subjects

Neurochemical studies have pointed to a modulatory role in human aggression for various central neurotransmitters. Some (e.g., serotonin) appear to play an inhibitory role, while others appear to play a facilitator role. While recent animal studies of glutaminergic activity suggest a facilitator role for central glutamate in the modulation of aggression, no human studies of central glutaminergic indices have yet been reported regarding aggression. Basal lumbar cerebrospinal fluid (CSF) was obtained from 38 physically healthy subjects with DSM-IV Personality Disorder (PD: n = 28) and from Healthy Volunteers (HV: n = 10) and assayed for glutamate, and other neurotransmitters, in CSF and correlated with measures of aggression and impulsivity. CSF Glutamate levels did not differ between the PD and HC subjects but did directly correlate with composite measures of both aggression and impulsivity and a composite measure of impulsive aggression in both groups. These data suggest a positive relationship between CSF Glutamate levels and measures of impulsive aggression in human subjects. Thus, glutamate function may contribute to the complex central neuromodulation of impulsive aggression in human subjects.

Pretreatment with Memantine Prevents Alzheimer-Like Alterations Induced by Intrahippocampal Okadaic Acid Administration in Rats

Cerebral okadaic acid (OA) administration induces Alzheimer's disease (AD)-like phenotype in rats. Alterations in glutamate levels associated with hyperactivation of cyclin dependent kinase 5 (Cdk5) signaling pathway downstream Tau phosphorylation may participate in the genesis of this pathological phenotype. Here, we examined the efficacy of memantine (MN) pretreatment on reducing OA-induced AD-like phenotypes in rats. Wistar rats were given daily intraperitoneal injections of MN for 3 days and then given an intrahippocampal infusion of OA. Animals were divided into four groups: control (CO), MN, OA and MN/OA. Spontaneous locomotion and spatial memory performance were assessed by open field and Morris water maze respectively. Additionally, we measured glutamate levels in the cerebrospinal fluid (CSF) and the immunocontent of Cdk5, p35, p25 and phosphorylated Tau (pTauSer199/202) in the hippocampus. Spontaneous locomotion did not differ between groups. The OA group showed a significant decrease in spatial memory performance compared to all groups. The OA infusion also increased CSF glutamate levels and the immunocontents of Cdk5, p25 and pTauSer199/202 in the hippocampus. Conversely, pretreatment with MN prevented OA-induced spatial memory deficits and the increment of CSF glutamate level; which paralleled with normal immunocontents of Cdk5, p25 and pTau- Ser199/202 proteins. There were positive correlations between spatial memory performance and the neurochemical parameters. In summary, pretreatment with MN prevents spatial memory deficits induced by intrahippocampal OA administration in rats. The prevention of increase CSF glutamate levels, along with the reduced hippocampal phosphorylation of TauSer199/202 by Cdk5/p25 signaling pathway, are the mechanisms proposed to participate in the prophylactic effects of MN in this AD-like model.

Cerebrospinal fluid levels of glutamate and corticotropin releasing hormone in major depression before and after treatment

BackgroundGlutamate and corticotropin releasing hormone (CRH) are pro-stress neurotransmitters and may be altered in the plasma and cerebrospinal fluid (CSF) of persons with major depressive disorder (MDD). The goal of this study was to compare the CSF levels of glutamate, glutamine and CRH between patients with depression and healthy controls. MethodsEighteen patients with MDD and 25 healthy controls underwent a lumbar puncture (LP); CSF samples were withdrawn and assays were done for glutamine, glutamate, and CRH. Patients with MDD underwent 8 weeks of treatment with the antidepressant venlafaxine and then had a repeat LP post treatment. ResultsPatients had higher baseline scores on depression and suicide rating scales and those scales improved significantly post-treatment. Higher suicidal ratings at baseline were correlated with higher glutamate levels (p=0.016). There were no significant differences between the control and patient group in any baseline CSF measures of glutamate (p=0.761), glutamine (p=0.226) or CRH (p=0.675). Despite no significant change in glutamate (p=0.358) and CRH (p=0.331) in the treatment group, there was a post-treatment decrease in glutamine (p=0.045) in patients. LimitationsThere was a small sample size, age discordance between patients and controls, lack of a follow-up LP in controls, absence of dexamethasone suppression testing, and fluctuating sample sizes among various measures. ConclusionAlthough no significant differences were noted between patients and controls at baseline there was an association of high CSF glutamate and suicidal ideation and lower glutamine post-treatment which may be correlated with attenuation of dysfunction in the glutamatergic system after antidepressant treatment.

Reduced urinary glutamate levels are associated with the frequency of migraine attacks in females

Recent evidences indicate that glutamatergic homeostasis disorders are implicated in the pathogenesis of migraine. In particular, plasma and cerebrospinal fluid glutamate levels seem to be altered in migraine patients. However, the impacts of glutamate on migraine and especially on aura symptoms, alterations in the frequency of migraine attacks as well as investigations on glutamate on migraine-related metabolic dysfunctions, like hyperinsulinaemia, and an atherogenic lipid profile remain elusive to date. The aim of the present study was to investigate the impact of glutamate on migraine and related metabolic dysfunctions. We investigated the urinary glutamate levels of female migraineurs (n = 48) in the interictal phase and healthy controls (n = 48). Parameters of the insulin- and lipid metabolism, inflammatory parameters and anthropometric parameters were additionally determined. Urinary glutamate levels of female migraineurs were significantly decreased with respect to the control group. Logistic regression revealed an odds ratio of 4.04 for migraine. We found a significant correlation with the time-period of patients' last attack and a significant inverse correlation with the annual frequency of migraine attacks. Other parameters of the insulin- and lipid metabolism, anthropometric and inflammatory parameters showed no significant correlation with glutamate levels. We show here that female migraineurs exhibit decreased urinary glutamate levels which are associated with a 4.04-fold higher risk for migraine and correlated with patients' frequency of migraine attacks.

A case of glycine-receptor antibody-associated encephalomyelitis with rigidity and myoclonus (PERM): clinical course, treatment and CSF findings

Over several months a 58-year-old man developed muscle stiffness, myoclonus and experienced several sudden falls caused by sensory and acoustic stimuli. On neurological examination, a severe startle reaction could be triggered by unexpected noises and there was stiffness, especially of the back and lower limb muscles, with myoclonus, lower limb paraparesis, muscle rigidity and increased tendon reflexes without further pyramidal signs. He was not able to walk without help. He also exhibited a mild pontine syndrome with disturbed smooth pursuit eye movements and diplopia. Electrophysiological studies revealed ubiquitous early recruitment and continuous motor unit activity as described for stiff person syndrome by Meinck and Thompson [1]. Cerebral MRI scans were normal. Antibodies against glutamic acid decarboxylase (GAD), amphiphysin, CYFRA 21-1, CEA, Ri, Hu, Yo, MA1, MA2, CV2 and CRMP5 could not be detected in serum. Neuron-specific enolase (NSE) enzyme concentrations were not raised. An extensive cancer search including 18-F-FDG-PET, abdominal ultrasound, X-ray of the chest and bronchoscopy was negative. However, serum glycine receptor (GlyR) antibodies were detected by a cell-based assay (Fig. 1) [2]. Initial lumbar puncture revealed oligoclonal IgG bands and 45 lymphocytes/ll (normal: \4 cells/ll) in the cerebrospinal fluid (CSF). GlyR antibodies could also be found in the patient’s CSF. Gamma-aminobutyric acid (GABA) and glutamate levels in CSF were measured by HPLC, with electrochemical detection after precolumn o-phthaldialdehyde sulphite derivatization, in the patient’s CSF and control samples from 10 subjects (4 males, 6 females); age range 35–83 years (mean 54 years) undergoing diagnostic lumbar puncture as part of their investigations. Their CSF analyses were normal and neurological disorders were excluded. All lumbar punctures were done between 11.00 am and 2.00 pm. Their GABA levels were 42.7 ± 14.2 nmol/l. As shown in Fig. 2, before any treatment the patient’s GABA level was higher (89.0 nmol/l) than upper limit of the control range (mean ? 3SDs, 85.3 nmol/l). Glutamate levels were also lower (initial: 0.33 lmol/l; after 18 months: 0.35 lmol/l) than controls (0.49 ± 0.2 lmol/l) although not significantly different. The neurological symptoms ameliorated after an initial therapy of six plasmaphereses followed by oral corticosteroids (1 mg/kg body weight). The GABAA receptor agonist clonazepam led to a further improvement of muscle stiffness and rigidity. Only a mild pontine symptom with diplopia persisted. CSF GABA levels fell over the treatment period to 28.5 nmol/l (18 months after initial lumbar puncture). GlyR antibody titers also declined but were still just detectable in the serum at 12 months (Fig. 1). Once the improvement had stabilised for 18 months, we tried to wean the steroids. After 2 weeks without steroids the patient developed again neurological symptoms with a left internuclear ophthalmoplegia, and without signs on the MRI. Steroids were therefore increased to 0.5 mg/kg and a steroidsparing drug, azathioprine (2 mg/kg), was introduced. Under this regime the patient is now without symptoms. Up to now, medical examinations are being done every 6 months. A. Piotrowicz (&) A. Thumen A. Moser Neurochemical Research Group, Department of Neurology, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany e-mail: agnieszka.piotrowicz@neuro.uni-luebeck.de

Effect of Acamprosate on Magnetic Resonance Spectroscopy Measures of Central Glutamate in Detoxified Alcohol-Dependent Individuals

Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking. To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol-dependent patients as measured using proton nuclear magnetic resonance spectroscopy (¹H-MRS). A 4-week, double-blind, placebo-controlled, randomized controlled experimental medicine study, with ¹H-MRS measures obtained on days 4 and 25. An inpatient research unit at the NIH Clinical Center. Patients Thirty-three patients who met the DSM-IV criteria for alcohol dependence and who were admitted for medically supervised withdrawal from ongoing alcohol use. Intervention Four weeks of acamprosate (initial oral loading followed by 1998 mg daily) or matched placebo, initiated at the time of admission. The glutamate to creatine ratio as determined using single-voxel ¹H-MRS in the anterior cingulate. Exploratory neuroendocrine, biochemical, and behavioral outcomes were also collected, as were safety- and tolerability-related measures. There was a highly significant suppression of the glutamate to creatine ratio across time by acamprosate (time × treatment interaction: F₁(,)₂₉ = 13.5, P < .001). Cerebrospinal fluid levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and unaffected by treatment but were strongly correlated (R² = 0.48, P < .001) with alcohol dependence severity. Other exploratory outcomes, including repeated dexamethasone-corticotropin-releasing hormone tests, and psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate-treated individuals, in agreement with the established profile of acamprosate. The MRS measures of central glutamate are reduced across time when acamprosate therapy is initiated at the onset of alcohol abstinence. clinicaltrials.gov Identifier: NCT00106106.

Comparison of the effects of intrathecal administration of levobupivacaine and lidocaine on the prostaglandin E2 and glutamate increases in cerebrospinal fluid: a microdialysis study in freely moving rats

Bupivacaine has a lower incidence of transient neurological symptoms than lidocaine after intrathecal (i.t.) injection. The increased toxic potential of lidocaine does not support its use in the clinical setting and could be related to augmented levels of spinal prostaglandin E(2) (PGE(2)). We tested whether levobupivacaine leads to lower PGE(2) levels than lidocaine. Moreover, we compared the release of PGE(2) and glutamate after i.t. injections of levobupivacaine or lidocaine. Rats were anaesthetized for implantation of an i.t. dialysis catheter. This allowed sampling dialysates of cerebrospinal fluid (CSF) for measuring PGE(2) and glutamate levels. The microdialysis setting included baseline sampling and was followed by an i.t. injection of levobupivacaine 250 microg, 100 microg, or saline. PGE(2) and glutamate levels in CSF were analysed for 4 h. In addition, the residual effect of a second i.t. injection on, respectively, of PGE(2) and glutamate changes was compared after injection of either 250 or 100 microg levobupivacaine, 1000 or 400 microg lidocaine, or saline. Prolonged spinal PGE(2) increases lasting 50-120 min were observed after levobupivacaine injection. Higher PGE(2) concentrations were observed after the second lidocaine 1000 microg injection. Glutamate release after the second injection did not vary between the local anaesthetic groups. Spinal PGE(2) levels are similarly increased after i.t. levobupivacaine injection of 250 and 100 microg. A higher PGE(2) response was observed after a second i.t. injection in the animals receiving 1000 microg lidocaine than those receiving 400 mg lidocaine or either dose of levobupivacaine.

Glutamate Levels in Cerebrospinal Fluid and Triptans Overuse in Chronic Migraine

Chronic migraine (CM) is a common disorder, affecting 2% to 3% of the general population. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, central sensitization, and may be linked to migraine chronification. Triptans brought a novel option for the acute migraine treatment. As the development of central sensitization impacts upon the effectiveness of triptan therapy, we hypothesized that glutamate might be related to triptan response mechanisms. We studied 19 patients diagnosed with CM according to the International Headache Society (2004) criteria. Patients were divided in those overusing analgesics (NSAIDs); those without overuse, and those overusing triptans. Cerebrospinal fluid (CSF) glutamate levels were similar in patients overusing acute medications (0.335 +/- 0.225 micromol) compared to those without overuse (0.354 +/- 0.141 micromol), P= NS). In contrast, patients overusing triptans had CSF glutamate levels significantly lower than that observed in nonoverusers (0.175 +/- 0.057 vs 0.354 +/- 0.141 micromol, P= 0.015), and significantly higher than controls (0.175 +/- 0.057 vs 0.109 +/- 0.066 micromol, P= 0.039). In triptan overusers, CSF glutamate levels, although lower, were not significantly different from patients overusing other types of analgesics. Our study showed lower glutamate levels in CSF of CM patients overusing triptans. Glutamate may be implicated in triptan response mechanisms, triptans may work in part by reducing extracellular glutamate levels in the brain.

Alterations of plasma and cerebrospinal fluid glutamate levels in rats treated with the N‐methyl‐D‐aspartate receptor antagonist, ketamine

It has been reported that the repeated administration of a sub-anesthetic dose of an N-methyl-D-aspartate receptor antagonist, ketamine, can produce an animal model of schizophrenia. Since no information is available on the alterations of the amino acid levels in ketamine-treated rats, we investigated the amino acid composition in the plasma and cerebrospinal fluid of rats that were repeatedly administered with ketamine for 5 consecutive days (30 mg/kg/day). The plasma and cerebrospinal fluid amino acid compositions in the fifth week after cessation of repeated ketamine administration were determined by highperformance liquid chromatography with fluorescence detection using a pre-column fluorescence reagent, i.e. 4-fluoro-7nitro-2,1,3-benzoxadiazole. Among the amino acids investigated in the present study, the level of plasma glutamic acid increased significantly (p < 0.05), while that of the cerebrospinal fluid glutamic acid decreased significantly in the ketamine-treated rats as compared with these levels in control rats injected with saline (p < 0.05, n = 7). These alterations in the glutamic acid level in the plasma and cerebrospinal fluid resemble those in schizophrenic patients, suggesting that ketamine-treated rats may be a useful model for performing research on the pathophysiology of schizophrenia.