Cerebrospinal fluid tyrosine and 3,4-dihydroxyphenylacetic acid levels in migraine patients

We studied biochemical parameters related with central dopaminergic neurotransmission in migraine patients during crisis. We determined tyrosine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in cerebrospinal fluid (CSF) of 47 patients, 29 suffering migraine without aura and 18 suffering migraine with aura, comparing them with 27 control subjects. Tyrosine levels did not differ significantly between patients and controls. The CSF concentration of DOPAC was 0.73±0.55 ng/ml in the control population, 3.84±2.08 ng/ml in patients with migraine without aura and 3.30±l.49ng/ml in patients suffering migraine with aura. The concentration of DOPAC correlated positively with the intensity of headache. These results suggest that patients with migraine have a central dopaminergic hyperfunction, probably related to a coexisting central dysfunction of noradrenergic neurotransmision.     

Marked Elevation of Excitatory Amino Acids in Cerebrospinal Fluid Obtained From Patients With Rotavirus‐Associated Encephalopathy

Rotavirus is the most common cause of severe gastroenteritis in young children; however, its pathogenesis and immunity are not completely understood. Even less well recognized is rotavirus‐induced central nervous system (CNS) involvement, which has been associated with seizure, encephalopathy and death, among others. To elucidate the host response to rotavirus infection, we retrospectively examined neurotransmitter amino acids in the cerebrospinal fluid (CSF) of 19 children with CNS involvement associated with rotavirus infection. Subjects were classified into two groups: those with encephalopathy followed by prolonged seizure (encephalopathy group) and those who had experienced afebrile, brief cluster of seizures without encephalopathy (cluster group). The levels of glutamate, glycine, and taurine in the encephalopathy group were significantly higher than those in the cluster group. Increased levels of excitatory amino acids in the CSF may induce neurological disorders and be related to disorder severity. To the best of our knowledge, this is the first report regarding amino acids in the CSF obtained from patients with rotavirus‐induced CNS involvement. Further study is necessary to elucidate the role of CSF amino acid levels in rotavirus‐induced CNS involvement.     

Cerebrospinal fluid glutamate levels in chronic migraine

Both preclinical and clinical data link glutamate to the migraine pathophisiology. Altered plasma, platelets and cerebrospinal (CSF) glutamate levels have been reported in migraine patients. Chronic migraine is comorbid with several conditions. It has been recently shown chronic migraine comorbidity with fibromyalgia. The objective of this study was to study cerebrospinal fluid glutamate levels in chronic migraine patients with and without fibromyalgia. We studied 20 chronic migraine patients, with and without fibromyalgia, compared to age-sex matched controls. CSF glutamate levels were measured by HPLC. CSF glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia. Patients overall had higher CSF glutamate levels than controls. Mean pain score correlated with glutamate levels in chronic migraine patients. Tender points, the hallmark of fibromyalgia, can be considered as pressure allodynia, and is probably mediated by central sensitization, with increase in CSF glutamate levels. We postulate chronic migraine patients with fibromyalgia, in addition to have more disabling headaches, suffer from a more severe central sensitization process. This subtype of patients may respond to medications modulating glutamate receptors. Headache intensity correlate with glutamate levels in chronic migraine patients.     

Effect of respiratory acidosis on plasma and CSF free amino acids

Acid-base data and levels of selected cerebrospinal fluid (CSF) free amino acids were analyzed in a series of 8 patients in acute respiratory failure. In these patients, there were increased CSF concentrations of methionine, phenylalanine, tyrosine, histidine, alpha-amino-N-butyric acid, glutamic acid, glutamine, glycine, alanine, and ammonia, while arginine decreased. Phenylalanine, tryosine, and alanine were correlated with CSF PCO2; and alpha-amino-N-butyric acid to the buffer capacity of CO2 and pH. The data suggest the hypothesis that there are two metabolic phases for ammonia removal from brain tissue, that could explain some of these pathhophysiological conditions.     

PATHOPHYSIOLOGY, CLINICAL RESEARCH, NEW TREATMENTS, AND BASIC SCIENCE

Both preclinical and clinical data link glutamate to the migraine pathophysiology. Altered plasma, platelets and cerebrospinal (CSF) glutamate levels have been reported in migraine patients. Chronic migraine is comorbid with several conditions. It has been recently shown chronic migraine comorbidity with fibromyalgia. The objective of this study was to study cerebrospinal fluid glutamate levels in chronic migraine patients with and without fibromyalgia. We studied 20 chronic migraine patients, with and without fibromyalgia, compared to age-sex matched controls. CSF glutamate levels were measured by HPLC. CSF glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia. Patients overall had higher CSF glutamate levels than controls. Mean pain score correlated with glutamate levels in chronic migraine patients. Tender points, the hallmark of fibromyalgia, can be considered as pressure allodynia, and is probably mediated by central sensitization, with increase in CSF glutamate levels. We postulate chronic migraine patients with fibromyalgia, in addition to have more disabling headaches, suffer from a more severe central sensitization process. This subtype of patients may respond to medications modulating glutamate receptors. Headache intensity correlate with glutamate levels in chronic migraine patients.
Comment: As noted in Ramadan et al's review and in this study, glutamate antagonists are an attractive target for migraine, confirmed in a proof of concept study published this year, Sang CN, Ramadan RM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LS, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia 2004;24:596-602.—Stewart J. Tepper, MD     

Glial cell line-derived neurotrophic factor and somatostatin levels in cerebrospinal fluid of patients affected by chronic migraine and fibromyalgia

The aim of the present study was to verify cerebrospinal fluid (CSF) levels of glial cell line-derived neurotrophic factor (GDNF) and somatostatin, both measured by sensitive immunoassay, in: 16 chronic migraine (CM) patients, 15 patients with an antecedent history of migraine without aura diagnosed as having probable chronic migraine (PCM) and probable analgesic-abuse headache (PAAH), 20 patients affected by primary fibromyalgia syndrome (PFMS), and 20 control subjects. Significantly lower levels of GDNF and somatostatin were found in the CSF of both CM and PCM + PAAH patients compared with controls (GDNF =P < 0.001, P < 0.002; somatostatin = P < 0.002, P < 0.0003), without significant difference between the two groups. PFMS patients, with and without analgesic abuse, also had significantly lower levels of both somatostatin and GDNF (P < 0.0002, P < 0.001), which did not differ from those of CM and PCM + PAAH patients. A significant positive correlation emerged between CSF values of GDNF and those of somatostatin in CM (r = 0.70, P < 0.02), PCM + PAAH (r = 0.78, P < 0.004), and PFMS patients (r = 0.68, P < 0.008). Based on experimental findings, it can be postulated that reduced CSF levels of GDNF and somatostatin in both CM and PCM + PAAH patients can contribute to sustained central sensitization underlying chronic head pain. The abuse of simple or combination analgesics does not seem to influence the biochemical changes investigated, which appear to be more strictly related to the chronic pain state, as demonstrated also for fibromyalgia.     

Progressive impairment of CSF beta-EP levels in migraine sufferers

Common migraine (CM) is an evolutive disease characterized by a progressive increase in the number of attacks and a consequent reduction in the free periods, eventually reaching a state of continuous migraine with interparoxysmal headache (MIH). To evaluate the role of central pro-opiocortin-related peptides in the pathogenesis of the disease, cerebrospinal fluid (CSF) levels of beta-lipotropin (beta-LPH), beta-endorphin (beta-EP) and ACTH were measured in two groups of migraine sufferers with increasing severity of the disease (CM and MIH), and in healthy controls. ACTH values were similar in the 3 groups, while beta-LPH levels were significantly lower (P less than 0.005) in patients affected by MIH (10.4 +/- 8.6 fmol/ml) than in patients with CM (35.7 +/- 8.3) and in controls (32.9 +/- 15.33). beta-EP levels were closely correlated with the severity of the disease: they decreased significantly from those found in healthy controls (86.1 +/- 37 fmol/ml) to those of CM sufferers (38.5 +/- 3.5; P less than 0.005) and showed a further significant fall (P less than 0.01) to the lowest levels which were found in MIH patients (14.8 +/- 9.8). These data showing that the progressive evolution of migraine is concomitant with a progressive impairment in the CSF levels of beta-EP, sustain the concept that non-organic central pain is related to a reduced activity of the neurons responsible for the CSF content of beta-EP.     

Neurotransmitters in cerebrospinal fluid reflect pathological activity

The excitatory transmitters glutamate and aspartate become toxic whenever their extracellular levels are increased because of neuronal, glial and endothelial impairment. Taurine, a volume-regulating amino acid, is released upon excitotoxin-induced cell swelling. Our aim was to investigate if glutamate and aspartate in cerebrospinal fluid (CSF) reveal neuropathology in neurological patients, and if taurine unmasks glutamate-mediated toxicity. Glutamate and aspartate are doubled in viral meningitis, acute multiple sclerosis (MS) and myelopathy compared with control subjects and patients with peripheral facial nerve palsy. These levels do not coincide with a disturbed blood–brain barrier, as estimated by the albumin ratio, are independent of their precursors (glutamine, asparagine) and are not associated with cell lysis. Taurine is significantly increased in meninigitis, acute MS, and myelopathy, suggesting glutamate-mediated toxicity. Analysis of transmitters in lumbar CSF can be used to identify patients with cerebral and spinal pathology who might benefit from specific receptor-modulating agents.     

Taurine Levels in Plasma and Cerebrospinal Fluid in Migraine Patients

SYNOPSIS
Taurine is the amino acid with the highest concentration in the human body. Its physiologic functions arenot yet well understood. As a neurotransmitter or neuromodulator it may display inhibitory functions. We havemeasured taurine levels in plasma and cerebrospinal fluid of migraine patients during attacks, comparing themwith controls. Patients with migraine had significantly higher concentrations than controls. No sex or ageinfluence over the amino acid levels were observed. Plasma taurine levels in patients with classic migrainecorrelated negatively with severity of headache. Central taurine liberation during migraine crisis may be due tospontaneous depolarization or a defensive reaction in the context of cerebral homeostatic processes.     

Glutamate levels in cerebrospinal fluid and triptans overuse in chronic migraine

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Cerebrospinal fluid (CSF) investigations in migraine

A normal cell count as well as normal CSF pressure levels were found in both classic and common migraine patients during and between attacks. Total protein content was significantly lower in the migraine patients than in the controls, but no changes were found in the CSF protein fractions. The CSF 5-hydroxyindoleacetic acid level of the migraine patients proved to be higher than in the controls, whereas the homovanillic acid concentration was within the control limits.     

Intracellular free amino acid patterns in duodenal and colonic mucosa

We report for the first time the concentrations of free amino acids in human intestinal biopsies obtained by routinely performed endoscopy. We studied 15 medical patients with no changes of the mucosa and six HIV-infected persons with duodenitis. The mean (and SD) sum of all amino acids, taurine excepted, was 61.9 (5.4) mmol/kg dry weight in duodenal biopsies of HIV-negative subjects (n = 11) and 82.9 (0.6) mmol/kg in colonic specimens: 50% (44%) of the total (minus taurine) consisted of aspartate and glutamate and 14% (12%), of the essential amino acids. The relative amino acid pattern in duodenum and colon differed completely from that for muscle: aspartate was fourfold higher; glutamate, phenylalanine, glycine, valine, leucine, and isoleucine were about twofold higher. In contrast, glutamine amounted only to 4% (duodenum) to 14% (colon) of muscle glutamine. In duodenal biopsies of the HIV-infected persons, we found significantly (P less than 0.01, except glutamine: P less than 0.025) increased concentrations of glutamate (24.1 vs 17 mmol/kg dry weight), ornithine (1.4 vs 0.4), valine (2.2 vs 1.7), and glutamine.     

Free amino acids in fibromyalgia syndrome: relationship with clinical picture

The objectives of our study were to evaluate free amino acid (FAA) concentrations in the serum of patients affected by fibromyalgia syndrome (FMS) and to determine the relationships between FAA levels and FMS clinical parameters. Thus, serum amino acid concentrations were quantified (HPLC analysis) in 23 females with fibromyalgia (according to the American College of Rheumatology classification criteria) and 20 healthy females. The results showed significantly higher serum concentrations of aspartate, cysteine, glutamate, glycine, isoleucine, leucine, methionine, ornithine, phenylalanine, sarcosine, serine, taurine, tyrosine and valine in FMS patients vs. healthy controls. Patients with higher Fibromyalgia Impact Questionnaire (FIQ) scores showed increased levels of alanine, glutamine, isoleucine, leucine, phenylalanine, proline and valine. In conclusion, our results indicate an imbalance in some FAAs in FMS patients. Increased Glu is particularly interesting, as it could explain the deficit in monoaminergic transmission involved in pain.     

Changes in the concentrations of amino acids in the cerebrospinal fluid that correlate with pain in patients with fibromyalgia: implications for nitric oxide pathways

Substance P (SP), a putative nociceptive transmitter, is increased in the CSF of patients with fibromyalgia syndrome (FMS). Because excitatory amino acids (EAAs) also appear to transmit pain, we hypothesized that CSF EAAs may be similarly involved in this syndrome. We found that the mean concentrations of most amino acids in the CSF did not differ amongst groups of subjects with primary FMS (PFMS), fibromyalgia associated with other conditions (SFMS), other painful conditions not exhibiting fibromyalgia (OTHER) or age-matched, healthy normal controls (HNC). However, in SFMS patients, individual measures of pain intensity, determined using an examination-based measure of pain intensity, the tender point index (TPI), covaried with their respective concentrations of glutamine and asparagine, metabolites of glutamate and aspartate, respectively. This suggests that re-uptake and biotransformation mask pain-related increases in EAAs. Individual concentrations of glycine and taurine also correlated with their respective TPI values in patients with PFMS. While taurine is affected by a variety of excitatory manipulations, glycine is an inhibitory transmitter as well as a positive modulator of the N-methyl-D-asparate (NMDA) receptor. In both PFMS and SFMS patients, TPI covaried with arginine, the precursor to nitric oxide (NO), whose concentrations, in turn, correlated with those of citrulline, a byproduct of NO synthesis. These events predict involvement of NO, a potent signaling molecule thought to be involved in pain processing. Together these metabolic changes that covary with the intensity of pain in patients with FMS may reflect increased EAA release and a positive modulation of NMDA receptors by glycine, perhaps resulting in enhanced synthesis of NO.     

Neuroexcitatory amino acid levels in plasma and cerebrospinal fluid during migraine attacks

A current hypothesis for migraine suggests that neuroexcitatory amino acids may participate in the triggering of attacks. To investigate this possibility we measured glutamic and aspartic acid level in plasma and cerebrospinal fluid (CSF) of patients with common and classic migraine during attacks, making comparisons with controls suffering from stress. Plasma levels of amino acids in migraine patients were lower than in controls. CSF concentrations of glutamic acid were higher in migraineurs than in controls. Our results suggest an excess of neuroexcitatory amino acids in the CNS of migraine patients during attacks, possibly favoring a state of neuronal hyperexcitability.     

Metabolic changes in ischemic brain infarct

Serum and cerebrospinal fluid (CSF) from 17 patients less than 3 days after brain infarction (measurement 1) and during recovery 7 +/- 2 days after infarction (measurement 2) were analysed for organic acids (energy metabolites, keto acids and amino acids). Clinical parameters improved by 32% over the period of assessment. Only serum pyruvate levels were elevated at both measurement times. Acute infarction was characterized by significant correspondence of serum and CSF concentrations for pyruvate and alpha-oxo-beta-methyl valeric acid which was lost during the recovery period. Amino acids of the L-system were roughly doubled (phenylalanine 7-fold in the CSF); increased concentrations were recorded for amino acids of the basic transport system, while amino acids of the A-system stayed unchanged (with the exception of alpha-amino butyric acid--20-fold in CSF). Except in the case of taurine, serum and CSF amino acid concentrations remained unchanged between the two measurement times. Mutual dependence of CSF and serum amino acid concentrations, existing initially for glycine, valine, leucine, tyrosine, as well as ornithine, lysine and histidine was lost in the recovery phase. This is interpreted as indication of a normalization of the blood-brain barrier.     

Amino acid uptake and release by colorectal cancer in man

Little information is available regarding the amino acid exchange by human tumors. To characterize this exchange in vivo, 21 patients with resectable colorectal carcinomas were studied during curative operations. Concerning the amino acid uptake and release by peripheral tissues, 20 non-cancer patients served as controls. Both groups of subjects were well-nourished, as indicated by anthropometric and biochemical variables. In the cancer patients, we cannulated a peripheral artery and vein as well as a central tumor-draining vein and the portal vein. Plasma concentrations and concentration differences were determined in mumol/l and in percentages of the total amino acid amounts. Peripheral glutamate uptake per liter plasma was reduced in the cancer patients (p = 0.02). In these patients, the central tumor-draining vein contained less glutamine (p = 0.002) and more glutamate (p = 0.002) than the peripheral vein. Glutamine uptake by the tumor occurred more often than glutamine release, while glutamate had a negative balance across the tumor in all but three cases. The qualitative differences between the peripheral tissues and the tumors with respect to glutamine and glutamate exchange reached high levels of significance (p = 0.002 for both of the amino acids). In addition, the tumors released more glycine, ornithine, and tyrosine than the periphery. As to glutamine and glutamate metabolism, there was a significant difference between the tumors and the portal-drained organs (p greater than or equal to 0.05). The discussion of the results emphasizes the contributions made by the periphery and the tumor to the plasma amino pattern. The role of glutamine as a potential high importance energy source for neoplastic tissues is delineated.     

Amino acid metabolism during the anabolic phase of severely burned patients: with special reference to sulphur amino acids

Abstract. Owing to the high content of cyst(e)ine and sulphated mucopolysaccharides in skin tissues, an increased demand for sulphur amino acids could be expected during the anabolic phase in severely burned patients. As a marker for sulphur amino acid deficiency, leucocyte glutathione, methionine and taurine concentrations and urinary excretion of sulphur amino acids and inorganic sulphate were followed in five severely burned patients during a 5-month period (1–6 months post injury). Reduced leucocyte concentrations of glutathione, methionine and taurine, and decreased urinary excretion of inorganic sulphate, methionine, cyst(e)ine and taurine were observed, and were most pronounced 2 or 3 months after injury. Simultaneously a minor decrease in urinary output and leucocyte concentration of branched-chain amino acids and serine were also found, whereas normal levels of glycine, threonine, and glutamine were registered. The episode of limited availability of sulphur amino acids coincides with the period of most intensive collagen and keratin resynthesis of burned skin tissue.     

Platelet and plasma levels of glutamate and glutamine in migraine with and without aura

We evaluated plasma and platelet glutamate and glutamine levels in migraine with and without aura during headache-free periods and compared the results with those of normal controls. The plasma and platelet levels of glutamine in migraine with and without aura were normal. Migraine without aura patients had higher glutamate levels in plasma, and normal platelet levels. In migraine with aura patients, glutamate levels were high in platelets, but not in plasma. This suggests different profiles of excitatory amino acid metabolism in migraine with and without aura.     

中度海拔地区偏头痛患者血浆及脑脊液内皮素含量变化的研究

目的：探讨内皮素（ＥＴ）在中度海拔地区偏头痛发病中的作用。方法：对１００ 例中度海拔地区偏头痛患者血浆和脑脊液ＥＴ １ 含量的变化进行动态观察。结果：偏头痛患者（先兆型及无先兆型）发作期血浆及脑脊液的ＥＴ １ 含量均明显高于对照组（Ｐ均＜ ０．０５）;先兆型发作期ＥＴ １ 升高更明显（Ｐ＜ ０．０５）;发作后随时间推移、头痛缓解则血浆及脑脊液的ＥＴ １ 含量逐渐下降,头痛完全缓解后与对照组无明显区别（Ｐ 均＞０．０５）。结论：ＥＴ １ 可能通过缩血管作用或作为一种神经激素在中度海拔地区偏头痛发作中起作用