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The pathogenesis of migraine, as well as cluster headache (CH), is yet a debated question. In this review, we discuss the possible role of tyrosine and tryptophan metabolism in the pathogenesis of primary headaches, including the abnormalities in the synthesis of neurotransmitters. High level of dopamine, low level of norepinephrine, and very elevated levels of octopamine and synephrine were found in the plasma of episodic migraine without aura. We hypothesize that the imbalance between the levels of neurotransmitters and elusive amines synthesis is due to a metabolic shift directing tyrosine toward increased decarboxylase and reduced hydroxylase enzyme activities, favored by a state of neuronal hyperexcitability and a reduced mitochondrial activity. In addition, we present biochemical studies performed in chronic migraine (CM) and chronic tension-type headache patients (CTTH) to verify if the same anomalies are present in these primary headaches and, if so, their possible role in the chronicity process of CM and CTTH. The results show that important abnormalities of tyrosine-related metabolites are present only in CM patients while tryptamine plasma levels were found significantly lower in both CM and CTTH patients. Because of this, we propose that migraine and, possibly, CH attacks derive from neurotransmitter and neuromodulator metabolic abnormalities in a hyperexcitable and hypoenergetic brain that spread from the frontal lobe, downstream, resulting in abnormally activated nuclei of the pain matrix. The low tryptamine plasma levels found in CM and CTTH patients suggest that these two primary chronic headaches are characterized by a common insufficient serotoninergic control of the pain threshold. [ABSTRACT FROM AUTHOR]

Background and aim: The pathogenesis of the pain that occurs in episodic migraine attack is due to the activation of the trigeminal system's first neuron receptors located on vessel wall. The release from the endothelium of nitric oxide, a product of arginine metabolism, causes vasodilation and stretching of the vascular trigeminal system and promotes pain. It is unknown whether this same metabolic event is involved in the pain accompanying chronic migraine. To understand the possible role of arginine in the pathogenesis of chronic migraine patients, we evaluated the metabolism of arginine in plasma of chronic migraine and control subjects. Methods: We evaluated the metabolism of arginine in a group of patients affected by chronic migraine. Quantification of arginine, ornithine, citrulline, monomethyl arginine (NMMA), dimethylarginines (ADMA, SDMA), and tyramine was performed by ultra-performance liquid chromatography coupled with a triple quadrupole mass spectrometer. Results: Chronic migraine patients showed low plasma levels of arginine, significantly elevated levels of ornithine, ADMA, and NMMA whereas the levels of citrulline and SDMA were in the range of controls. Conclusions: The elevated levels of ADMA and NMMA, inhibitors of nitric oxide synthase, suggest that the metabolism of arginine may be inhibited with a possible reduction of NO release in the circulation of chronic patients. This suggests that the origin of pain may not be related to the vasodilation of trigeminal vascular system that occurs in episodic migraine patients. [ABSTRACT FROM AUTHOR]

Abstract Background In patients with acute respiratory distress syndrome (ARDS), it is well known that only part of the lungs is aerated and surfactant function is impaired, but the extent of lung damage and changes in surfactant turnover remain unclear. The objective of the study was to evaluate surfactant disaturated-phosphatidylcholine turnover in patients with ARDS using stable isotopes. Methods We studied 12 patients with ARDS and 7 subjects with normal lungs. After the tracheal instillation of a trace dose of 13C-dipalmitoyl-phosphatidylcholine, we measured the 13C enrichment over time of palmitate residues of disaturated-phosphatidylcholine isolated from tracheal aspirates. Data were interpreted using a model with two compartments, alveoli and lung tissue, and kinetic parameters were derived assuming that, in controls, alveolar macrophages may degrade between 5 and 50% of disaturated-phosphatidylcholine, the rest being lost from tissue. In ARDS we assumed that 5–100% of disaturated-phosphatidylcholine is degraded in the alveolar space, due to release of hydrolytic enzymes. Some of the kinetic parameters were uniquely determined, while others were identified as lower and upper bounds. Results In ARDS, the alveolar pool of disaturated-phosphatidylcholine was significantly lower than in controls (0.16 ± 0.04 vs. 1.31 ± 0.40 mg/kg, p < 0.05). Fluxes between tissue and alveoli and de novo synthesis of disaturated-phosphatidylcholine were also significantly lower, while mean resident time in lung tissue was significantly higher in ARDS than in controls. Recycling was 16.2 ± 3.5 in ARDS and 31.9 ± 7.3 in controls (p = 0.08). Conclusion In ARDS the alveolar pool of surfactant is reduced and disaturated-phosphatidylcholine turnover is altered.

Abstract: Background: Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) formation inhibitor, has emerged as a promising biomarker of NO-associated endothelial dysfunction in cardiovascular diseases as well in chronic renal failure. The interest in potentially fundamental role of this metabolite, in basic and clinical research, led to the development of numerous analytical methods for the quantitative determination of ADMA and dimethylarginines in biological systems, notably plasma, serum and urine. Objectives: The aim of this work was to present a simple, fast and accurate UPLC–tandem-MS-based method for the simultaneous determination and quantification of arginine, ADMA, SDMA, NMMA, homo-arginine and citrulline. This method is designed for high sample throughput of only 10μL of human plasma, serum or urine. Methods: The analysis time is reduced to 1.9min by an ultrahigh-performance liquid chromatography run coupled with electrospray ionization (ESI) in the positive mode tandem mass spectrometry detection. Results: The method was validated in plasma, serum and urine. Correlation coefficients (r 2) of the calibration curves in all matrices considered ranged from 0.9810 to 0.9993. Inter- and intra-assay precision, accuracy, recovery and carry-over were evaluated for validation. The LOD was 0.01μM for all compounds in water, plasma and serum and 0.1μM in urine. The LOQ was 0.05μM for ADMA, SDMA, NMMA and H-Arg and 0.5μM for Arg and Cit in water, plasma and serum; while in urine was 0.1μM for ADMA, SDMA, NMMA and H-Arg and 0.5μM for Arg and Cit. The precision was ranged from 1% to 15% expressed as CV% and the accuracy (bias %) was <±7% for all added concentrations with the exception of NMMA (−10%). ADMA mean plasma levels, measured in healthy adults and newborns, were in accord with literature data published: (M±SD) 0.56±0.10μM and 0.84±0.21μM, respectively, showing that ADMA levels in plasma decreased with age. In serum we have similar data (0.54±0.18μM and 1.14±0.36μM), while in neonatal urine ADMA was 11.98±7.13μmolmmol−1 creatinine. Conclusions: Data from calibration curves and method validation reveal that the method is accurate and precise. The fast run time, the feasibility of high sample throughput and the small amount of sample required make this method very suitable for routine analysis in the clinical setting. [Copyright &y& Elsevier]

Aim: To address whether, in patients with chronic migraine and medication overuse headache, mindfulness-based treatment is associated with changes in plasma levels of catecholamines and elusive amines that are similar to those observed in patients undergoing pharmacological prophylaxis.Methods: In this non-randomized, clinic-based effectiveness study, patients aged 18-65, with a history of chronic migraine ≥ 10 years and overuse of triptans or non-steroidal anti-inflammatory drugs ≥ 5 years, were enrolled. Upon completion of a structured withdrawal program, patients received either pharmacological prophylaxis or six weekly sessions of mindfulness-based treatment and were followed for 12 months. Daily headache diaries were used to record headache frequency and medication intake; catecholamines (noradrenaline, epinephrine and dopamine) and levels of elusive amines were assayed from poor platelet plasma.Results: Complete follow-up data were available for 15 patients in the pharmacological prophylaxis-group (14 females, average age 44.1) and 14 in the mindfulness treatment-group (all females, average age 46.4), and all variables were comparable between groups at baseline. At 12 months, significant improvement ( p < .001) was found in the pharmacological prophylaxis group for headache frequency and medication intake (by 51% and 48.7%, respectively), noradrenaline, epinephrine and dopamine (by 98.7%, 120.8% and 501.9%, respectively); patients in the mindfulness treatment-group performed similarly. For elusive amines, no longitudinal changes were found.Conclusions: The similar improvement trends observed in the two groups of patients further support the utility of mindfulness-based treatment in migraine care, and reinforce the hypothesis that alteration and normalization of tyrosine metabolism are implicated in migraine chronification and in remission of chronic migraine. [ABSTRACT FROM AUTHOR]

Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache. [ABSTRACT FROM AUTHOR]

Early diagnosis of Parkinson's disease (PD) remains a challenge to date. New evidence highlights the potential clinical value of circulating trace amines (TAs) in early-stage PD and their involvement in disease progression. A new ultra performance chromatography mass spectrometry (UPLC-MS/MS) method was developed to quantify plasmatic TAs, and the catecholamines and indolamines pertaining to the same biochemical pathways. Three groups of subjects were recruited: 21 de novo, drug untreated, PD patients, 27 in treatment PD patients and 10 healthy subjects as controls. Multivariate and univariate data analyses were applied to reveal metabolic changes among the groups in attempt to discover new putative markers for early PD detection and disease progression. Different circulating levels of tyrosine (p = 0.002), tyramine (p < 0.001), synephrine (p = 0.015), norepinephrine (p = 0.012), metanephrine (p = 0.001), β-phenylethylamine (p = 0.001) and serotonin (p = 0.006) were found among the three groups. While tyramine behaves as a putative biomarker for early-stage PD (AUC = 0.90) tyramine, norepinephrine, and tyrosine appear to act as biomarkers of disease progression (AUC > 0.75). The findings of this pilot cross-sectional study suggest that biochemical anomalies of the aminergic and indolic neurotransmitters occur in PD patients. Compounds within the TAs family may constitute putative markers for early stage detection and progression of PD.

Enzyme deficiencies in amino acid metabolism may increase the levels of a single or several compounds in physiological fluids becoming diagnostically significant biomarkers for one or a group of metabolic disorders. Therefore, it is important to monitor a wide range of free amino acids simultaneously and to quantify them. This is time consuming if we use the classical methods and, especially now that many laboratories have introduced Newborn Screening Programs for the semiquantitative analysis, the detection and quantification of some amino acids need to be performed in a short time to reduce the rate of false positives.We have modified the stable isotope dilution HPLC-ESI-MS/MS method previously described by Qu (Qu et al., 2002) for a more rapid, robust, sensitive, and specific detection and quantification of underivatized amino acids. The modified method reduces the time of analysis to 10 min with very good reproducibility of retention times and a better separation of the metabolites and their isomers.The omission of the derivatization step, enabled to achieve some important advantages: fast and simple sample preparation, exclusion of artifacts, and interferences. The use of this technique is highly sensitive and specific and allowed to monitor 40 underivatized amino acids including the key isomers and quantification of some of them, in order to cover many diagnostically important intermediates of metabolic pathways.We propose this HPLC-ESI-MS/MS method for underivatized amino acids as a support for the newborn screening as secondary test using the same dried blood spots for a more accurate and specific examination in case of suspected metabolic diseases. In this way we avoid plasma collection from the patient as it normally occurs, reducing anxiety for the parents and further costs for analysis.The same method was validated and applied also to plasma and urine samples with good reproducibility, accuracy, and precision. The fast run time, the feasibility of high sample throughput, and the small amount of sample required make this method very suitable for routine analysis in the clinical setting.

Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache.

Enzyme deficiencies in amino acid (AA) metabolism affecting the levels of amino acids and their derivatives in physiological fluids may serve as diagnostically significant biomarkers for one or a group of metabolic disorders. Therefore, it is important to monitor a wide range of free amino acids simultaneously and to quantify them. This is time consuming if we use the classical methods and more than ever now that many laboratories have introduced Newborn Screening Programs for the semiquantitative analysis, detection, and quantification of some amino acids needed to be performed in a short time to reduce the rate of false positives.We have modified the stable isotope dilution HPLC-electrospray ionization (ESI)-MS/MS method previously described by Qu et al. (Anal Chem 74: 2034-2040, 2002) for a more rapid, robust, sensitive, and specific detection and quantification of underivatised amino acids. The modified method reduces the time of analysis to 10 min with very good reproducibility of retention times and a better separation of the metabolites and their isomers.The omission of the derivatization step allowed us to achieve some important advantages: fast and simple sample preparation and exclusion of artefacts and interferences. The use of this technique is highly sensitive, specific, and allows monitoring of 40 underivatized amino acids, including the key isomers and quantification of some of them, in order to cover many diagnostically important intermediates of metabolic pathways.We propose this HPLC-ESI-MS/MS method for underivatized amino acids as a support for the Newborn Screening as secondary test using the same dried blood spots for a more accurate and specific examination in case of suspected metabolic diseases. In this way, we avoid plasma collection from the patient as it normally occurs, reducing anxiety for the parents and further costs for analysis.The same method was validated and applied also to plasma and urine samples with good reproducibility, accuracy, and precision. The fast run time, feasibility of high sample throughput, and small amount of sample required make this method very suitable for routine analysis in the clinical setting.