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Sample records for neurotoxic catecholamine metabolite

  1. Neurotoxic Catecholamine Metabolite in Nociceptors Contributes to Painful Peripheral Neuropathy

    PubMed Central

    Dina, Olayinka A.; Khasar, Sachia G.; Alessandri-Haber, Nicole; Bogen, Oliver; Chen, Xiaojie; Green, Paul G.; Reichling, David B.; Messing, Robert O.; Levine, Jon D.

    2009-01-01

    Neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. Since some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO) we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine β-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons, and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain. PMID:18783367

  2. Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy.

    PubMed

    Dina, Olayinka A; Khasar, Sachia G; Alessandri-Haber, Nicole; Bogen, Oliver; Chen, Xiaojie; Green, Paul G; Reichling, David B; Messing, Robert O; Levine, Jon D

    2008-09-01

    The neurotoxic effects of catecholamine metabolites have been implicated in neurodegenerative diseases. As some sensory neurons express tyrosine hydroxylase and monoamine oxidase (MAO), we investigated the potential contribution of catecholamine metabolites to neuropathic pain in a model of alcoholic neuropathy. The presence of catecholamines in sensory neurons is supported by capsaicin-stimulated epinephrine release, an effect enhanced in ethanol-fed rats. mRNA for enzymes in dorsal root ganglia involved in catecholamine uptake and metabolism, dopamine beta-hydroxylase and MAO-A, were decreased by neonatal administration of capsaicin. Ethanol-induced hyperalgesia was attenuated by systemic and local peripheral administration of inhibitors of MAO-A, reduction of norepinephrine transporter (NET) in sensory neurons and a NET inhibitor. Finally, intradermal injection of 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), a neurotoxic MAO-A catecholamine metabolite, produced robust mechanical hyperalgesia. These observations suggest that catecholamines in nociceptors are metabolized to neurotoxic products by MAO-A, which can cause neuronal dysfunction underlying neuropathic pain.

  3. Symptomatic pheochromocytoma with normal urinary catecholamine metabolites.

    PubMed

    Zianni, Dimitra; Tzanela, Marinella; Klimopoulos, Serafim; Thalassinos, N C

    2004-01-01

    A 61-year old female presented with paroxysmal hypertension and a 4.5cm left adrenal mass on CT scan. Repeated measurements of 24-hour urinary fractionated metanephrines, total catecholamines and vanillylmandelic acid (VMA) were within normal range. A further scintigraphic study with (131)I -metaiodobenzylguanidine ((131)I-MIBG) revealed selective concentration of the radiotracer, corresponding to the CT mass. After adequate preoperative treatment, successful surgical excision of the tumor was performed and the pathological examination confirmed the diagnosis of a cystic pheochromocytoma with a 2cm solid tumor. On reevaluation three months later using (131)I-MIBG, no evidence of remaining or recurrent disease was found. The patient, off any antihypertensive medication, reported mild recurrent hypertension and panic attacks that were adequately controlled with antidepressants. This is a rare case of a symptomatic pheochromocytoma without elevated urine catecholamines and metanephrines. According to the literature, plasma free metanephrines would be the ideal test for biochemical detection of the tumor. However, in the event that they are not available and there is a high clinical suspicion for the presence of pheochromocytoma, as in our patient, we suggest performance of a functional nuclear medicine study, such as (131)I-MIBG, to confirm the clinical diagnosis.

  4. The metabolites of catecholamines in urine of patients irradiated therapeutically.

    PubMed

    Pericić, D; Deanović, Z

    1976-04-01

    The metabolites of catecholamines were determined in 24-hour urine samples of patients with genital carcinoma and treated by radio therapy. The patients were irradiated first with gamma-rays of radium and then with X-rays. The radium sources (80 mCi) were placed intracavitarily for 46 hours twice within 2 weeks. X-irradiation (800 R daily), applied 1 month after radium treatment, was delivered on four abdominal fields over 15 days. The quantities of excreted catecholamine metabolites during irradiation were compared with control values (obtained before irradiation) in the same patients. Gamma-irradiation provoked a significant increase in the excretion of 3-methoxy-4-hydroxy-mandelic acid, metadrenaline and normetadrenaline, as well as of homovanillic acid, whereas X-irradiation provoked only a significant increase in the excretion of free 3-methoxy-4-hydroxy-phenylglycol. The increased excretion might be explained: (1) in the case of radium application, by direct radiation-induced release of catecholamines from the peripheral symphathetic nerves; (2) in the case of X-irradiation, by putting in the motion the complex of early neuroendocrine reactions via irradiated adrenal medulla.

  5. Clozapine response and plasma catecholamines and their metabolites.

    PubMed

    Green, A I; Alam, M Y; Sobieraj, J T; Pappalardo, K M; Waternaux, C; Salzman, C; Schatzberg, A F; Schildkraut, J J

    1993-02-01

    The atypical neuroleptic clozapine has an unusual profile of clinical effects and a distinctive spectrum of pharmacological actions. Plasma measures of catecholamines and their metabolites have been used in the past to study the action of typical neuroleptics. We obtained longitudinal assessments of plasma measures of dopamine (pDA), norepinephrine (pNE), and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG), in eight treatment-resistant or treatment-intolerant schizophrenic patients who were treated with clozapine for 12 weeks following a prolonged drug-washout period. Our findings from the study of these eight patients suggest the following: Plasma levels of HVA and possibly NE derived from the neuroleptic-free baseline period may predict response to clozapine; plasma levels of HVA and MHPG decrease during the initial weeks of treatment in responders but not in nonresponders; and plasma levels of DA and NE increase in both responders and nonresponders to clozapine.

  6. ALTERATION OF CATECHOLAMINES IN PHOECHROMOCYTOMA (PC12) CELLS IN VITRO BY THE METABOLITES OF CHLOROTRIAZINE HERBICIDE

    EPA Science Inventory

    The effects of four major chlorotriazine metabolites on the constitutive synthesis of the catecholamines dopamine (DA) and norepinephrine (NE) were examined using undifferentiated PC12 cells. NE release and intracellular DA and NE concentrations were quantified following treatme...

  7. ALTERATION OF CATECHOLAMINES IN PHOECHROMOCYTOMA (PC12) CELLS IN VITRO BY THE METABOLITES OF CHLOROTRIAZINE HERBICIDE

    EPA Science Inventory

    The effects of four major chlorotriazine metabolites on the constitutive synthesis of the catecholamines dopamine (DA) and norepinephrine (NE) were examined using undifferentiated PC12 cells. NE release and intracellular DA and NE concentrations were quantified following treatme...

  8. Haloperidol response and plasma catecholamines and their metabolites.

    PubMed

    Green, A I; Alam, M Y; Boshes, R A; Waternaux, C; Pappalardo, K M; Fitzgibbon, M E; Tsuang, M T; Schildkraut, J J

    1993-06-01

    Eleven acutely psychotic patients with schizophrenia or schizoaffective disorder underwent a 5-7 day drug-washout period (with lorazepam allowed) prior to participating in a 6-week controlled dose haloperidol trial. Patients were evaluated longitudinally with clinical ratings and with plasma measures of the catecholamines dopamine (pDA) and norepinephrine (pNE) and their metabolites, homovanillic acid (pHVA) and 3-methoxy-4-hydroxyphenylglycol (pMHPG). All patients exhibited clinical improvement with haloperidol; the decrease in their Brief Psychiatric Rating Scale (BPRS) scores ranged from 32 to 89%. Measures of pHVA increased within the first week of treatment and returned to baseline by week 5. The pattern of change of pDA resembled that of pHVA. The pattern of change of pNE and pMHPG revealed a decrease over the course of treatment. The early increase and the subsequent decrease in pHVA were strongly correlated with improvement in positive symptoms on the BPRS. These data are consistent with previous reports on the change in pHVA and pMHPG during clinical response to haloperidol. The data on change of pDA and pNE further describe the nature of the biochemical response to this drug.

  9. Neurogenic hypertension associated with an excessively high excretion rate of catecholamine metabolites.

    PubMed Central

    Funck-Brentano, C; Pagny, J Y; Menard, J

    1987-01-01

    A 60 year old hypertensive patient suffered several cerebral infarctions. A phaeochromocytoma was suspected because the excretion rates of vanillylmandelic acid and its methoxy derivatives were raised and the patient had hypertensive crises. No tumour was found, however, by 131mI-iodobenzylguanidine scintigraphy and computed tomography of the abdomen. Moreover, the enhanced orthostatic plasma catecholamine response suggested that the high excretion rates of catecholamine metabolites were more likely to be caused by the syndrome of raised catecholamines after cerebrovascular accidents than a phaeochromocytoma. A phaeochromocytoma should not be diagnosed within several months of cerebral infarction without first excluding the possibility of a hyperadrenergic state induced by cerebral infarction. PMID:3593621

  10. Effects of Trilostane on urinary Catecholamines and their metabolites in dogs with Hypercortisolism.

    PubMed

    Sieber-Ruckstuhl, Nadja; Salesov, Elena; Quante, Saskia; Riond, Barbara; Rentsch, Katharina; Hofmann-Lehmann, Regina; Reusch, Claudia; Boretti, Felicitas

    2017-09-04

    Glucocorticoids influence the synthesis and metabolism of catecholamines (epinephrine and norepinephrine) and metanephrines (metanephrine and normetanephrine). The aim of this study was to measure urinary catecholamines and metanephrines in dogs with hypercortisolism before and during trilostane therapy. Urine samples were collected during initial work up and during therapy with trilostane in 14 dogs with hypercortisolism and in 25 healthy dogs. Epinephrine, norepinephrine, metanephrine and normetanephrine were measured using high-pressure liquid chromatography and expressed as ratios to urinary creatinine concentration. Untreated dogs with hypercortisolism had significantly higher epinephrine, norepinephrine, and normetanephrine:creatinine ratios compared to healthy dogs. During trilostane therapy, urinary catecholamines and their metabolites did not decrease significantly. However, dogs with low post-ACTH cortisol concentrations during trilostane therapy had less increased epinephrine, norepinephrine and normetanephrine:creatinine ratios compared to healthy dogs. There was no correlation of urinary catecholamines and their metabolites with baseline or post-ACTH cortisol or endogenous ACTH concentrations during trilostane therapy. Influences between steroid hormones and catecholamines seem to occur, as dogs with hypercortisolism have significantly higher urinary epinephrine, norepinephrine, and normetanephrine:creatinine ratios. Once-daily trilostane therapy does not lead to a significant decrease in catecholamines and their metabolites. Trilostane-treated dogs still have increased urinary epinephrine, norepinephrine and normetanephrine:creatinine ratios during trilostane therapy.

  11. Increased biogenic catecholamine and metabolite levels in two patients with malignant catatonia.

    PubMed

    Nisijima, Koichi

    2013-01-01

    The pathophysiology of malignant catatonia, a rare life-threatening psychiatric syndrome, has not yet been elucidated. This paper reports on two patients with malignant catatonia who showed elevated urinary or plasma catecholamine levels. Patient 1 had high catecholamine and metabolite levels in a 24-hour urine sample, and patient 2 had elevated plasma catecholamine levels. These findings indicate the presence of peripheral sympathetic nervous system hyperactivity in malignant catatonia. Symptoms of autonomic dysfunction, including tachycardia, labile blood pressure, and diaphoresis, are typical features of malignant catatonia and may be related to the increased levels of biogenic amines in these cases. Although the findings in the present study cannot entirely explain the pathophysiology of malignant catatonia, they do indicate that hyperactivity of the sympathetic nervous system may be involved in the pathology of this condition.

  12. Plasma free metanephrines are superior to urine and plasma catecholamines and urine catecholamine metabolites for the investigation of phaeochromocytoma.

    PubMed

    Hickman, Peter E; Leong, Michelle; Chang, Julia; Wilson, Susan R; McWhinney, Brett

    2009-02-01

    To compare the relative diagnostic efficacy of several different tests used to establish a diagnosis of phaeochromocytoma, in patients with a proven diagnosis of phaeochromocytoma, and in hospital patients with significant disease of other types. We prospectively compared biochemical markers of catecholamine output and metabolism in plasma and urine in 22 patients with histologically proven phaeochromocytoma, 15 intensive care unit (ICU) patients, 30 patients on chronic haemodialysis and both hypertensive (n = 10) and normotensive (n = 16) controls. Receiver operating characteristic curves were plotted. At the point of maximum efficiency, plasma free metanephrines showed 100% sensitivity and 97.6% specificity, compared with plasma catecholamines (78.6% and 70.7%), urine catecholamines (78.6% and 87.8%), urine metanephrines (85.7% and 95.1%), and urine hydroxymethoxymandelic acid (HMMA or VMA) (93.0% and 75.8%). All patients with phaeochromocytoma had plasma free metanephrine concentrations at least 27% above the upper limit of the reference range. Only three other patients (two on haemodialysis and one in ICU) had PFM concentrations more than 50% above the upper limit of the reference range. In patients with phaeochromocytoma, plasma free metanephrines displayed superior diagnostic sensitivity and specificity compared with other biochemical markers of catecholamine output and metabolism.

  13. COMT haplotypes, catecholamine metabolites in plasma and clinical response in schizophrenic and bipolar patients.

    PubMed

    Zumárraga, Mercedes; Arrúe, Aurora; Basterreche, Nieves; Macías, Isabel; Catalán, Ana; Madrazo, Arantza; Bustamante, Sonia; Zamalloa, María I; Erkoreka, Leire; Gordo, Estibaliz; Arnaiz, Ainara; Olivas, Olga; Arroita, Ariane; Marín, Elena; González-Torres, Miguel A

    2016-06-01

    We examined the association of COMT haplotypes and plasma metabolites of catecholamines in relation to the clinical response to antipsychotics in schizophrenic and bipolar patients. We studied 165 patients before and after four weeks of treatment, and 163 healthy controls. We assessed four COMT haplotypes and the plasma concentrations of HVA, DOPAC and MHPG. Bipolar patients: haplotypes are associated with age at onset and clinical evolution. In schizophrenic patients, an haplotype previously associated with increased risk, is related to better response of negative symptoms. Haplotypes would be good indicators of the clinical status and the treatment response in bipolar and schizophrenic patients. Larger studies are required to elucidate the clinical usefulness of these findings.

  14. [Catecholamines and their metabolites in children with Asperger and Kanner syndromes].

    PubMed

    Gorina, A S; Kolesnichenko, L S; Mikhnovich, V I

    2011-01-01

    Children with Asperger and Kanner syndromes in the stable state demonstrate similar decrease in plasma norepinephrine. In the aggravated state, these changes become more expressed and are characterized by a decrease in plasma tyrosine, norepinephrine, normetanephrine and by an increase in dopamine and homovanylic acid and a decrease in excretion of norepinephrine and an increase in excretion of homovanylic acid, epinephrine and MHPG. Only in children with Kanner syndrome in the aggravated state plasma MHPG increases, excretion of tyrosine decreases and excretion of normetanephrine increases. The observed imbalance in dopamine and epinephrine/norepinephrine systems justifies combined analysis of changes in catecholamines and their metabolites levels as the most informative approach in the study of the effect of autistic disorders.

  15. Spectroscopic study on the inclusion complexes of β-cyclodextrin with selected metabolites of catecholamines

    NASA Astrophysics Data System (ADS)

    Korytkowska-Wałach, Anna; Dubrawska, Beata; Śmiga-Matuszowicz, Monika; Bieg, Tadeusz

    2017-01-01

    Inclusion complexes formed between β-cyclodextrin (β-CD) and metabolites of catecholamines, i.e. vanillylmandelic acid (VMA), homovanillic acid (HVA) as well as vanillin (VA) were studied using NMR spectroscopy. Due to the importance of these compounds for the diagnosis tumours of the sympathoadrenal system, hydrogels containing β-CD moieties for enhancing entrapping metabolites of catecholamine from aqueous solutions are located in the area of our interest. Stoichiometry and association constants of the complexes of β-CD with VMA, HVA and VA respectively were determined by using continuous variation and 1H NMR titration methods. Significant discrepancies were pointed out depending on used referencing method. In this study water solution of 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt as an external reference was used to avoid errors in the determination of association constants. β-CD formed the most stable complexes with VA and HVA molecules whilst smallest value of association constant was determined for the VMA/β-CD complex. Two-dimensional rotating-frame Overhauser effect spectroscopy (2D ROESY) allowed to establish definite information on the molecular structures of the complexes formed. Geometry of the latter was proposed basing on contour plots of the 2D ROESY spectra, which also indicated two possibilities of complexed molecule arrangement into β-cyclodextrin interior. The values of determined association constants are in good agreement with postulated geometry of the complexes. Value of association constant determined for inclusion complexes of β-cyclodextrin with homovanillic acid an vanillin indicates the strongest binding of molecules among investigated complexes, so it was finally concluded that β-CD moiety introduced into hydrogel network could be effective for homovanillic acid and vanillin entrapping.

  16. Catecholamines 101

    PubMed Central

    2010-01-01

    This review of clinical catecholamine neurochemistry is based on the Streeten Memorial Lecture at the 19th annual meeting of the American Autonomic Society and lectures at a satellite of the 6th Congress of the International Society of Autonomic Neuroscience. Here I provide historical perspective, describe sources and meanings of plasma levels of catecholamines and their metabolites, present a model of a sympathetic noradrenergic neuron that conveys how particular aspects of sympathetic nervous function affect plasma levels of catecholamines and their metabolites, and apply the model to understand plasma neurochemical patterns associated with some drugs and disease states. PMID:20623313

  17. Thin-layer chromatography--an image-processing method for the determination of acidic catecholamine metabolites.

    PubMed

    Casoni, Dorina; Sima, Ioana Anamaria; Sârbu, Costel

    2014-10-01

    A sensitive and convenient method for acidic catecholamine metabolites (including homovanillic acid, vanillylmandelic acid, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylacetic acid) determination was developed based on thin-layer chromatography and image-processing analysis. The metabolites were separated without a prederivatization step using reversed phase RP-18W high-performance plates. The mobile phase composition, detection, and quantification conditions were systematically investigated through several trials. The reaction with 2,2-diphenyl-1-picrylhydrazyl radical allowed specific detection of acidic catecholamine metabolites with a high sensitivity and a wide linear range. The limit of detection and the limit of quantification were in the range of 13-103 and 18-120 ng/spot, respectively, in all cases. Mean recoveries determined were in the range 95-106% for all of the investigated compounds. The proposed method allowed rapid simultaneous determination of acidic catecholamine metabolites from spiked human urine sample. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Neurotoxicity of Ecstasy metabolites in rat cortical neurons, and influence of hyperthermia.

    PubMed

    Capela, João Paulo; Meisel, Andreas; Abreu, Artur Reis; Branco, Paula Sério; Ferreira, Luísa Maria; Lobo, Ana Maria; Remião, Fernando; Bastos, Maria Lurdes; Carvalho, Félix

    2006-01-01

    3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a widely abused, psychoactive recreational drug. There is growing evidence that the MDMA neurotoxic profile may be highly dependent on both its hepatic metabolism and body temperature. Metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, both of which are catechols that can undergo oxidation to the corresponding ortho-quinones. In the presence of glutathione (GSH), ortho-quinones may be conjugated with GSH to form glutathionyl adducts. In this study, we evaluated the neurotoxicity of MDMA and three of its metabolites obtained by synthesis, N-Me-alpha-MeDA, alpha-MeDA, and 5-(GSH)-alpha-MeDA [5-(glutathion-S-yl)-alpha-methyldopamine] in rat cortical neuronal serum-free cultures under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Cell viability was assessed, and the mechanism of cell death was also evaluated. Our study shows that these metabolites are more neurotoxic [5-(GSH)-alpha-MeDA being the most toxic] than the parent compound MDMA. The neurotoxicity of MDMA metabolites was partially prevented by the antioxidants N-acetylcystein and also, in a minor extent, by alpha-phenyl-N-tert-butyl nitrone. All the tested compounds induced apoptotic cell death in cortical neurons, and their neurotoxic effect was potentiated under hyperthermic conditions. These data suggest that MDMA metabolites, especially under hyperthermic conditions, contribute to MDMA-induced neurotoxicity.

  19. Predictive factors for responding to sertraline treatment: views from plasma catecholamine metabolites and serotonin transporter polymorphism.

    PubMed

    Umene-Nakano, Wakako; Yoshimura, Reiji; Ueda, Nobuhisa; Suzuki, Akihito; Ikenouchi-Sugita, Atsuko; Hori, Hikaru; Otani, Koichi; Nakamura, Jun

    2010-12-01

    In the present study, we investigated the effects of sertraline on plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and serum brain-derived neurotrophic factor (BDNF) levels in 59 depressed patients treated with sertraline. We also examined the relationship between the dynamics of the catecholamine metabolites, BDNF, serotonin transporter-linked polymorphic region (5-HTTLPR) gene polymorphism (long and short alleles), and the clinical response to sertraline. The extent of clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (Ham-D) before and 8 weeks after treatment with sertraline. Responders were defined as showing at least a 50% decrease in the Ham-D score. Baseline plasma HVA levels of responders to sertraline treatment were significantly lower than those of non-responders (p = 0.02). In addition, a positive correlation was identified between changes in plasma HVA levels and the rate of response to sertraline treatment (p = 0.001). A trend toward higher baseline serum BDNF levels was found in responders compared with non-responders (p = 0.095). In addition, serum BDNF levels were slightly increased (not significant) in responders (p = 0.058), but not in non-responders. Responders had a higher short-allele genotype frequency in the 5-HTTLPR for the promoter region than did non-responders (p = 0.037). These results suggest that pre-treatment plasma HVA levels and the 5-HTTLPR genotype for the promoter might be associated with a response to sertraline.

  20. Preservation of urine free catecholamines and their free O-methylated metabolites with citric acid as an alternative to hydrochloric acid for LC-MS/MS-based analyses.

    PubMed

    Peitzsch, Mirko; Pelzel, Daniela; Lattke, Peter; Siegert, Gabriele; Eisenhofer, Graeme

    2016-01-01

    Measurements of urinary fractionated metadrenalines provide a useful screening test to diagnose phaeochromocytoma. Stability of these compounds and their parent catecholamines during and after urine collection is crucial to ensure accuracy of the measurements. Stabilisation with hydrochloric acid (HCl) can promote deconjugation of sulphate-conjugated metadrenalines, indicating a need for alternative preservatives. Urine samples with an intrinsically acidic or alkaline pH (5.5-6.9 or 7.1-8.7, respectively) were used to assess stability of free catecholamines and their free O-methylated metabolites over 7 days of room temperature storage. Stabilisation with HCl was compared with ethylenediaminetetraacetic acid/metabisulphite and monobasic citric acid. Catecholamines and metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Free catecholamines and their O-methylated metabolites were stable in acidic urine samples over 7 days of room temperature storage, independent of the presence or absence of any stabilisation method. In contrast, free catecholamines, but not the free O-methylated metabolites, showed rapid degradation within 24 h and continuing degradation over 7 days in urine samples with an alkaline pH. Adjustment of alkaline urine samples to a pH of 3-5 with HCl or 4.8-5.4 with citric acid completely blocked degradation of catecholamines. Ethylenediaminetetraacetic acid/metabisulphite, although reducing the extent of degradation of catecholamines in alkaline urine, was largely ineffectual as a stabiliser. Citric acid is equally effective as HCl for stabilisation of urinary free catecholamines and minimises hazards associated with use of strong inorganic acids while avoiding deconjugation of sulphate-conjugated metabolites during simultaneous LC-MS/MS measurements of free catecholamines and their free O-methylated metabolites.

  1. Plasma levels of catecholamine metabolites predict the response to sulpiride or fluvoxamine in major depression.

    PubMed

    Ueda, N; Yoshimura, R; Shinkai, K; Nakamura, J

    2002-09-01

    We investigated the relationships between the changes in plasma catecholamine metabolites obtained from depressed patients before and after administration of sulpiride, a benzamide compound, or fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), and between clinical responses to treatment with each of these drugs. Responders to sulpiride had significantly lower plasma homovanillic acid (pHVA) levels before administration of sulpiride than did non-responders or controls (responders: 4.5 +/- 3.1 ng/ml, non-responders: 11.1 +/- 5.9 ng/ml, controls: 10.9 +/- 5.3 ng/ml). Positive relationships were observed between changes in pHVA levels and improvement rates in the 17-item Hamilton Depression Rating Scale (Ham-D). In contrast, responders to fluvoxamine had significantly higher plasma free 3-methoxy-4-hydroxyphenylglycol (pMHPG) levels before administration of fluvoxamine than did non-responders or controls (responders: 8.5 +/- 1.8 ng/ml, non-responders: 5.9 +/- 2.I ng/ml, controls: 5.2 +/- 2.9 ng/ml). Negative relationships were observed between changes in pMHPG levels and improvement rates in Ham-D. These results suggest that lower pretreatment pHVA levels and higher pretreatment levels of pMHPG might be predictors of response to sulpiride and fluvoxamine, respectively, and that sulpiride might produce a functional increase in the dopaminergic system, resulting in improvement in some depressive symptoms; fluvoxamine, on the other hand, might produce a functional decrease in the noradrenergic system via serotonergic neurons, resulting in improvement of those symptoms.

  2. The Metabolic Fate of ortho-Quinones Derived from Catecholamine Metabolites.

    PubMed

    Ito, Shosuke; Yamanaka, Yuta; Ojika, Makoto; Wakamatsu, Kazumasa

    2016-01-27

    ortho-Quinones are produced in vivo through the oxidation of catecholic substrates by enzymes such as tyrosinase or by transition metal ions. Neuromelanin, a dark pigment present in the substantia nigra and locus coeruleus of the brain, is produced from dopamine (DA) and norepinephrine (NE) via an interaction with cysteine, but it also incorporates their alcoholic and acidic metabolites. In this study we examined the metabolic fate of ortho-quinones derived from the catecholamine metabolites, 3,4-dihydroxyphenylethanol (DOPE), 3,4-dihydroxyphenylethylene glycol (DOPEG), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylmandelic acid (DOMA). The oxidation of catecholic substrates by mushroom tyrosinase was followed by UV-visible spectrophotometry. HPLC analysis after reduction with NaBH₄ or ascorbic acid enabled measurement of the half-lives of ortho-quinones and the identification of their reaction products. Spectrophotometric examination showed that the ortho-quinones initially formed underwent extensive degradation at pH 6.8. HPLC analysis showed that DOPE-quinone and DOPEG-quinone degraded with half-lives of 15 and 30 min at pH 6.8, respectively, and >100 min at pH 5.3. The major product from DOPE-quinone was DOPEG which was produced through the addition of a water molecule to the quinone methide intermediate. DOPEG-quinone yielded a ketone, 2-oxo-DOPE, through the quinone methide intermediate. DOPAC-quinone and DOMA-quinone degraded immediately with decarboxylation of the ortho-quinone intermediates to form 3,4-dihydroxybenzylalcohol (DHBAlc) and 3,4-dihydroxybenzaldehyde (DHBAld), respectively. DHBAlc-quinone was converted to DHBAld with a half-life of 9 min, while DHBAld-quinone degraded rapidly with a half-life of 3 min. This study confirmed the fact that ortho-quinones from DOPE, DOPEG, DOPAC and DOMA are converted to quinone methide tautomers as common intermediates, through proton rearrangement or decarboxylation. The unstable quinone

  3. Accumulation of neurotoxic thioether metabolites of 3,4-(+/-)-methylenedioxymethamphetamine in rat brain.

    PubMed

    Erives, Gladys V; Lau, Serrine S; Monks, Terrence J

    2008-01-01

    The serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-alpha-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA (20 mg/kg s.c.) at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-alpha-MeDA thioether metabolites in striatal dialysate. The area under the curve (AUC)(0-300 min) for 5-(glutathion-S-yl)-N-Me-alpha-MeDA increased 33% between the first and fourth injections and essentially doubled for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA. Likewise, accumulation of the mercapturic acid metabolites was reflected by increases in the AUC(0-300 min) for both 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (35%) and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (85%), probably because processes for their elimination become saturated. Indeed, the elimination half-life of 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA increased by 53 and 28%, respectively, between the first and third doses. Finally, although the C(max) values for the monothioether conjugates were essentially unchanged after each injection, the values increased by 38 and approximately 50% for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA, respectively, between the first and fourth injections. The data indicate that neurotoxic metabolites of MDMA may accumulate in brain after

  4. Diurnal Profiles of Melatonin Synthesis-Related Indoles, Catecholamines and Their Metabolites in the Duck Pineal Organ

    PubMed Central

    Lewczuk, Bogdan; Ziółkowska, Natalia; Prusik, Magdalena; Przybylska-Gornowicz, Barbara

    2014-01-01

    This study characterizes the diurnal profiles of ten melatonin synthesis-related indoles, the quantitative relations between these compounds, and daily variations in the contents of catecholamines and their metabolites in the domestic duck pineal organ. Fourteen-week-old birds, which were reared under a 12L:12D cycle, were killed at two-hour intervals. The indole contents were measured using HPLC with fluorescence detection, whereas the levels of catecholamines and their metabolites were measured using HPLC with electrochemical detection. All indole contents, except for tryptophan, showed significant diurnal variations. The 5-hydroxytryptophan level was approximately two-fold higher during the scotophase than during the photophase. The serotonin content increased during the first half of the photophase, remained elevated for approximately 10 h and then rapidly decreased in the middle of the scotophase. N-acetylserotonin showed the most prominent changes, with a more than 15-fold increase at night. The melatonin cycle demonstrated only an approximately 5-fold difference between the peak and nadir. The 5-methoxytryptamine content was markedly elevated during the scotophase. The 5-hydroxyindole acetic acid, 5-hydroxytryptophol, 5-methoxyindole acetic acid and 5-methoxytryptophol profiles were analogous to the serotonin rhythm. The norepinephrine and dopamine contents showed no significant changes. The DOPA, DOPAC and homovanillic acid levels were higher during the scotophase than during the photophase. Vanillylmandelic acid showed the opposite rhythm, with an elevated level during the daytime. PMID:25032843

  5. Evaluation of the effects of zilpateral hydrochloride supplementation on catecholamin response and other blood metabolites following a combined corticotropin releasing hormone and vasopressin challenge

    USDA-ARS?s Scientific Manuscript database

    The stress response of cattle supplemented with zilpaterol hydrochloride (ZH) has become a topic due to anecdotal claims of supplemented cattle responding poorly to stress. This study was designed to determine if differences exist in the catecholamine and blood metabolite response of ZH-supplemente...

  6. Catechol O-methyltransferase and monoamine oxidase A genotypes, and plasma catecholamine metabolites in bipolar and schizophrenic patients.

    PubMed

    Zumárraga, Mercedes; Dávila, Ricardo; Basterreche, Nieves; Arrue, Aurora; Goienetxea, Biotza; Zamalloa, María I; Erkoreka, Leire; Bustamante, Sonia; Inchausti, Lucía; González-Torres, Miguel A; Guimón, José

    2010-01-01

    Metabolites of dopamine and norepinephrine measured in the plasma have long been associated with symptomatic severity and response to treatment in schizophrenic, bipolar and other psychiatric patients. Plasma concentrations of catecholamine metabolites are genetically regulated. The genes encoding enzymes that are involved in the synthesis and degradation of these monoamines are candidate targets for this genetic regulation. We have studied the relationship between the Val158Met polymorphism in catechol O-methyltransferase gene, variable tandem repeat polymorphisms in the monoamine oxidase A gene promoter, and plasma concentrations of 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxyphenylacetic acid and homovanillic acid in healthy control subjects as well as in untreated schizophrenic and bipolar patients. We found that the Val158Met substitution in catechol O-methyltransferase gene influences the plasma concentrations of homovanillic and 3,4-dihydroxyphenylacetic acids. Although higher concentrations of plasma homovanillic acid were found in the high-activity ValVal genotype, this mutation did not affect the plasma concentration of 3-methoxy-4-hydroxyphenylglycol. 3,4-dihydroxyphenylacetic acid concentrations were higher in the low-activity MetMet genotype. Interestingly, plasma values 3-methoxy-4-hydroxyphenylglycol were greater in schizophrenic patients and in bipolar patients than in healthy controls. Our results are compatible with the previously reported effect of the Val158Met polymorphism on catechol O-methyltransferase enzymatic activity. Thus, our results suggest that this polymorphism, alone or associated with other polymorphisms, could have an important role in the genetic control of monoamine concentration and its metabolites.

  7. Plasma levels of brain derived-neurotrophic factor and catecholamine metabolites are increased during active phase of psychotic symptoms in CNS lupus: a case report.

    PubMed

    Ikenouchi, Atsuko; Yoshimura, Reiji; Ikemura, Naomi; Utsunomiya, Kensuke; Mitoma, Masae; Nakamura, Jun

    2006-09-30

    In the present study, the authors reported a case of systemic lupus erythematosus (SLE) with central nervous system involvement (CNS lupus). The authors also longitudinally investigated plasma levels of brain-derived neurotrophic factor (BDNF) and catecholamine metabolites in the patient, and found that plasma levels of BDNF, 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were raised in accordance with the severity of psychotic symptoms in this case of CNS lupus. These results suggest that it is useful to measure plasma levels of BDNF and the catecholamine metabolites in order to predict the severity of psychotic symptoms in CNS lupus and to provide a differential diagnosis from that of steroid-induced psychosis.

  8. Comparative neurochemical profile of 3,4-methylenedioxymethamphetamine and its metabolite alpha-methyldopamine on key targets of MDMA neurotoxicity.

    PubMed

    Escubedo, E; Abad, S; Torres, I; Camarasa, J; Pubill, D

    2011-01-01

    The neurotoxicity of MDMA or "Ecstasy" in rats is selectively serotonergic, while in mice it is both dopaminergic and serotonergic. MDMA metabolism may play a key role in this neurotoxicity. The function of serotonin and dopamine transporter and the effect of MDMA and its metabolites on them are essential to understand MDMA neurotoxicity. The aim of the present study was to investigate and compare the effects of MDMA and its metabolite alpha-methyldopamine (MeDA) on several molecular targets, mainly the dopamine and serotonin transporter functionality, to provide evidence for the role of this metabolite in the neurotoxicity of MDMA in rodents. MeDA had no affinity for the serotonin transporter but competed with serotonin for its uptake. It had no persistent effects on the functionalism of the serotonin transporter, in contrast to the effect of MDMA. Moreover, MeDA inhibited the uptake of dopamine into the serotonergic terminal and also MAO(B) activity. MeDA inhibited dopamine uptake with a lower IC(50) value than MDMA. After drug washout, the inhibition by MeDA persisted while that of MDMA was significantly reduced. The effect of MDMA on the dopamine transporter is related with dopamine release from vesicular stores, as this inhibition disappeared in reserpine-treated animals. However, the effect of MeDA seems to be a persistent conformational change of this transporter. Moreover, in contrast with MDMA, MeDA did not show affinity for nicotinic receptors, so no effects of MeDA derived from these interactions can be expected. The metabolite reduced cell viability at lower concentrations than MDMA. Apoptosis plays a key role in MDMA induced cellular toxicity but necrosis is the major process involved in MeDA cytotoxicity. We conclude that MeDA could protect against the serotonergic lesion induced by MDMA but potentiate the dopaminergic lesion as a result of the persistent blockade of the dopamine transporter induced this metabolite.

  9. Formic acid, a novel metabolite of chronic ethanol abuse, causes neurotoxicity, which is prevented by folic acid.

    PubMed

    Kapur, Bhushan M; Vandenbroucke, Arthur C; Adamchik, Yana; Lehotay, Denis C; Carlen, Peter L

    2007-12-01

    Methanol is endogenously formed in the brain and is present as a congener in most alcoholic beverages. Because ethanol is preferentially metabolized over methanol (MeOH) by alcohol dehydrogenase, it is not surprising that MeOH accumulates in the alcohol-abusing population. This suggests that the alcohol-drinking population will have higher levels of MeOH's neurotoxic metabolite, formic acid (FA). FA elimination is mediated by folic acid. Neurotoxicity is a common result of chronic alcoholism. This study shows for the first time that FA, found in chronic alcoholics, is neurotoxic and this toxicity can be mitigated by folic acid administration. To determine if FA levels are higher in the alcohol-drinking population and to assess its neurotoxicity in organotypic hippocampal rat brain slice cultures. Serum and CSF FA was measured in samples from both ethanol abusing and control patients, who presented to a hospital emergency department. FA's neurotoxicity and its reversibility by folic acid were assessed using organotypic rat brain hippocampal slice cultures using clinically relevant concentrations. Serum FA levels in the alcoholics (mean +/- SE: 0.416 +/- 0.093 mmol/l, n = 23) were significantly higher than in controls (mean +/- SE: 0.154 +/- 0.009 mmol/l, n = 82) (p < 0.0002). FA was not detected in the controls' CSF (n = 20), whereas it was >0.15 mmol/l in CSF of 3 of the 4 alcoholic cases. Low doses of FA from 1 to 5 mmol/l added for 24, 48 or 72 hours to the rat brain slice cultures caused neuronal death as measured by propidium iodide staining. When folic acid (1 micromol/l) was added with the FA, neuronal death was prevented. Formic acid may be a significant factor in the neurotoxicity of ethanol abuse. This neurotoxicity can be mitigated by folic acid administration at a clinically relevant dose.

  10. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor.

    PubMed

    Bunzow, J R; Sonders, M S; Arttamangkul, S; Harrison, L M; Zhang, G; Quigley, D I; Darland, T; Suchland, K L; Pasumamula, S; Kennedy, J L; Olson, S B; Magenis, R E; Amara, S G; Grandy, D K

    2001-12-01

    The trace amine para-tyramine is structurally and functionally related to the amphetamines and the biogenic amine neurotransmitters. It is currently thought that the biological activities elicited by trace amines such as p-tyramine and the psychostimulant amphetamines are manifestations of their ability to inhibit the clearance of extracellular transmitter and/or stimulate the efflux of transmitter from intracellular stores. Here we report the discovery and pharmacological characterization of a rat G protein-coupled receptor that stimulates the production of cAMP when exposed to the trace amines p-tyramine, beta-phenethylamine, tryptamine, and octopamine. An extensive pharmacological survey revealed that psychostimulant and hallucinogenic amphetamines, numerous ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of the catecholamine neurotransmitters are also good agonists at the rat trace amine receptor 1 (rTAR1). These results suggest that the trace amines and catecholamine metabolites may serve as the endogenous ligands of a novel intercellular signaling system found widely throughout the vertebrate brain and periphery. Furthermore, the discovery that amphetamines, including 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), are potent rTAR1 agonists suggests that the effects of these widely used drugs may be mediated in part by this receptor as well as their previously characterized targets, the neurotransmitter transporter proteins.

  11. Cerebrospinal fluid levels of catecholamines and its metabolites in Parkinson's disease: Effect of L-DOPA treatment and changes in levodopa-induced dyskinesia.

    PubMed

    Andersen, A D; Blaabjerg, M; Binzer, M; Kamal, A; Thagesen, H; Kjaer, T W; Stenager, E; Gramsbergen, J B

    2017-02-28

    Levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) is the most effective drug in the symptomatic treatment of Parkinson's disease (PD), but chronic use initiates a maladaptive process leading to L-DOPA-induced dyskinesia (LID). Risk factors for early onset LID include younger age, more severe disease at baseline and higher daily L-DOPA dose, but biomarkers to predict the risk of motor complications are not yet available. Here we investigated whether CSF levels of catecholamines and its metabolites are altered in PD patients with LID (PD-LID, n=8)) as compared to non-dyskinetic PD patients receiving L-DOPA (PD-L, n=6), or not receiving L-DOPA (PD-N, n=7) as well as non-PD controls (n=16). PD patients were clinically assessed using the Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale and CSF was collected after overnight fasting and 1-2 hours after oral intake of L-DOPA or other anti-Parkinson medication. CSF catecholamines and its metabolites were analyzed by HPLC with electrochemical detection. We observed (1) decreased levels of dihydroxyphenylacetic acid and homovanillic acid in PD patients not receiving L-DOPA (2) higher DA levels in LID as compared to controls (3) higher DA/L-DOPA and lower DOPAC/DA ratio's in LID as compared to PDL and (4) an age-dependent increase of DA and decrease of DOPAC/DA ratio in controls. These results suggest increased DA release from non-DA cells and deficient DA re-uptake in PD-LID. Monitoring DA and DOPAC in CSF of L-DOPA-treated PD patients may help identify patients at risk of developing LID. This article is protected by copyright. All rights reserved.

  12. High-performance Liquid Chromatography Measured Metabolites of Endogenous Catecholamines and Their Relations to Chronic Kidney Disease and High Blood Pressure in Heart Transplant Recipients.

    PubMed

    Wasilewski, G; Przybylowski, P; Wilusz, M; Sztefko, K; Janik, Ł; Koc-Żórawska, E; Malyszko, J

    2016-06-01

    Patients after solid organ transplantation, especially heart and kidneys, are prone to be hypertensive. Recently chronic kidney disease and renalase metabolism of endogenous catecholamines are thought to make major contribution to the pathogenesis of hypertension. We analyzed 75 heart recipients (80% male, 20% female), medium age 54.9 years (range, 25-75) at 0.5 to 22 years after heart transplantation (median, 10.74). Diagnosis of hypertension was made on the basis of ambulatory blood pressure monitoring. Complete blood count, urea, creatinine, estimated glomerular filtration rate (eGFR), renalase in serum, and levels of metanefrine, normetanefrine, and 3-metoxytyramine in 24-hour urine collection calculated with a high-performance liquid chromatography were recorded. Urine endogenous catecholamine metabolites were estimated according to creatinine clearance. Normetanefrine was correlated with age (r = 0.27; P < .05), urea (r = 0.64; P < .01), creatinine (r = 0.6; P < .01), eGFR (r = -0.51; P < .01), renalase (r = 0.5; P < .01), and diastolic blood pressure (r = 0.26; P < .05). Metanefrine was correlated with urea (r = 0.43; P < .01), creatinine (0.32; P < .01), eGFR (r = -0.4; P < .01), renalase (r = 0.34; P < .05), height (r = -0.26; P < .05), weight (r = -0.23; P < .05), and time after heart transplantation (r = 0.27; P < .05). 3-Metoxytyramine was correlated with urea (r = 0.43; P < .01), creatinine (r = 0.32; P < .01), and the eGFR (r = -0.24; P < .05). Creatinine was correlated with age (r = 0.36; P < .01), diastolic blood pressure (r = 0.26; P < .05), time after heart transplantation (r = 0.24; P < .05), and renalase (r = 0.69; P < .01). Systolic blood pressure was correlated with proteinuria (r = 0.26; P < .05). Chronic kidney disease and concomitant hypertension are the most prevalent comorbidities in the population of heart transplant recipients. Urine catecholamine metabolites were related to kidney

  13. Putative neuroprotective and neurotoxic kynurenine pathway metabolites are associated with hippocampal and amygdalar volumes in subjects with major depressive disorder.

    PubMed

    Savitz, Jonathan; Drevets, Wayne C; Smith, Chelsey M; Victor, Teresa A; Wurfel, Brent E; Bellgowan, Patrick S F; Bodurka, Jerzy; Teague, T Kent; Dantzer, Robert

    2015-01-01

    Inflammation-related changes in the concentrations of kynurenine pathway metabolites occur in depression secondary to medical conditions but are not firmly established in primary mood disorders. Reductions in hippocampal and amygdalar volume that putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD). Here we tested whether the relative serum concentrations of putatively neuroprotective (kynurenic acid (KA)) and neurotoxic (3-hydroxykynurenine (3HK) and quinolinic acid (QA)) kynurenine pathway metabolites were altered in primary MDD and whether these metabolites were associated with hippocampal and amygdalar volume. A total of 29 moderately to severely depressed unmedicated subjects who met DSM-IV criteria for MDD and 20 healthy controls (HCs) completed a structural MRI scan and provided blood sample for kynurenine metabolite analysis, performed using high-performance liquid chromatography with tandem mass spectrometry. Cytokine concentrations were measured with ELISA and gray matter volumes were measured with the automated segmentation software, FreeSurfer. An a priori defined variable of interest, the KA/QA ratio, a putative neuroprotective index, trended lower in the MDD versus the HC group and correlated negatively with anhedonia but positively with the total hippocampal and amygdala volume in the MDD subjects. The post hoc data reduction methods yielded three principal components. Component 1 (interleukin-1 receptor antagonist, QA, and kynurenine) was significantly elevated in MDD participants versus the HCs, whereas component 2 (KA, tryptophan, and kynurenine) was positively correlated with hippocampal and amygdala volume within the MDD group. Our results raise the possibility that an immune-related imbalance in the relative metabolism of KA and QA predisposes to depression-associated dendritic atrophy and anhedonia.

  14. Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder.

    PubMed

    Meier, Timothy B; Drevets, Wayne C; Wurfel, Brent E; Ford, Bart N; Morris, Harvey M; Victor, Teresa A; Bodurka, Jerzy; Teague, T Kent; Dantzer, Robert; Savitz, Jonathan

    2016-03-01

    Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p<0.01) and BA32 (p<0.05) regions and MDD patients with a greater number of depressive episodes displayed thinner cortex in BA32 (p<0

  15. Relationship between neurotoxic kynurenine metabolites and reductions in right medial prefrontal cortical thickness in major depressive disorder

    PubMed Central

    Meier, Timothy B.; Drevets, Wayne C.; Wurfel, Brent E.; Ford, Bart N.; Morris, Harvey M.; Victor, Teresa A.; Bodurka, Jerzy; Teague, T. Kent; Dantzer, Robert; Savitz, Jonathan

    2015-01-01

    Reductions in gray matter volume of the medial prefrontal cortex (mPFC), especially the rostral and subgenual anterior cingulate cortex (rACC, sgACC) are a widely reported finding in major depressive disorder (MDD). Inflammatory mediators, which are elevated in a subgroup of patients with MDD, activate the kynurenine metabolic pathway and increase production of neuroactive metabolites such as kynurenic acid (KynA), 3-hydroxykynurenine (3HK) and quinolinic acid (QA) which influence neuroplasticity. It is not known whether the alterations in brain structure and function observed in major depressive disorders are due to the direct effect of inflammatory mediators or the effects of neurotoxic kynurenine metabolites. Here, using partial posterior predictive distribution mediation analysis, we tested whether the serum concentrations of kynurenine pathway metabolites mediated reductions in cortical thickness in mPFC regions in MDD. Further, we tested whether any association between C-reactive protein (CRP) and cortical thickness would be mediated by kynurenine pathway metabolites. Seventy-three unmedicated subjects who met DSM-IV-TR criteria for MDD and 91 healthy controls (HC) completed MRI scanning using a pulse sequence optimized for tissue contrast resolution. Automated cortical parcellation was performed using the PALS-B12 Brodmann area atlas as implemented in FreeSurfer in order to compare the cortical thickness and cortical area of six PFC regions: Brodmann areas (BA) 9, 10, 11, 24, 25, and 32. Serum concentrations of kynurenine pathway metabolites were determined by high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection, while high-sensitivity CRP concentration was measured immunoturbidimetrically. Compared with HCs, the MDD group showed a reduction in cortical thickness of the right BA24 (p<0.01) and BA32 (p<0.05) regions and MDD patients with a greater number of depressive episodes displayed thinner cortex in BA32 (p<0

  16. Detection of a novel neurotoxic metabolite of Parkinson's disease-related neurotoxin, 1-benzyl-1,2,3,4- tetrahydroisoquinoline.

    PubMed

    Kotake, Yaichiro; Sekiya, Yoko; Okuda, Katsuhiro; Ohta, Shigeru

    2014-01-01

    Naturally occurring low-molecular weight compounds with a chemical structure like that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline(1BnTIQ), are candidates for the endogenous neurotoxins that cause Parkinson's disease (PD). 1BnTIQ is an endogenous amine in human CSF and increases in the CSF of patients with PD. It inhibits complex Iand elicits PD-like behavioral abnormalities in monkey and mouse. In this study, we searched metabolites of 1BnTIQ by rat liver S9 using liquid chromatography-tandem mass spectrometry, and identified a dehydrated metabolite, 1-benzyl-3,4-dihydroisoquinoline (1BnDIQ). 1BnDIQ was identified by corresponding mass spectra and precursor ion scans in authentic and complete enzyme samples. Multiple reaction monitoring analysis showed microsome-dependent 1BnDIQ production. We previously reported that 1BnDIQ is more toxic than 1BnTIQ in cytotoxicity study in SH-SY5Y neuroblastoma cells. In addition, 1BnTIQ is reported to pass through the blood-brain barrier of the rat brain, and 1BnDIQ is supposed to be more lipophilic than 1BnTIQ. 1BnDIQ may easily reach the brain, and it might contribute to PD-related neurotoxicity.

  17. Plasma levels of free metanephrines and 3-methoxytyramine indicate a higher number of biochemically active HNPGL than 24-h urinary excretion rates of catecholamines and metabolites.

    PubMed

    van Duinen, N; Corssmit, E P M; de Jong, W H A; Brookman, D; Kema, I P; Romijn, J A

    2013-09-01

    A substantial number of patients with head and neck paragangliomas (HNPGLs) have biochemically active tumors, evidenced by increased urinary excretion of catecholamines and metabolites, including 3-methoxytyramine (3MT). It is unclear whether plasma levels of these parameters are more sensitive to detect biochemical activity in HNPGL patients than urinary excretion rates. To compare plasma free levels vs urinary excretion rates of deconjugated 3MT and combined metanephrines (MNs) in patients with HNPGL. We included 124 consecutive patients with HNPGL for screening of catecholamine excess by measurement of 24-h urinary excretion rates of deconjugated (nor)metanephrine, (nor)epinephrine, dopamine, vanillylmandelic acid, 3MT, and plasma free levels of (nor)metanephrine and 3MT. Plasma free 3MT levels were increased in 35 of the 124 patients (28%), whereas 24-h urinary excretion of deconjugated 3MT was increased in 30 patients (24%) (P=0.13). Plasma free MN levels were increased in seven patients (6%) and urinary deconjugated MN levels in six patients (5%) (P=1.00). Plasma free normetanephrine (NMN) levels were increased in seven patients (6%), and five patients had increased urinary excretion of deconjugated NMN (4%) (P=0.69). Plasma free combined MN levels (NMN, MN, and 3MT) were increased in 41 patients (33%), whereas 24-h urinary excretion rates of deconjugated combined MNs were increased in 33 patients (27%, P<0.05). The combined levels of free MNs and free 3MT in plasma indicate a higher number of biochemically active HNPGLs than the 24-h urinary excretion rates of these markers.

  18. [An experimental study on the neurotoxicity of 2-octanone and 2-hexanol, a metabolite of n-hexane].

    PubMed

    Misumi, J; Nagano, M; Nomura, S

    1982-09-01

    An electrophysiological study of the neurotoxicity of 2-octanone (an analogue of methyl n-butyl ketone) and 2-hexanol (a metabolite of n-hexane) was conducted on rats as a part of the study to determine the specific molecular arrangement required for the development of peripheral neuropathy. The compound 2-octanone or 2-hexanol was administered subcutaneously in the daily dose of 400 mg/kg of each compound into the back of seven rats, weighing 290 g, 5 days per week for a period of 21 weeks. Animals treated with 2-octanone for 21 weeks failed to exhibit apparent clinical and neurophysiological evidence except a slight inhibition of weight gain and narcotic effects after treatment with the compound. The same doses of 2-hexanol for 21 weeks caused hypersalivation, gait disturbances, crossing phenomena of hind limbs and a failure of normal growth. Retardation of the conduction velocity in the motor and sensory nerve fibers and the prolonged motor latencies of the tail nerves (distal part) began to appear at the 14th week of the experiment when 9.6 g in the total dose had been given to each animal. These changes were intensified in the subsequent course of the experiment. Our previous experiments and the present results showed that n-hexane barely produced peripheral neuropathy in doses over 10.5 g, and that 2-hexanone (MBK), 2,5-hexanediol or 2,5-hexanedione never failed to produce a neuropathy even in doses less than 9.6 g of each compound. The above results suggest that the neurotoxic potency of 2-hexanol is greater than that of n-hexane but less than that of MBK, 2,5-hexanediol or 2,5-hexanedione.

  19. Pharmacological studies confirm neurotoxic metabolite(s) produced by the bloom-forming Cylindrospermopsis raciborskii in Hungary.

    PubMed

    Vehovszky, Á; Kovács, A W; Farkas, A; Győri, J; Szabó, H; Vasas, G

    2015-05-01

    A rapid cyanobacterial bloom of Cylindrospermopsis raciborskii (3.2 × 10(4) filaments/mL) was detected early November, 2012, in the Fancsika pond (East Hungary). The strong discoloration of water was accompanied by a substantial fish mortality (even dead cats were seen on the site), raising the possibility of some toxic metabolites in the water produced by the bloom-forming cyanobacteria (C. raciborskii). The potential neuronal targets of the toxic substances in the bloom sample were studied on identified neurons (RPas) in the central nervous system of Helix pomatia. The effects of the crude aqueous extracts of the Fancsika bloom sample (FBS) and the laboratory isolate of C. raciborskii from the pond (FLI) were compared with reference samples: C. raciborskii ACT 9505 (isolated in 1995 from Lake Balaton, Hungary), the cylindrospermopsin producer AQS, and the neurotoxin (anatoxin-a, homoanatoxin-a) producer Oscillatoria sp. (PCC 6506) strains. Electrophysiological tests showed that both FBS and FLI samples as well the ACT 9505 extracts modulate the acetylcholine receptors (AChRs) of the neurons, evoking ACh agonist effects, then inhibiting the ACh-evoked neuronal responses. Dose-response data suggested about the same range of toxicity of FBS and FLI samples (EC50  = 0.397 mg/mL and 0.917 mg/mL, respectively) and ACT 9505 extracts (EC50  = 0.734 mg/mL). The extract of the neurotoxin-producing PCC 6506 strain, however, proved to be the strongest inhibitor of the ACh responses on the same neurons (EC50  = 0.073 mg/mL). The presented results demonstrated an anatoxin-a-like cholinergic inhibitory effects of cyanobacterial extracts (both the environmental FBS sample, and the laboratory isolate, FLI) by some (yet unidentified) toxic components in the matrix of secondary metabolites. Previous pharmacological studies of cyanobacterial samples collected in other locations (Balaton, West Hungary) resulted in similar conclusions; therefore, we cannot exclude that

  20. Neurotoxic metabolites of ''commercial hexane'' in the urine of shoe factory workers

    SciTech Connect

    Perbellini, L.; Brugnone, F.; Gaffuri, E.

    1981-12-01

    Urinary metabolites were tested in 41 shoe-factory workers exposed to a mixture of 10 solvents among which ''commercial hexane'' was the prevailing component. Cyclohexanol, 2-methyl-2-pentanol, 3-methyl-2-pentanol, and trichloroethanol were determined in connection with exposure to cyclohexane, 2-methylpentane, 3-methylpentane, and trichloroethylene, respectively. 2-Hexanol, 2,5-hexanedione, 2,5-dimethylfuran, and gamma-valerolactone were all determined in connection with n-hexane exposure only. 2,5-Hexanedione was the principal n-hexane metabolite found in the workers' urine. This finding of the experimentally proven neurotoxin 2,5-hexanedione in the urine of shoe-factory workers exposed to ''commercial hexane'' is consistent with the idea that this compound is responsible for the development of neuropathy in this group of individuals.

  1. Neurotoxic metabolites of "commercial hexane" in the urine of shoe factory workers.

    PubMed

    Perbellini, L; Brugnone, F; Gaffuri, E

    1981-12-01

    Urinary metabolites were tested in 41 shoe-factory workers exposed to a mixture of 10 solvents among which "commercial hexane" was the prevailing component. Cyclohexanol, 2-methyl-2-pentanol, 3-methyl-2-pentanol, and trichloroethanol were determined in connection with exposure to cyclohexane, 2-methylpentane, 3-methylpentane, and trichloroethylene, respectively. 2-Hexanol, 2,5-hexanedione, 2,5-dimethylfuran, and gamma-valerolactone were all determined in connection with n-hexane exposure only. 2,5-Hexanedione was the principal n-hexane metabolite found in the workers' urine. This finding of the experimentally proven neurotoxin 2,5-hexanedione in the urine of shoe-factory workers exposed to "commercial hexane" is consistent with the idea that this compound is responsible for the development of neuropathy in this group of individuals.

  2. Arsenic metabolites affect expression of the neurofilament and tau genes: an in-vitro study into the mechanism of arsenic neurotoxicity.

    PubMed

    Vahidnia, A; van der Straaten, R J H M; Romijn, F; van Pelt, J; van der Voet, G B; de Wolff, F A

    2007-09-01

    Neurological studies indicate that the central (CNS) and peripheral nervous system (PNS) may be affected by arsenic (As). As-exposed patients show significantly lower nerve conduction velocities (NCVs) in their peripheral nerves in comparison to healthy subjects. As may play a role in the disruption of neuroskeletal integrity, but the mechanisms by which it exerts a toxic effect on the peripheral and central nervous system are still unclear. In the present study, we examined the neurotoxic effects of various arsenic metabolites (iAs(III), iAs(V), MMA(V) and DMA(V)) on two different cell lines derived from the peripheral (ST-8814) and central (SK-N-SH) nervous system. The effects of the arsenic metabolites were examined on the relative quantification levels of the cytoskeletal genes, neurofilament-light (NEFL), neurofilament-medium (NEF3), neurofilament-heavy (NEFH) and microtubule-associated protein-tau (MAPT), using real-time PCR. Our results show that iAs(III) and iAs(V) have no significant effects on either cell lines. On the other hand, MMA(V) and DMA(V) cause significant changes in expression levels of NEF3 and NEFL genes, while the expression level of the NEFH gene is significantly increased in both cell lines.

  3. Metabolite

    MedlinePlus

    A metabolite is any substance produced during metabolism (digestion or other bodily chemical processes). The term metabolite may also refer to the product that remains after a drug is broken down (metabolized) by the body.

  4. Attention deficit disorder symptoms and urine catecholamines.

    PubMed

    Rogeness, G A; Maas, J W; Javors, M A; Macedo, C A; Fischer, C; Harris, W R

    1989-03-01

    The symptoms of hyperactivity, impulsivity, and concentration deficits associated with attention deficit disorder (ADD) may be related, in part, to alterations in dopaminergic and noradrenergic functioning. In this study we correlate the above symptoms with 24-hour urinary catecholamines and their metabolites in emotionally disturbed boys divided into two groups based on their plasma dopamine-beta-hydroxylase (DBH) activities and also divided into the following diagnostic groups: conduct disorder, undersocialized; conduct disorder, socialized; and subjects without conduct disorder. Boys in the low DBH group showed significant correlations between the ADD symptoms and the biochemical measures. The low DBH group may be more genetically homogeneous with regard to catecholamine function, making relationships between catecholamine function and behavior more visible. The group of boys with conduct disorder, socialized had higher 24-hour urinary norepinephrine and vanillylmandelic acid output. The relationship between monoamines and their metabolites appeared to differ among diagnostic groups.

  5. Evidence for extratumoural storage of catecholamines in pheochromocytoma patients.

    PubMed

    Hengstmann, J H; Dengler, H J

    1978-03-01

    Following the removal of a pheochromocytoma in three female patients the daily excretion of catecholamines and their metabolites was still considerably elevated for about one week. The excretion rates declined during this period with half-lives of 1.8 to 10.9 days for catecholamines and 2.1 to 4.7 days for metanephrines, vanilmandelic acid, and vanilglycol. The cumulative urinary excretion of catecholamines and their metabolites following surgical removal of the tumour was nearly as high as the catecholamine content of the pheochromocytomas. This large amount of catecholamines must have been located outside the tumour, most probably within the sympathetic nerve, where it is subject to release following physiological stimuli. Furthermore, this fact may provide an explanation for hypertensive crises in pheochromocytoma patients.

  6. Acrylamide neurotoxicity.

    PubMed

    Erkekoglu, Pinar; Baydar, Terken

    2014-02-01

    Acrylamide, a food contaminant, belongs to a large class of structurally similar toxic chemicals, 'type-2 alkenes', to which humans are widely exposed. Besides, occupational exposure to acrylamide has received wide attention through the last decades. It is classified as a neurotoxin and there are three important hypothesis considering acrylamide neurotoxicity: inhibition of kinesin-based fast axonal transport, alteration of neurotransmitter levels, and direct inhibition of neurotransmission. While many researchers believe that exposure of humans to relatively low levels of acrylamide in the diet will not result in clinical neuropathy, some neurotoxicologists are concerned about the potential for its cumulative neurotoxicity. It has been shown in several studies that the same neurotoxic effects can be observed at low and high doses of acrylamide, with the low doses simply requiring longer exposures. This review is focused on the neurotoxicity of acrylamide and its possible outcomes.

  7. PHEOCHROMOCYTOMA: A CATECHOLAMINE AND OXIDATIVE STRESS DISORDER

    PubMed Central

    Pacak, Karel

    2012-01-01

    The WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla — an intra-adrenal paraganglioma. Closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. Almost all pheochromocytomas and paragangliomas produce catecholamines. The concentrations of catecholamines in pheochromocytoma tissues are enormous, potentially creating a volcano that can erupt at any time. Significant eruptions result in catecholamine storms called “attacks” or “spells”. Acute catecholamine crisis can strike unexpectedly, leaving traumatic memories of acute medical disaster that champions any intensive care unit. A very well-defined genotype-biochemical phenotype relationship exists, guiding proper and cost-effective genetic testing of patients with these tumors. Currently, the production of norepinephrine and epinephrine is optimally assessed by the measurement of their O-methylated metabolites, normetanephrine or metanephrine, respectively. Dopamine is a minor component, but some paragangliomas produce only this catecholamine or this together with norepinephrine. Methoxytyramine, the O-methylated metabolite of dopamine, is the best biochemical marker of these tumors. In those patients with equivocal biochemical results, a modified clonidine suppression test coupled with the measurement of plasma normetanephrine has recently been introduced. In addition to differences in catecholamine enzyme expression, the presence of either constitutive or regulated secretory pathways contributes further to the very unique mutation-dependent catecholamine production and release, resulting in various clinical presentations. Oxidative stress results from a significant imbalance between levels of prooxidants, generated during oxidative phosphorylation, and antioxidants. The gradual accumulation of prooxidants due to metabolic oxidative stress results in proto

  8. Cyclosporine neurotoxicity.

    PubMed

    Hauben, M

    1996-01-01

    A comprehensive search of the published literature was undertaken to identify reports providing patient-specific data relating to adverse neurologic events with cyclosporine. References cited in the articles identified by the search were manually reviewed to ensure that articles were pertinent. Studies and case reports on cyclosporine neurotoxicity in which individualized patient data were provided were included for review and analysis. Information pertaining to all aspects of cyclosporine neurotoxicity, including epidemiology, clinical manifestations, postulated mechanisms, and management implications, was evaluated. Estimates from case series suggest a 0.5-35% frequency of the disorder. Risk factors include supratherapeutic blood concentrations of cyclosporine, and pharmacokinetic and pharmacodynamic drug interactions, hypocholesterolemia, and other metabolic abnormalities. Postulated mechanisms include a vasculopathy based on cyclosporine's effect on endothelial cell synthesis of prostaglandin, and release and uptake of endothelin as well as inhibition of mitochondrial steroid 26-hydroxylase. Reported adverse events involved all levels of the neuraxis. Associated abnormalities include elevated cerebrospinal fluid protein and pleocytosis, various electroencephalogram abnormalities, and characteristic neuroimaging findings. In most patients these events were reversible with dosage reduction or withdrawal of therapy. Many reports described positive rechallenge, and in rare instances the events regressed despite continuing or reintroducing the drug.

  9. Probing Mechanisms of Axonopathy. Part II: Protein Targets of 2,5-Hexanedione, the Neurotoxic Metabolite of the Aliphatic Solvent n-Hexane

    PubMed Central

    Tshala-Katumbay, Desire; Monterroso, Victor; Kayton, Robert; Lasarev, Michael; Sabri, Mohammad; Spencer, Peter

    2009-01-01

    Neuroprotein changes in the spinal cord of rodents with aliphatic γ-diketone axonopathy induced by 2,5-hexanedione (2,5-HD) are compared with those reported previously in aromatic γ-diketone–like axonopathy induced by 1,2-diacetylbenzene (1,2-DAB). Sprague-Dawley rats were treated intraperitoneally with 500 mg/kg/day 2,5-HD, equimolar doses of 2,3-hexanedione (negative control), or an equivalent amount of saline containing 50% dimethyl sulfoxide (vehicle), 5 days a week, for 3 weeks. Analysis of the lumbosacral proteome by 2-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight/tandem mass spectrometry revealed 34 proteins markedly modified by 2,5-HD of which neurofilament triplet L, gelsolin, protein disulfide isomerase, glutathione S-transferase, nicotinamide adenine dinucleotide (reduced) dehydrogenase 1α, pyruvate kinase, and fatty acid synthase were also modified by 1,2-DAB. The expression of proteins involved in maintaining the physical integrity of the cytoskeleton or controlling the redox and protein-folding mechanisms was reduced, whereas that of proteins supporting energy metabolism was mainly increased. The similarity of the neuroproteomic patterns of 2,5-HD and 1,2-DAB axonopathy suggests common biomarkers and/or mechanisms of neurotoxicity associated with exposure to their parent chemicals, namely the industrial solvents n-hexane and 1,2-diethylbenzene, respectively. PMID:19033394

  10. Catecholamine distribution in feline hypothalamus.

    PubMed

    Cheung, Y; Sladek, J R

    1975-12-01

    Catecholamine distribution was examined in cat hypothalamus using the histochemical fluorescence technique of Falck and Hillarp. The heaviest accumulations of catecholamine-containing varicosities were seen within the: anterior periventricular nucleus; dorsal hypothalamic area; bed nucleus of the inferior thalamic peduncle; doral component of the paraventricular nucleus; dorsomedial nucleus; infundibular nucleus; bed nucleus of the stria terminalis-medial division; and supraoptic nucelus. Catecholaminergic perikarya were observed within periventricular, dorsal, and caudal hypothalamic areas as well as within the supramamillary nucleus and caudal diencephalon. Catecholamine distribution in cat hypothalamus possesses both similarities and dissimilarities in relation to distributions reported in other mammals.

  11. A review of neurotoxicity of microcystins.

    PubMed

    Hu, Yufei; Chen, Jun; Fan, Huihui; Xie, Ping; He, Jun

    2016-04-01

    Cyanobacterial blooms-produced microcystins are secondary metabolites which can accumulate in the food chain and contaminate water, thus posing a potential threat to the health of aquatic animals and even humans. Microcystin toxicity affects not only the liver but also the other organs, i.e., the brain. The serious neurotoxicity effects caused by microcystins then lead to various symptoms. This review focuses on the neurotoxicity of microcystins. Microcystins can cross blood-brain barrier with the transport of Oatps/OATPs, causing neurostructural, functional, and behavioral changes. In this review, potential uptake mechanisms and neurotoxicity mechanisms are summarized, including neurotransmissions, neurochannels, signal transduction, oxidative stress, and cytoskeleton disruption. However, further researches are needed for detailed studies on signaling pathways and the downstream pathways of neurotoxicity of microcystins.

  12. Plasma catecholamine activity in chronic lead poisoning

    SciTech Connect

    deCastro, F.J.

    1990-04-01

    Plasma catecholamines where measured in 15 children with chronic lead poisoning and 15 matched controls by radioimmunassay. The data suggest that plasma catecholamines (norepinephrine and epinphrine) were significantly elevated in chronic lead poisoning. Plasma catecholamine elevation may well be important in the clinical finding of hyperactivity and hypertension associated with chronic lead poisoning.

  13. Unexpected changes in urinary catecholamines and vanillylmandelic acid following rape assault.

    PubMed

    Ende, N; Gertner, S B; Socha, B

    1990-03-01

    Although psychological changes are recognized to occur in rape assault survivors there is no information on the biochemical changes in these victims. This study compares urinary catecholamines and metabolites in 17 rape victims to two female control groups (one of which engaged in normal sexual intercourse and the other did not). We found, in the rape victims, unexpected changes in the excretion pattern of catecholamines and metabolites as compared to the various control groups. The most significant difference was the dramatic increase in urinary conjugated dopamine (P less than 0.01) in the rape victims which remained elevated for over 24 hr. Urinary vanillylmandelic acid (VMA) rose significantly in rape assault victims when compared to the normal control group. The VMA levels in rape victims were significantly lower, however, than in the women who had undergone (normal) sexual intercourse (P less than 0.01). Urinary free epinephrine showed a marked decline and remained depressed for over 24 hr in the rape assault victims (P less than 0.01) compared to normal controls. Some possible reasons for these patterns in catecholamines and metabolite excretion are suggested. These changes may be of importance in the poststress syndrome that occurs following the rape assault. In summary, a different profile of catecholamine and metabolite excretion patterns was found in rape compared to normal sexual intercourse. The enhanced dopamine excretion is contrary to the expected change of enhanced epinephrine secretion in severe stress.

  14. Effects of mental workload and caffeine on catecholamines and blood pressure compared to performance variations.

    PubMed

    Papadelis, Christos; Kourtidou-Papadeli, Chrysoula; Vlachogiannis, Emmanouil; Skepastianos, Petros; Bamidis, Panayiotis; Maglaveras, Nikos; Pappas, Kostantinos

    2003-02-01

    Caffeine is characterised as a central nervous system stimulant, also affecting metabolic and cardiovascular functions. A number of studies have demonstrated an effect of caffeine on the excretion of catecholamines and their metabolites. Urinary epinephrine and norepinephrine have been shown to increase after caffeine administration. Similar trends were observed in our study in adrenaline (ADR) and noradrenaline (NORADR) levels and additionally a dose dependent effect of caffeine. The effect of caffeine on cognitive performance, blood pressure, and catecholamines was tested under resting conditions and under mental workload. Each subject performed the test after oral administration of 1 cup and then 3 cups of coffee. Root mean square error (RMSE) for the tracking task was continuously monitored. Blood pressure was also recorded before and after each stage of the experiment. Catecholamines were collected and measured for three different conditions as: at rest, after mental stress alone, after one dose of caffeine under stress, and after triple dose of caffeine under stress. Comparison of the performance of each stage with the resting conditions revealed statistically significant differences between group of smokers/coffee drinkers compared with the other two groups of non-coffee drinkers/non-smokers and non-smokers/coffee drinkers. There was no statistically significant difference between the last two groups. There was an increase of urine adrenaline with 1 cup of coffee and statistically significant increase of urine noradrenaline. Both catecholamines were significantly increased with triple dose of caffeine. Mental workload increased catecholamines. There was a dose dependent effect of caffeine on catecholamines.

  15. Effect of microgravity on plasma catecholamine responses to stressors during space flight.

    PubMed

    Kvetnansky, R; Macho, L; Koska, J; Pacak, K; Hoff, T; Ksinantova, L; Noskov, V B; Kobzev, E; Grigoriev, A I; Vigas, M

    2001-07-01

    The effect of microgravity on the sympathicoadrenal system (SAS) activity in humans and animals has not yet been clarified. Our previous studies suggested that the SAS activity, evaluated by circulating and/or urinary catecholamine (CA) levels in astronauts during space flights, was found to be rather unchanged. However, CA levels were measured in astronauts only at rest conditions. The aim of the present study was to investigate effect of microgravity during space flight and post-flight readaptation on responsiveness of the SAS to somatic and psychic stressors evaluated by levels of catecholamines and their metabolite in the blood of the Slovak cosmonaut during his stay on board the space station Mir.

  16. Alteration of catecholamine concentrations in rat testis after methamphetamine exposure.

    PubMed

    Janphet, S; Nudmamud-Thanoi, S; Thanoi, S

    2017-03-01

    Methamphetamine (METH) is an illicit drug that can lead to changes in catecholamines in the brain. It also has substantial effects on reproductive function. We investigated whether rat models of METH abuse could induce changes in the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), in testis. Four groups of rats received vehicle, acute dose (AB), escalating dose (ED) or ED with an acute high dose (ED-binge) METH. DOPAC, NE and DHPG were determined using HPLC. DOPAC was significantly increased in the AB while NE was significantly decreased in the ED-binge. DHPG was also significantly decreased in the ED and ED-binge. METH induces alterations of DOPAC, NE and DHPG testicular concentrations that may result in male reproductive dysfunction.

  17. Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders☆

    PubMed Central

    Goldstein, David S.; Kopin, Irwin J.; Sharabi, Yehonatan

    2015-01-01

    Several neurodegenerative diseases involve loss of catecholamine neurons—Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of “autotoxicity”—inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the “catecholaldehyde hypothesis” for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis. PMID:24945828

  18. Dietary influences on plasma and urinary metanephrines: implications for diagnosis of catecholamine-producing tumors.

    PubMed

    de Jong, Wilhelmina H A; Eisenhofer, Graeme; Post, Wendy J; Muskiet, Frits A J; de Vries, Elisabeth G E; Kema, Ido P

    2009-08-01

    Measurements of the 3-O-methylated metabolites of catecholamines [metanephrines (MNs)] in plasma or urine are recommended for diagnosis of pheochromocytoma. It is unclear whether these tests are susceptible to dietary influences. The aim of the study was to determine the short-term influence of a catecholamine-rich diet on plasma and urinary fractionated MNs. We conducted a crossover study in a specialist medical center involving 26 healthy adults. Subjects consumed catecholamine-rich nuts and fruits at fixed times on one day (about 35 mumol dopamine and 1 mumol norepinephrine) and catecholamine-poor products on another day. Blood and urine samples were collected at timed intervals before, during, and after experimental and control interventions. Isotope-dilution mass spectrometry-based measurements of plasma and urinary concentrations of free and deconjugated 3-methoxytyramine (3-MT), normetanephrine (NMN), and MN were made. The catecholamine-rich diet had substantial effects (up to 3-fold increases) on plasma concentrations and urinary outputs of free and deconjugated 3-MT. Dietary catecholamines had negligible influences on free NMN in plasma and urine, but substantial effects (up to 2-fold increases) on deconjugated NMN in plasma and urine. Concentrations of free and deconjugated MN in plasma and urine remained unaffected. Dietary restrictions should be considered to minimize false-positive results for urinary and plasma deconjugated MNs during diagnosis of pheochromocytoma. Similar considerations appear warranted for plasma and urinary free 3-MT, but not for free NMN or MN, indicating advantages of measurements of the free compared to deconjugated metabolites.

  19. Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders.

    PubMed

    Goldstein, David S; Kopin, Irwin J; Sharabi, Yehonatan

    2014-12-01

    Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the "catecholaldehyde hypothesis" for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

  20. Neurotoxicity of ecstasy (MDMA): an overview.

    PubMed

    Sarkar, Sumit; Schmued, Larry

    2010-08-01

    "Ecstasy" (MDMA) is a powerful hallucinogenic drug which has raised concern worldwide because of its high abuse liability. A plethora of studies have demonstrated that MDMA has the potential to induce neurotoxicity both in human and laboratory animals. Although research on MDMA has been carried out by many different laboratories, the mechanism underlying MDMA induced toxicity has not been fully elucidated. MDMA has the ability to reduce serotonin levels in terminals of axons in the cortex of rats and mice. Recently we have shown that it also has the potential to produce degenerate neurons in discrete areas of the brain such as insular and parietal cortex, thalamus, tenia tecta and bed nucleus of stria terminalis (BST). Acute effects of MDMA can result in a constellation of changes including arrthymias, hypertension, hyperthermia, serotonin (5-HT) syndrome, liver problems, seizures and also long lasting neurocognitive impairments including mood disturbances. In human MDMA abusers, there is evidence for reduction of serotonergic biochemical markers. Several factors may contribute to the MDMA-induced neurotoxicity, especially hyperthermia. Other factors potentially influencing MDMA toxicity include monoamine oxidase metabolism of dopamine and serotonin, nitric oxide generation, glutamate excitotoxicity, serotonin 2A receptor agonism and the formation of MDMA neurotoxic metabolites. In this review we will cover the following topics: pharmacological mechanisms, metabolic pathways and acute effects in laboratory animals, as well as in humans, with special attention on the mechanism and pathology of MDMA induced neurotoxicity.

  1. Plasma catecholamine and nephrine responses following 7 weeks of sprint cycle training.

    PubMed

    Bracken, Richard Michael; Brooks, Stephen

    2010-05-01

    The catecholamine metabolites normetanephrine (NMET) and metanephrine (MET) increase in response to acute exercise. However, changes in catecholamine 'nephrines' during sprint training are unclear. Therefore, the aim of this study was to examine the plasma nephrine and catecholamine (noradrenaline, NA; adrenaline, AD) responses to a laboratory-based cycle test before and after a 7-week period of cycle sprint training. Ten healthy men completed a 2-min cycle test at a power output equivalent to 110% of pre-training VO(2)max before and after 7 weeks of laboratory based sprint cycle training, three times per week. Resting and post-sprint venous blood samples were taken. Resting plasma nephrines and catecholamines increased significantly following exercise (P < 0.05). Post-exercise NA and NMET were reduced after training (P < 0.05) and a trend for a reduction in AD (P = 0.09) and MET (P = 0.07) was observed. The results demonstrate a reduction in exercise-induced increases in plasma nephrine concentrations following sprint training. This suggests catechol-O-methyl transferase activity is coupled to high intensity cycle exercise. These findings may aid in the understanding of catecholamine regulation during high intensity exercise and sprint training.

  2. Improved Quantification of Plasma Catecholamines by the Radioenzymic Kit Method.

    DTIC Science & Technology

    1982-11-01

    RECIPIENT’S CATALOG NUMBER SAM-TR-8 2-40 n &Ie 4. TITLE (and Subtitle) S. TYPE OF REPORT G PERIOD COVERED IMPROVED QUANTIFICATION OF PLASMA CATECHOLAMINES...side i 1nocesCary and Identily by block nmuber) Human/swine plasma catecholamine assays Plasma catecholamines by kit method Enzymic catecholamine...for plasma catecholamine analyses is reported. The departure features use of "mean net standards" instead of individual internal standards

  3. Catecholamine metabolism in a psychoactive cactus.

    PubMed

    Keller, W J; Yeary, R A

    1980-04-01

    The Dona Ana cactus, Coryphantha macromeris (Engelm.) Br. and R. and its runyonii (Br. and R.) L. Benson variety are being promoted as natural and legal psychedelic agents with about one-fifth potency of peyote [Lophophora williamsii (Lem.) Coult.]. Like peyote, Dona Ana produces and accumulates various methylated catecholamine derivatives. Of these phenethylamines, normacromerine (N-methyl-3,4-dimethoxy-beta-hydroxyphenethylamine) is by far the most abundant and has been shown to affect animal behavior in such a way as to suggest psychoactivity. It has been demonstrated that the catecholamines epinephrine and norepinephrine occur naturally in C. macromeris var. runyonii and serve as biosynthetic intermediates in normacromerine biosynthesis. Catecholamine precursors and derivatives have also been shown to be part of the metabolic pathway leading to the formation of normacromerine in Dona Ana. Normacromerine appears to be the end product of catecholamine metabolism since recent studies have revealed that very little of this compound is metabolized once it has been formed by the cactus. Completed research of this type has allowed the comparison of catecholamine metabolism leading to the formation of a mind-altering drug in a cactus plant and the metabolism of catecholamines in humans. These data together with evidence from future research will allow biochemical analogies which may suggest etiologies for certain types of mental illness.

  4. Arsenic neurotoxicity--a review.

    PubMed

    Vahidnia, A; van der Voet, G B; de Wolff, F A

    2007-10-01

    Arsenic (As) is one of the oldest poisons known to men. Its applications throughout history are wide and varied: murder, make-up, paint and even as a pesticide. Chronic As toxicity is a global environmental health problem, affecting millions of people in the USA and Germany to Bangladesh and Taiwan. Worldwide, As is released into the environment by smelting of various metals, combustion of fossil fuels, as herbicides and fungicides in agricultural products. The drinking water in many countries, which is tapped from natural geological resources, is also contaminated as a result of the high level of As in groundwater. The environmental fate of As is contamination of surface and groundwater with a contaminant level higher than 10 particle per billion (ppb) as set by World Health Organization (WHO). Arsenic exists in both organic and inorganic species and either form can also exist in a trivalent or pentavalent oxidation state. Long-term health effects of exposure to these As metabolites are severe and highly variable: skin and lung cancer, neurological effects, hypertension and cardiovascular diseases. Neurological effects of As may develop within a few hours after ingestion, but usually are seen in 2-8 weeks after exposure. It is usually a symmetrical sensorimotor neuropathy, often resembling the Guillain-Barré syndrome. The predominant clinical features of neuropathy are paresthesias, numbness and pain, particularly in the soles of the feet. Electrophysiological studies performed on patients with As neuropathy have revealed a reduced nerve conduction velocity, typical of those seen in axonal degeneration. Most of the adverse effects of As, are caused by inactivated enzymes in the cellular energy pathway, whereby As reacts with the thiol groups of proteins and enzymes and inhibits their catalytic activity. Furthermore, As-induced neurotoxicity, like many other neurodegenerative diseases, causes changes in cytoskeletal protein composition and hyperphosphorylation

  5. Neurotoxicity in risk assessment

    SciTech Connect

    Weiss, B.

    1988-01-01

    Neurotoxicity is a property of many metals, even those deemed biologically essential. Manganese, one of the essential elements, can induce a syndrome displaying aspects of both Parkinsonism and dystonia, but accompanied, as well, by psychological abnormalities. At low exposure levels, however, neurotoxicity may be detectable with psychological tests. Mercury vapor exposure also induces neurological signs, psychological aberrations, and subtle evidence of dysfunction on psychological tests. Methylmercury and lead are particularly toxic to the developing brain. The most recent research indicates that psychological testing may uncover deficits even in children showing no evidence of impairment. Because of their special features, neurotoxic endpoints may have to be evaluated for risks by a process that diverges significantly from the standard program based on carcinogenicity.

  6. Pattern of elevation of urine catecholamines in intracerebral haemorrhage.

    PubMed

    Hamann, G F; Strittmatter, M; Hoffmann, K H; Holzer, G; Stoll, M; Keshevar, T; Moili, R; Wein, K; Schimrigk, K

    1995-01-01

    Autonomic nervous system dysfunction is a common complication of severe intracranial disease. The aim of this study was to reveal the autonomic changes in patients suffering from acute intracerebral haemorrhage (ICH). 25 patients with spontaneous ICH within 24 hours of onset of symptoms were included. All patients were treated with standardised medical management and the meta- and normetanephrines were detected by high performance liquid chromatography (HPLC) in 24-hour urine every day. The mean level of normetanephrine (709 +/- 579 micrograms/day) and metanephrine (244 +/- 161 mg/day) were significantly elevated in comparison with a control group, p < or = 0.01. The norepinephrine elevation was of greater diagnostic and prognostic importance. Maximum urinary catecholamine metabolite levels occurred between day 3 to 10 after the bleeding. Normetanephrines correlated with the prognosis and the complications of ICH: intraventricular involvement resulted in significantly elevated normetanephrine levels (896 +/- 520 micrograms/day versus 311 +/- 78 micrograms/day) p < or = 0.01. Patients with a great volume of haematoma developed severe autonomic dysregulation (normetanephrines 1114 +/- 493 micrograms/day), whereas patients with smaller haematoma did not (339 +/- 125 micrograms/day) p < or = 0.0001; patients with bad outcome (1014 +/- 620 mg/day) had higher levels of normetanephrines than those with a good prognosis (322 +/- 110 micrograms/day) p < or = 0.001. A close relationship to elevated intracranial pressure was established. This study demonstrated the feasibility of detecting autonomic nervous system dysfunction in neurological intensive care patients by means of examination of the metabolites of the catecholamines in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Neurotoxicity and Behavior

    EPA Science Inventory

    Neurotoxicity is important to consider as a component of occupational and environmental safety and health programs. The failure to do so has contributed to a number of cases in which workers, consumers of manufactured products, and people exposed in the environment were irreparab...

  8. Neurotoxicity and Behavior

    EPA Science Inventory

    Neurotoxicity is important to consider as a component of occupational and environmental safety and health programs. The failure to do so has contributed to a number of cases in which workers, consumers of manufactured products, and people exposed in the environment were irreparab...

  9. Neurotoxic Weapons and Syndromes.

    PubMed

    Carota, Antonio; Calabrese, Pasquale; Bogousslavsky, Julien

    2016-01-01

    The modern era of chemical and biological warfare began in World War I with the large-scale production and use of blistering and choking agents (chlorine, phosgene and mustard gases) in the battlefield. International treaties (the 1925 Geneva Protocol, the 1975 Biological and Toxin Weapons Convention and the 1993 Chemical Weapons Convention) banned biological and chemical weapons. However, several countries are probably still engaged in their development. Hence, there is risk of these weapons being used in the future. This chapter will focus on neurotoxic weapons (e.g. nerve agents, chemical and biological neurotoxins, psychostimulants), which act specifically or preeminently on the central nervous system and/or the neuromuscular junction. Deeply affecting the function of the nervous system, these agents either have incapacitating effects or cause clusters of casualties who manifest primary symptoms of encephalopathy, seizures, muscle paralysis and respiratory failure. The neurologist should be prepared both to notice patterns of symptoms and signs that are sufficiently consistent to raise the alarm of neurotoxic attacks and to define specific therapeutic interventions. Additionally, extensive knowledge on neurotoxic syndromes should stimulate scientific research to produce more effective antidotes and antibodies (which are still lacking for most neurotoxic weapons) for rapid administration in aerosolized forms in the case of terrorist or warfare scenarios. © 2016 S. Karger AG, Basel.

  10. Tyrosine - Effects on catecholamine release

    NASA Technical Reports Server (NTRS)

    Acworth, Ian N.; During, Matthew J.; Wurtman, Richard J.

    1988-01-01

    Tyrosine administration elevates striatal levels of dopamine metabolites in animals given treatments that accelerate nigrostriatal firing, but not in untreated rats. We examined the possibility that the amino acid might actually enhance dopamine release in untreated animals, but that the technique of measuring striatal dopamine metabolism was too insensitive to demonstrate such an effect. Dopamine release was assessed directly, using brain microdialysis of striatal extracellular fluid. Tyrosine administration (50-200 mg/kg IP) did indeed cause a dose related increase in extracellular fluid dopamine levels with minor elevations in levels of DOPAC and HVA, its major metabolites, which were not dose-related. The rise in dopamine was short-lived, suggesting that receptor-mediated feedback mechanisms responded to the increased dopamine release by diminishing neuronal firing or sensitivity to tyrosine. These observations indicate that measurement of changes in striatal DOPAC and HVA, if negative, need not rule out increases in nigrostriatal dopamine release.

  11. Determination of catecholamines in plasma and urine.

    PubMed

    Grouzmann, Eric; Lamine, Faiza

    2013-10-01

    For more than 20 years, measurement of catecholamines in plasma and urine in clinical chemistry laboratories has been the cornerstone of the diagnosis of neuroendocrine tumors deriving from the neural crest such as pheochromocytoma (PHEO) and neuroblastoma (NB), and is still used to assess sympathetic stress function in man and animals. Although assay of catecholamines in urine are still considered the biochemical standard for the diagnosis of NB, they have been progressively abandoned for excluding/confirming PHEOs to the advantage of metanephrines (MNs). Nevertheless, catecholamine determinations are still of interest to improve the biochemical diagnosis of PHEO in difficult cases that usually require a clonidine-suppression test, or to establish whether a patient with PHEO secretes high concentrations of catecholamines in addition to metanephrines. The aim of this chapter is to provide an update about the catecholamine assays in plasma and urine and to show the most common pre-analytical and analytical pitfalls associated with their determination. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Functionally active ganglioneuroma with increased plasma and urinary catecholamines and positive iodine 131-meta-iodobenzylguanidine scintigraphy

    SciTech Connect

    Clerico, A.; Jenkner, A.; Castello, M.A.; Ciofetta, G.; Lucarelli, C.; Codini, M. )

    1991-01-01

    Ganglioneuromas are usually considered not to be functionally active. Studies of their catecholamine excretory pattern and of their imaging by means of the adrenergic tracing agent 131-I-MIBG have been therefore sparse. We report on a case of secretory ganglioneuroma, as demonstrated by the increased urinary excretion of the catecholamine metabolites HVA and VMA, increased plasma dopamine and epinephrine levels, and positive 131-I-MIBG scintigraphy. We must therefore be aware that a functionally active tumor is not necessarily a neuroblastoma, and that the diagnosis should be biopsy proven.

  13. Arterio-venous differences in cord levels of catecholamines, glucose, lactate and blood gases.

    PubMed

    Koh, Daisy K M; Hume, Robert; Eisenhofer, Graeme; Watson, Jennifer; Williams, Fiona L R

    2016-08-01

    Norepinephrine (NE) and epinephrine (EPI) levels are higher in cord arterial blood relative to venous blood, consistent with active mechanisms of placental-maternal clearance. There are no contemporary studies of cord arteriovenous blood levels of sulfated and non-sulfated catechols. To assess the arteriovenous differences in cord blood levels of dopamine (DA), the sulfated catecholamines and their sulfated and non-sulfated metabolites. To correlate levels of oxygen, H+/CO2, and glucose with cord catecholamine levels. Fifty-seven term infants, delivered by elective cesarean section, were recruited. Cord arterial and venous blood was sampled; levels of glucose, lactate, blood gases, six catechols and their sulfated conjugates were measured. With one exception (DOPA sulfate), mean cord arterial levels of sulfated and non-sulfated catechols were significantly higher than venous levels. Arterial lactate and glucose levels were independently associated with NE levels, but only lactate was associated with levels of EPI and DA. This study establishes that in vivo metabolic parameters of hypoxia, respiratory and metabolic acidosis are associated with catecholamine levels, a key relationship for perinatal adaptation and homeostasis, and findings that are consistent with in vitro studies of the regulators of catecholamine secretion.

  14. [Radioenzymatic assay for catecholamines (author's transl)].

    PubMed

    Oshima, T; Maruyama, Y

    1978-11-01

    Catecholamines are neurotransmitters produced and secreted by the central and autonomic nervous systems. In addition to being neurotransmitters, amines produced mainly by the adrenal medulla also act as hormones. Fluorometric measurements of amines yield variable results because of the poor sensitivity of the techniques, and the low concentration of these amines in tissues and biological fluids. The lack of specific and sensitive analytical methods has been an obstacle to resolving the mechanism of action of these neurotransmitters and hormones. The possibility of achieving qualitative and quantitative determination of picomole or femtomole amounts of these amines is a major need. Recently, radioenzymatic procedures for catecholamine assay have been developed and there has been a significant improvement in both sensitivity and accuracy of catecholamine assays. In this article, details of these radioenzymatic assay methods are reviewed.

  15. Clinical catecholamine neurochemistry: a legacy of Julius Axelrod.

    PubMed

    Goldstein, David S; Eisenhofer, Graeme; Kopin, Irwin J

    2006-01-01

    1. Discoveries, insights, and concepts that Julius Axelrod introduced about the disposition and metabolism of catecholamines provided the scientific basis and spurred the development of clinical catecholamine neurochemistry. 2. Here, we provide examples of this aspect of Axelrod's scientific legacy.

  16. Noncholinergic control of adrenal catecholamine secretion.

    PubMed Central

    Livett, B G; Marley, P D

    1993-01-01

    It has been known for over 70 years that adrenal catecholamine secretion can be modulated or elicited by noncholinergic neurotransmitters and hormones. However, our understanding of the cellular mechanisms by which these agents produce their effects and the physiological conditions under which they act are not well characterised. Here we briefly review the mechanisms by which one such agent (the neuropeptide substance P) modulates the cholinergic secretory response of adrenal chromaffin cells, and another agent (angiotensin II) elicits catecholamine secretion independently of the cholinergic innervation. PMID:7507911

  17. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression.

    PubMed

    Bhatia, Pankaj; Singh, Nirmal

    2015-12-01

    Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid derived from dietary methionine through demethylation. Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CβS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia. Hcy excess decreases the S-adenosylmethionine (SAM)-dependent synthesis of catecholamines, viz. dopamine, norepinephrine, epinephrine, and noncatecholamine, viz. serotonin (5-HT), due to genetic alteration in key enzyme MTHFR in the homocysteine metabolism pathway that leads to depression. Thus, hyperhomocysteinemia (HHcy)-induced SAM level is influenced by the single nucleotide polymorphism (SNP) MTHFR C677T. Furthermore, HHcy leads to production of precarious neurotoxic product homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has neurotoxic effects on dopaminergic neurons. In the current review, an attempt has been made to discuss the neurotoxic effects of HHcy in the pathogenesis of depression.

  18. Nitric oxide neurotoxicity.

    PubMed

    Dawson, V L; Dawson, T M

    1996-06-01

    Derangements in glutamate neurotransmission have been implicated in several neurodegenerative disorders including, stroke, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Activation of the N-methyl-D-aspartate (NMDA) receptor subtype of glutamate receptors results in the influx of calcium which binds calmodulin and activates neuronal nitric oxide synthase (nNOS), to convent L-arginine to citrulline and nitric oxide (NO). NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO-), the reaction product from NO and superoxide anion. In pathologic conditions, peroxynitrite and oxygen free radicals can be generated in excess of a cell antioxidant capacity resulting in severe damage to cellular constituents including proteins, DNA and lipids. The inherent biochemical and physiological characteristics of the brain, including high lipid concentrations and energy requirements, make it particularly susceptible to free radical and oxidant mediated insult. Increasing evidence indicates that many neurologic disorders may have components of free radical and oxidative stress induced injury.

  19. The Dipeptides Ile-Tyr and Ser-Tyr Exert Distinct Effects on Catecholamine Metabolism in the Mouse Brainstem

    PubMed Central

    Moriyasu, Kazuki; Ichinose, Takashi; Nakahata, Akane; Tanaka, Mitsuru; Matsui, Toshiro; Furuya, Shigeki

    2016-01-01

    Catecholamine synthesis and transmission in the brain are influenced by the availability of Tyr in the body. In this study, we compared the effects of oral administration of Tyr-containing dipeptides Ile-Tyr, Ser-Tyr, and Tyr-Pro with Tyr alone on catecholamine metabolism in the mouse brainstem. Among these dipeptides, Ile-Tyr administration led to increases in dopamine, the dopamine metabolites homovanillic acid, and 3,4-dihydroxyphenylacetic acid, compared to administration of Ser-Tyr, Tyr-Pro, or Tyr alone. In comparison, administration of Ser-Tyr induced significantly increasing noradrenaline turnover, while Tyr-Pro administration suppressed dopamine turnover. Therefore, oral administration of Ile-Tyr, Ser-Tyr, and Tyr-Pro differentially affected metabolism of dopamine and noradrenaline. These observations strongly suggest that Tyr-containing dipeptides exert distinct effects on catecholamine metabolism in the brainstem when ingested orally. PMID:26981137

  20. Catecholamines and cognition after traumatic brain injury

    PubMed Central

    Jenkins, Peter O.; Mehta, Mitul A.

    2016-01-01

    Cognitive problems are one of the main causes of ongoing disability after traumatic brain injury. The heterogeneity of the injuries sustained and the variability of the resulting cognitive deficits makes treating these problems difficult. Identifying the underlying pathology allows a targeted treatment approach aimed at cognitive enhancement. For example, damage to neuromodulatory neurotransmitter systems is common after traumatic brain injury and is an important cause of cognitive impairment. Here, we discuss the evidence implicating disruption of the catecholamines (dopamine and noradrenaline) and review the efficacy of catecholaminergic drugs in treating post-traumatic brain injury cognitive impairments. The response to these therapies is often variable, a likely consequence of the heterogeneous patterns of injury as well as a non-linear relationship between catecholamine levels and cognitive functions. This individual variability means that measuring the structure and function of a person’s catecholaminergic systems is likely to allow more refined therapy. Advanced structural and molecular imaging techniques offer the potential to identify disruption to the catecholaminergic systems and to provide a direct measure of catecholamine levels. In addition, measures of structural and functional connectivity can be used to identify common patterns of injury and to measure the functioning of brain ‘networks’ that are important for normal cognitive functioning. As the catecholamine systems modulate these cognitive networks, these measures could potentially be used to stratify treatment selection and monitor response to treatment in a more sophisticated manner. PMID:27256296

  1. Catecholamines and cognition after traumatic brain injury.

    PubMed

    Jenkins, Peter O; Mehta, Mitul A; Sharp, David J

    2016-09-01

    Cognitive problems are one of the main causes of ongoing disability after traumatic brain injury. The heterogeneity of the injuries sustained and the variability of the resulting cognitive deficits makes treating these problems difficult. Identifying the underlying pathology allows a targeted treatment approach aimed at cognitive enhancement. For example, damage to neuromodulatory neurotransmitter systems is common after traumatic brain injury and is an important cause of cognitive impairment. Here, we discuss the evidence implicating disruption of the catecholamines (dopamine and noradrenaline) and review the efficacy of catecholaminergic drugs in treating post-traumatic brain injury cognitive impairments. The response to these therapies is often variable, a likely consequence of the heterogeneous patterns of injury as well as a non-linear relationship between catecholamine levels and cognitive functions. This individual variability means that measuring the structure and function of a person's catecholaminergic systems is likely to allow more refined therapy. Advanced structural and molecular imaging techniques offer the potential to identify disruption to the catecholaminergic systems and to provide a direct measure of catecholamine levels. In addition, measures of structural and functional connectivity can be used to identify common patterns of injury and to measure the functioning of brain 'networks' that are important for normal cognitive functioning. As the catecholamine systems modulate these cognitive networks, these measures could potentially be used to stratify treatment selection and monitor response to treatment in a more sophisticated manner. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

  2. Localization of pheochromocytoma by selective venous catheterization and assay of plasma catecholamines.

    PubMed Central

    Davies, R. A.; Patt, N. L.; Sole, M. J.

    1979-01-01

    The diagnosis of pheochromocytoma rests primarily on determination of the 24-hour urinary excretion of catecholamines and their metabolites. In most cases nephrotomography and selective arteriography or venography, or both, are sufficient to localize the tumour. Selective venous catheterization and the assay of plasma catecholamines should be considered for pheochromocytoma localization in: (a) patients in whom standard techniques fail to localize the tumour; (b) patients who exhibit idiosyncratic reactions to the angiographic contrast materials; (c) young patients or patients with familial pheochromocytoma, including those with multiple neurofibromatosis or multiple endocrine adenomatosis, type 2; (d) patients with recurrent, malignant, or suspected multicentric or extra-adrenal tumours; and (e) patients excreting only norepinephrine in the urine. The validity of the results is particularly dependent on the skill with which venous catheterization is carried out. PMID:436033

  3. Plasma catecholamine concentrations associated with cerebral vasospasm.

    PubMed

    Loach, A B; Benedict, C R

    1980-03-01

    Plasma concentrations of adrenaline and noradrenaline were measured sequentially over the immediate post-operative period following clipping of an intracranial aneurysm in 11 patients. Those patients who developed local cerebral vasospasm showed a sustained rise in plasma catecholamines, particularly noradrenaline, whilst those patients who developed generalised cerebral vasospasm showed early peaks of very high concentrations of adrenaline and noradrenaline which preceded radiological evidence of generalized vasospam.

  4. Neurotransmitter alterations in PTSD: catecholamines and serotonin.

    PubMed

    Southwick, S M; Paige, S; Morgan, C A; Bremner, J D; Krystal, J H; Charney, D S

    1999-10-01

    In this chapter we review trauma-related studies involving epinephrine (E), norepinephrine (NE), and serotonin (5-HT). Central catecholamine neurons seem to play a critical role in level of alertness, vigilance, orienting, selective attention, memory, fear conditioning, and cardiovascular responses to life-threatening stimuli. Evidence of catecholamine dysregulation in post-traumatic stress disorder (PTSD) includes exaggerated increases in heart rate and blood pressure when exposed to visual and auditory reminders of trauma, elevated 24-hour urine catecholamine excretion, decreased platelet alpha-2 adrenergic receptor number, exaggerated behavioral, cardiovascular, and biochemical responses to IY yohimbine, decreased cortical brain metabolism secondary to IV yohimbine, and clinical efficacy of adrenergic blocking agents. Serotonin seems to play numerous roles in the central nervous system, including regulation of sleep, aggression, appetite, cardiovascular and respiratory activity, motor output, anxiety, mood, neuroendocrine secretion, and analgesia. Evidence of serotonergic dysregulation in PTSD includes frequent symptoms of aggression, impulsivity, depression and suicidality, decreased platelet paroxetine binding, blunted prolactin response to fenfluramine, exaggerated reactivity to m-chloro-phenyl-piperazine, and clinical efficacy of serotonin reuptake inhibitors. It has been suggested that alterations in NE, E, and 5-HT may have relevance for symptoms commonly seen in survivors with PTSD, including hypervigilance, exaggerated startle, irritability, impulsivity, aggression, intrusive memories, depressed mood, and suicidality.

  5. Coronary artery disease and lunar catecholamine cardiomyopathy.

    PubMed

    Rowe, William J

    2017-03-15

    Show how lunar catecholamine cardiomyopathy alone, exemplified by Neil Armstrong's single space walk, prior to exposure to inhalation of fine particulate matter, can trigger " Neil Armstrong Syndrome" or by Irwin with coronary, possibly hypertensive heart disease, and catecholamine cardiomyopathy. With space flight, invariably magnesium ion deficits, catecholamine elevations, vicious cycles. Design Use lunar heart rates while configuring rover to show severe tachycardia component of the syndrome. Use Irwin's stress test-" cyanotic fingernails" to support Apollo 15 Space Syndrome. Use Irwin's autobiography to compensate for often incomplete data. Results Paper shows that both Irwin as well as Armstrong meet criteria of my 2nd. Space Syndrome: severe thirst, severe shortness of breath, severe tachycardia, the latter, corrected by replenishing plasma volume. Conclusions Irwin, with a history of hypertension prior to the Apollo 15 mission and classical angina during Earth reentry, may have had coronary as well as hypertensive heart disease whereas there was no evidence that Armstrong had these conditions prior or during his mission. However both, on return to Earth, had abnormal stress tests. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. L-DOPA therapy interferes with urine catecholamine analysis in children with suspected neuroblastoma: a case series.

    PubMed

    Kelly, Alison U; Srivastava, Rajeev; Dow, Ellie; Davidson, D Fraser

    2017-09-01

    Neuroblastoma is the most common solid extracranial malignancy diagnosed in childhood. Clinical presentation is variable, and metastatic disease is common at diagnosis. Analyses of urinary catecholamines and their metabolites are commonly requested as a first-line investigation when clinical suspicion exists. Levodopa (L-Dopa) therapy is utilized as a treatment for a number of disorders in childhood, including Dopa-responsive dystonia. Neuroblastoma may mimic some of the clinical features of this disorder. L-Dopa can interfere with analysis of urinary catecholamines and their metabolites and complicate the interpretation of results. We present the cases of three children who were prescribed L-dopa at the time of analysis of urinary catecholamines and metabolites as a screen for neuroblastoma, but who did not have the disease. Comparison of their results with those from cases with true neuroblastoma reveal that it is impossible to reliably distinguish true neuroblastoma from L-Dopa therapy using these tests. We recommend that patients should be off L-dopa therapy, if possible when these tests are performed. These cases illustrate the importance of providing clinical details and drug history to the laboratory in order to avoid diagnostic confusion.

  7. Improved solid-phase extraction and liquid chromatography with electrochemical detection of urinary catecholamines and 5-S-L-cysteinyl-L-dopa.

    PubMed

    Huang, T H; Wall, J; Kabra, P

    1988-10-28

    We describe a rapid, precise, accurate liquid chromatographic procedure for determining urinary catecholamines and 5-S-L-cysteinyl-L-dopa. The catecholamines (norepinephrine, epinephrine, and dopamine) and 5-S-L-cysteinyl-L-dopa are extracted from 1.0 ml of urine together with internal standards, by using a Bond-Elut strong cation-exchange (SCX) and an affinity phenylboronic acid (PBA) extraction column in series. The eluate obtained from PBA column is then chromatographed on a reversed-phase C18 column with a mobile phase containing pentane- and heptanesulfonate as ion-pair reagents. The detection is achieved with an amperometric detector set at an oxidation potential of +0.55 V. The chromatography is complete is less than 8 min for catecholamines and less than 5 min for cysteinyldopa. The method can measure less than 2 micrograms/l for catecholamines and 5 micrograms/l for cysteinyldopa. Analytical recoveries of catecholamines and cysteinyldopa added to urine pool ranged from 90-107%. Between run coefficient of variation ranged from 4.7 to 8%. None of the drugs and catecholamines metabolites tested interfered with the assay.

  8. Chemotherapy-Related Neurotoxicity.

    PubMed

    Taillibert, Sophie; Le Rhun, Emilie; Chamberlain, Marc C

    2016-09-01

    Chemotherapy may have detrimental effects on either the central or peripheral nervous system. Central nervous system neurotoxicity resulting from chemotherapy manifests as a wide range of clinical syndromes including acute, subacute, and chronic encephalopathies, posterior reversible encephalopathy, acute cerebellar dysfunction, chronic cognitive impairment, myelopathy, meningitis, and neurovascular syndromes. These clinical entities vary by causative agent, degree of severity, evolution, and timing of occurrence. In the peripheral nervous system, chemotherapy-induced peripheral neuropathy (CIPN) and myopathy are the two main complications of chemotherapy. CIPN is the most common complication, and the majority manifest as a dose-dependent length-dependent sensory axonopathy. In severe cases of CIPN, the dose of chemotherapy is reduced, the administration delayed, or the treatment discontinued. Few treatments are available for CIPN and based on meta-analysis, duloxetine is the preferred symptomatic treatment. Myopathy due to corticosteroid use is the most frequent cause of muscle disorders in patients with cancer.

  9. Neurotoxicity of metals.

    PubMed

    Caito, Samuel; Aschner, Michael

    2015-01-01

    Metals are frequently used in industry and represent a major source of toxin exposure for workers. For this reason governmental agencies regulate the amount of metal exposure permissible for worker safety. While essential metals serve physiologic roles, metals pose significant health risks upon acute and chronic exposure to high levels. The central nervous system is particularly vulnerable to metals. The brain readily accumulates metals, which under physiologic conditions are incorporated into essential metalloproteins required for neuronal health and energy homeostasis. Severe consequences can arise from circumstances of excess essential metals or exposure to toxic nonessential metal. Herein, we discuss sources of occupational metal exposure, metal homeostasis in the human body, susceptibility of the nervous system to metals, detoxification, detection of metals in biologic samples, and chelation therapeutic strategies. The neurologic pathology and physiology following aluminum, arsenic, lead, manganese, mercury, and trimethyltin exposures are highlighted as classic examples of metal-induced neurotoxicity.

  10. Developmental Neurotoxicity of Lead.

    PubMed

    Caito, Samuel; Aschner, Michael

    2017-01-01

    Lead exposure is a major concern for the developing nervous system. Environmental exposures to lead, predominantly from contaminated water or lead paint chips, account for the majority of exposures to children. In utero and early life exposures to lead have been associated with lower IQ, antisocial and delinquent behaviors, and attention-deficit hyperactivity disorder. In this review, we will discuss sources of developmental lead exposure and mechanisms of lead neurotoxicity. We will highlight both human epidemiological studies showing associations between lead exposure and behavioral abnormalities as well as experimental data from animal studies. Finally, we will discuss the effects of lead on neurological endpoint past childhood, namely, development of Alzheimer's disease in old age.

  11. Neurotoxicity and risk assessment of brominated and alternative flame retardants.

    PubMed

    Hendriks, Hester S; Westerink, Remco H S

    2015-01-01

    Brominated flame retardants (BFRs) are widely used chemicals that prevent or slow the onset and spreading of fire. Unfortunately, many of these compounds pose serious threats for human health and the environment, indicating an urgent need for safe(r) and less persistent alternative flame retardants (AFRs). As previous research identified the nervous system as a sensitive target organ, the neurotoxicity of past and present flame retardants is reviewed. First, an overview of the neurotoxicity of BFRs in humans and experimental animals is provided, and some common in vitro neurotoxic mechanisms of action are discussed. The combined epidemiological and toxicological studies clearly underline the need for replacing BFRs. Many potentially suitable AFRs are already in use, despite the absence of a full profile of their environmental behavior and toxicological properties. To prioritize the suitability of some selected halogenated and non-halogenated organophosphorous flame retardants and inorganic halogen-free flame retardants, the available neurotoxic data of these AFRs are discussed. The suitability of the AFRs is rank-ordered and combined with human exposure data (serum concentrations, breast milk concentrations and house dust concentrations) and physicochemical properties (useful to predict e.g. bioavailability and persistence in the environment) for a first semi-quantitative risk assessment of the AFRs. As can be concluded from the reviewed data, several BFRs and AFRs share some neurotoxic effects and modes of action. Moreover, the available neurotoxicity data indicate that some AFRs may be suitable substitutes for BFRs. However, proper risk assessment is hampered by an overall scarcity of data, particularly regarding environmental persistence, human exposure levels, and the formation of breakdown products and possible metabolites as well as their toxicity. Until these data gaps in environmental behavioral and toxicological profiles are filled, large scale use of

  12. Neurotoxicity of organomercurial compounds.

    PubMed

    Sanfeliu, Coral; Sebastià, Jordi; Cristòfol, Rosa; Rodríguez-Farré, Eduard

    2003-01-01

    Mercury is a ubiquitous contaminant, and a range of chemical species is generated by human activity and natural environmental change. Elemental mercury and its inorganic and organic compounds have different toxic properties, but all them are considered hazardous in human exposure. In an equimolecular exposure basis, organomercurials with a short aliphatic chain are the most harmful compounds and they may cause irreversible damage to the nervous system. Methylmercury (CH(3)Hg(+)) is the most studied following the neurotoxic outbreaks identified as Minamata disease and the Iraq poisoning. The first description of the CNS pathology dates from 1954. Since then, the clinical neurology, the neuropathology and the mechanisms of neurotoxicity of organomercurials have been widely studied. The high thiol reactivity of CH(3)Hg(+), as well as all mercury compounds, has been suggested to be the basis of their harmful biological effects. However, there is clear selectivity of CH(3)Hg(+) for specific cell types and brain structures, which is not yet fully understood. The main mechanisms involved are inhibition of protein synthesis, microtubule disruption, increase of intracellular Ca(2+) with disturbance of neurotransmitter function, oxidative stress and triggering of excitotoxicity mechanisms. The effects are more damaging during CNS development, leading to alterations of the structure and functionality of the nervous system. The major source of CH(3)Hg(+) exposure is the consumption of fish and, therefore, its intake is practically unavoidable. The present concern is on the study of the effects of low level exposure to CH(3)Hg(+) on human neurodevelopment, with a view to establishing a safe daily intake. Recommendations are 0.4 micro g/kg body weight/day by the WHO and US FDA and, recently, 0.1 micro g/kg body weight/day by the US EPA. Unfortunately, these levels are easily attained with few meals of fish per week, depending on the source of the fish and its position in the

  13. "Ecstasy"-induced toxicity in SH-SY5Y differentiated cells: role of hyperthermia and metabolites.

    PubMed

    Barbosa, Daniel José; Capela, João Paulo; Silva, Renata; Ferreira, Luísa Maria; Branco, Paula Sério; Fernandes, Eduarda; Bastos, Maria Lourdes; Carvalho, Félix

    2014-02-01

    3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a recreational hallucinogenic drug of abuse known to elicit neurotoxic properties. Hepatic formation of neurotoxic metabolites is thought to play a major role in MDMA-related neurotoxicity, though the mechanisms involved are still unclear. Here, we studied the neurotoxicity mechanisms and stability of MDMA and 6 of its major human metabolites, namely α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) and their correspondent glutathione (GSH) and N-acetyl-cysteine (NAC) conjugates, under normothermic (37 °C) or hyperthermic conditions (40 °C), using cultured SH-SY5Y differentiated cells. We showed that MDMA metabolites exhibited toxicity to SH-SY5Y differentiated cells, being the GSH and NAC conjugates more toxic than their catecholic precursors and MDMA. Furthermore, whereas the toxicity of the catechol metabolites was potentiated by hyperthermia, NAC-conjugated metabolites revealed higher toxicity under normothermia and GSH-conjugated metabolites-induced toxicity was temperature-independent. Moreover, a time-dependent decrease in extracellular concentration of MDMA metabolites was observed, which was potentiated by hyperthermia. The antioxidant NAC significantly protected against the neurotoxic effects of MDMA metabolites. MDMA metabolites increased intracellular glutathione levels, though depletion in thiol content was observed in MDMA-exposed cells. Finally, the neurotoxic effects induced by the MDMA metabolite N-Me-α-MeDA involved caspase 3 activation. In conclusion, this study evaluated the stability of MDMA metabolites in vitro, and demonstrated that the catechol MDMA metabolites and their GSH and NAC conjugates, rather than MDMA itself, exhibited neurotoxic actions in SH-SY5Y differentiated cells, which were differently affected by hyperthermia, thus highlighting a major role for reactive metabolites and hyperthermia in MDMA's neurotoxicity.

  14. New advances in the biochemical diagnosis of pheochromocytoma: moving beyond catecholamines.

    PubMed

    Lenders, Jacques W M; Pacak, Karel; Eisenhofer, Graeme

    2002-09-01

    Pheochromocytomas are dangerous tumors that, although a rare cause of hypertension, require consideration among large numbers of patients. The resulting low prevalence of the tumor among tested populations and the inadequacies of commonly used biochemical tests make excluding or confirming the tumor an often difficult and time-consuming task. Recognition that catecholamines are metabolized to free metanephrines within pheochromocytoma tumor cells, and that this process is independent of catecholamine release, provides a rationale for use of these metabolites in the biochemical diagnosis of pheochromocytoma. Here we briefly review the history of biochemical diagnosis of pheochromocytoma in relation to recent data about the diagnostic utility of plasma free metanephrines for detection of these tumors. Measurements of urinary or plasma catecholamines have reasonable sensitivity for detection of most pheochromocytomas, particularly those in patients with sustained hypertension. False-negative test results can, however, occur in asymptomatic patients tested because of an adrenal incidentaloma or a familial predisposition for pheochromocytoma, or when sampling is carried out between episodes of paroxysmal hypertension. Measurements of urinary total metanephrines or vanillylmandelic acid are less reliable and are of little value as initial screening tests. In contrast, measurements of plasma concentrations or free metanephrines or 24-hour urinary outputs of fractionated normetanephrine and metanephrine almost always reveal the tumor. Although, both tests have similarly high sensitivity, the relatively low specificity of urinary fractionated metanephrines means that pheochromocytomas can be more efficiently excluded or confirmed using measurements of plasma free metanephrines.

  15. Phagocyte-derived catecholamines enhance acute inflammatory injury.

    PubMed

    Flierl, Michael A; Rittirsch, Daniel; Nadeau, Brian A; Chen, Anthony J; Sarma, J Vidya; Zetoune, Firas S; McGuire, Stephanie R; List, Rachel P; Day, Danielle E; Hoesel, L Marco; Gao, Hongwei; Van Rooijen, Nico; Huber-Lang, Markus S; Neubig, Richard R; Ward, Peter A

    2007-10-11

    It is becoming increasingly clear that the autonomic nervous system and the immune system demonstrate cross-talk during inflammation by means of sympathetic and parasympathetic pathways. We investigated whether phagocytes are capable of de novo production of catecholamines, suggesting an autocrine/paracrine self-regulatory mechanism by catecholamines during inflammation, as has been described for lymphocytes. Here we show that exposure of phagocytes to lipopolysaccharide led to a release of catecholamines and an induction of catecholamine-generating and degrading enzymes, indicating the presence of the complete intracellular machinery for the generation, release and inactivation of catecholamines. To assess the importance of these findings in vivo, we chose two models of acute lung injury. Blockade of alpha2-adrenoreceptors or catecholamine-generating enzymes greatly suppressed lung inflammation, whereas the opposite was the case either for an alpha2-adrenoreceptor agonist or for inhibition of catecholamine-degrading enzymes. We were able to exclude T cells or sympathetic nerve endings as sources of the injury-modulating catecholamines. Our studies identify phagocytes as a new source of catecholamines, which enhance the inflammatory response.

  16. Guidelines for Neurotoxicity Risk Assessment

    EPA Pesticide Factsheets

    These Guidelines set forth principles and procedures to guide EPA scientists in evaluating environmental contaminants that may pose neurotoxic risks, and inform Agency decision makers and the public about these procedures.

  17. INTRACELLULAR SIGNALING AND DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    A book chapter in ?Molecular Toxicology: Transcriptional Targets? reviewed the role of intracellular signaling in the developmental neurotoxicity of environmental chemicals. This chapter covered a number of aspects including the development of the nervous system, role of intrace...

  18. INTRACELLULAR SIGNALING AND DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    A book chapter in ?Molecular Toxicology: Transcriptional Targets? reviewed the role of intracellular signaling in the developmental neurotoxicity of environmental chemicals. This chapter covered a number of aspects including the development of the nervous system, role of intrace...

  19. Guidelines for neurotoxicity risk assessment

    SciTech Connect

    1998-04-01

    These Guidelines describe the principles, concepts, and procedures that the US Environmental Protection Agency (EPA) will follow in evaluating data on potential neurotoxicity associated with exposure to environmental toxicants. The procedures outlined are intended to help develop a sound scientific basis for neurotoxicity risk assessment, promote consistency in the Agency`s assessment of toxic effects on the nervous system, and inform others of the approaches used by the Agency in those assessments.

  20. [Hyperhomocysteinemia: atherothrombosis and neurotoxicity].

    PubMed

    Fridman, O

    1999-01-01

    The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation

  1. Plasma catecholamines during an ultrarapid heroin detoxification.

    PubMed

    Macedo, T R; Relvas, J; Fontes Ribeiro CA; Pacheco, F; Morgadinho, M T; Pinto, C M; Gomes, P C; Ventura, M; Henriques, V; Nunes, S V; Ruis, G R; Ramalheira, C; Boto, I; Vale, L L

    2000-09-01

    The adrenergic system has long been known to be activated in a situation of stress and thus during opiate withdrawal. A method for detoxification that decreases the stimulation of the sympathetic nervous system will prevent changes of catecholamine levels. Some of such methods have been developed. One of them uses direct transition from heroin to oral naltrexone after deep sedation with midazolam in conjunction with naloxone, droperidol, ondansetron, and clonidine treatment for 24 hours. Can such method prevent adrenergic changes? Moreover, 5-HT has been related to mood disorders. This study aims to determine plasma catecholamines and 5-HT before heroin withdrawal, during the day of the withdrawal, and at the ends of the first day, the first week, and the first 6 months. Forty-three patients with more than 6 years of drug abuse volunteered to seek help to detoxify. After clinical evaluation, blood samples were taken. Plasma catecholamines were isolated by standard alumina procedures and measured by high-performance liquid chromatography with electrochemical detection. Only for NE was there a significant decrease in the day of heroin withdrawal with deep sedation, followed the next day by an increase. During the following days, NE plasma concentrations returned slowly to basal levels. Epinephrine and dopamine plasma levels did not significantly change. Platelet 5-HT levels progressively decreased from the day before detoxification until the last period of observation. We also found that there were no abrupt changes in cardiovascular functions. In conclusion, our results suggest that this type of ultrarapid opiate detoxification prevents the dramatic activation of the autonomic nervous system.

  2. Neurotoxic Shellfish Poisoning

    PubMed Central

    Watkins, Sharon M.; Reich, Andrew; Fleming, Lora E.; Hammond, Roberta

    2008-01-01

    Neurotoxic shellfish poisoning (NSP) is caused by consumption of molluscan shellfish contaminated with brevetoxins primarily produced by the dinoflagellate, Karenia brevis. Blooms of K. brevis, called Florida red tide, occur frequently along the Gulf of Mexico. Many shellfish beds in the US (and other nations) are routinely monitored for presence of K. brevis and other brevetoxin-producing organisms. As a result, few NSP cases are reported annually from the US. However, infrequent larger outbreaks do occur. Cases are usually associated with recreationally-harvested shellfish collected during or post red tide blooms. Brevetoxins are neurotoxins which activate voltage-sensitive sodium channels causing sodium influx and nerve membrane depolarization. No fatalities have been reported, but hospitalizations occur. NSP involves a cluster of gastrointestinal and neurological symptoms: nausea and vomiting, paresthesias of the mouth, lips and tongue as well as distal paresthesias, ataxia, slurred speech and dizziness. Neurological symptoms can progress to partial paralysis; respiratory distress has been recorded. Recent research has implicated new species of harmful algal bloom organisms which produce brevetoxins, identified additional marine species which accumulate brevetoxins, and has provided additional information on the toxicity and analysis of brevetoxins. A review of the known epidemiology and recommendations for improved NSP prevention are presented. PMID:19005578

  3. NEUROTOXICITY OF TETRACHLOROETHYLENE ...

    EPA Pesticide Factsheets

    This paper is a background document for a meeting of neurotoxicity experts to discuss the central nervous system effects of exposure to perchloroethylene (perc). The document reviews the literature on neurological testing of people exposed to perc occupationally in dry cleaning facilities and on people living near dry cleaning facilities. It also reviews the neurobehavioral studies of laboratory animals exposed to perc via inhalation. The reports describe impairment of visual information processing and other adverse neurobehavioral effects in several studies of employees working in dry cleaning facilities using perc. Two studies of people living near dry cleaning facilities have also shown neurological effects, and their exposures have been at lower concentrations than the workers and the specific neurological tests used in the residential studies have been different. The expert panel will discuss issues centering on the question of whether this limited information at lower exposures is strong enough to infer that low concentrations of perc is a hazard to the general population. Discussion paper.

  4. [The brain catecholamines during domestication of the silver fox Vulpes fulvus].

    PubMed

    Nikulina, E M

    1990-01-01

    Studies have been made on the content of catecholamines (noradrenaline and dopamine) as well as metabolites of dopamine (3,4-dihydroxyphenylacetic and homovanillic acids) in the brain structures of silver foxes which differ in their handling reactions. The level of noradrenaline was found to be significantly higher in the anterior hypothalamus of domesticated animals; no differences in noradrenaline content were found in the frontal cortex, hippocamp, posterior hypothalamus and midbrain in animals from aggressive and domesticated groups. Dopamine content was higher in the tuberculum olfactorium of domesticated animals, being lower in the striatum and n. accumbens. Metabolite level remained unaffected which is presumably due to changes in dopamine synthesis in the investigated structures. It was concluded that domestication of animals favours the specimens with an altered state of catecholaminergic system of the brain.

  5. A test of the catecholamines hypothesis for an acute exercise-cognition interaction.

    PubMed

    McMorris, T; Collard, K; Corbett, J; Dicks, M; Swain, J P

    2008-03-01

    The purpose of the study was to examine the usage of norepinephrine (NE) and dopamine (DA) in the brain when exercising while simultaneously undertaking cognitive tests. Plasma concentrations of the NE metabolite 3-methoxy 4-hydroxyphenylglycol (MHPG) and the DA metabolite homovanillic acid (HVA) showed a linear increase from rest to exercising at 40% and 80% maximum power output (W.max) while simultaneously undertaking cognitive tasks (random number generation (RNG) and response time). Delta plasma concentrations of MHPG and HVA at each exercise intensity while undertaking cognitive tasks and while exercising without cognitive tasks did not differ. Taking blood samples at 0, 1, 3, and 5 min following cessation of exercise did not affect results. Regression correlations showed that delta MHPG and HVA plasma concentrations at the 1 and 3 min sampling times were strong predictors of delta RNG, response time and movement time. Reaction time at 80% W.max significantly increased, while movement time at 80% W.max significantly decreased. It was concluded that these results provide no support for a direct effect of increased catecholamines concentrations on cognitive performance during exercise. The regression data suggest that there is some relationship between exercise, catecholamines concentrations and cognition.

  6. A catecholamine crisis on Mount Kilimanjaro: a hypoxia effect?

    PubMed

    Ayala-Ramirez, Montserrat; Habra, Mouhammed Amir; Busaidy, Naifa; Cote, Gilbert; Rich, Thereasa; Waguespack, Steven; Jimenez, Camilo

    2010-01-01

    Sympathetic paragangliomas are autonomic nervous system tumors associated with dysregulation of intracellular oxygen metabolism. Exposure to high altitudes is reported to activate the production of catecholamines in the sympathoadrenal system. We describe an individual with a paraganglioma complicated by a catecholamine crisis that occurred on the summit of Mount Kilimanjaro. © 2010 International Society of Travel Medicine.

  7. Urinary catecholamine levels and bruxism in children.

    PubMed

    Vanderas, A P; Menenakou, M; Kouimtzis, T; Papagiannoulis, L

    1999-02-01

    This study was performed to test the hypothesis that emotionally stressful states measured by the urinary catecholamines may affect the development of bruxism. Three hundred and fourteen children, boys and girls, aged 6-8 years were included in this study. Bruxism was recorded by a clinical examination and an interview. Positive evidence of this parafunction was defined as the presence of both historical and clinical indicators. Information concerning systemic and socio-economic factors was collected by a questionnaire. A 24-h urine sample was collected for each subject and analysed by the high performance liquid chromatography technique to assay the catecholamine content. Of the total of 273 children who had a complete 24-h urine sample, 167 were identified to be with and without positive evidence of bruxism. The logistic multiple-regression analysis was carried out to test whether the presence of bruxism was affected by the variables studied; 95% probability was used. The results showed that epinephrine and dopamine had a significant and strong association with bruxism. The data therefore provide support for the concept that emotional stress is a prominent factor in the development of bruxing behaviour.

  8. Urinary catecholamine levels and gingivitis in children.

    PubMed

    Vanderas, A P; Kavvadia, K; Papagiannoulis, L

    1998-05-01

    This study investigated the relationship between gingivitis and emotionally stressful states measured by the urinary catecholamines in children. Three-hundred and fourteen (314) children, boys and girls, aged 6 to 8 years were included in the study. Gingivitis was recorded by the gingival bleeding index and dental plaque by the plaque control record index. Proximal decayed surfaces, faulty restorations, and stainless steel crowns were diagnosed clinically and radiographically. Information concerning systemic and socioeconomic factors was collected by a questionnaire. A 24-hour urine sample was collected for each subject and analyzed by the HPLC technique to assay the catecholamine content. The multiple-regression analysis was carried out to test whether gingivitis was affected by the studied variables. The 95% probability was used. The results showed that epinephrine, norepinephrine, and dopamine did not have a significant association with gingival index. Dental plaque and proximal decayed surfaces significantly affected gingivitis. Of the socioeconomic factors, mother's education had a significant association with gingivitis when all factors were included in the analysis. The data suggest that emotionally stressful states may not increase the probability of developing gingivitis in children of this age.

  9. [Excretion of catecholamines in juvenile diabetes mellitus].

    PubMed

    Kornas-Dubejko, A; Szewczyk, L; Zajackowska, M

    1979-01-01

    Twenty four hours' urinary excretion of catecholamines was examined in 30 children suffering from diabetes and in 30 healthy children. The results showed that in children suffering from diabetes, excretion of adrenaline was increased and that of noradrenaline decreased when compared with healthy children. Taking into consideration changes in the sympatho-adrenergic system activity in cases with different degrees of compensation of metabolic processes during insulinization, it should be stressed that in children with ketoacidosis, excretion of catecholamines was still different in comparison with control group. On the other hand in children with compensate diabetes after insulin therapy, that differences were little. Marked increase in free adrenaline excretion observed in children with ketoacidosis and its normalization by effective insulinization seems to support the diabetogenic and ketogenic role of this neurohormone. Decrease in free noradrenaline excretion in children suffering from juvenile diabetes appears to suggest that there is a diminished sensitivity of the sympathetic system resulting probably from specific autonomic neuropathy accompanying this disease.

  10. Intraoperative hypertensive crisis due to a catecholamine-secreting esthesioneuroblastoma

    PubMed Central

    Salmasi, Vafi; Schiavi, Adam; Binder, Zev A.; Ruzevick, Jacob; Orr, Brent A.; Burger, Peter C.; Ball, Douglas W.; Blitz, Ari M.; Koch, Wayne M.; Ishii, Masaru; Gallia, Gary L.

    2015-01-01

    Background Although uncommon, esthesioneuroblastomas may produce clinically significant amounts of catecholamines. Methods We report a patient with a catecholamine-secreting esthesioneuroblastoma who developed intraoperative hypertensive crisis. Results A patient with history of hypertension was referred to our skull base center for management of a residual esthesioneuroblastoma. A staged endonasal endoscopic approach was planned. At the conclusion of the first stage, a hypertensive crisis occurred. Work-up revealed elevated levels of serum and urinary catecholamines. The patient was treated with alpha adrenoceptor blockade prior to the second stage. Serum catecholamine levels following this second stage were normal. On immunohistochemical analysis, the tumor cells were found to be positive for tyrosine hydroxylase, the rate limiting enzyme in cathecholamine synthesis, and achaete-scute homologue 1, a transcription factor essential in the development of olfactory and sympathetic neurons. Conclusion Catecholamine production should be considered in the differential of unexpected extreme hypertension during surgical resection of esthesioneuroblastoma. PMID:25352487

  11. Effects of catecholamine depletion on D2 receptor binding, mood, and attentiveness in humans: a replication study.

    PubMed

    Verhoeff, Nicolaas P L G; Christensen, Bruce K; Hussey, Doug; Lee, Maggie; Papatheodorou, George; Kopala, Lili; Rui, Qing; Zipursky, Robert B; Kapur, Shitij

    2003-01-01

    The effect of catecholamine depletion, achieved by per-oral administration of 5250 mg alpha-methyl-para-tyrosine (AMPT) given in the 29 h prior to [11C]raclopride positron emission tomography (PET) was studied on measures of dopamine (DA) release, mood, and attention. Neostriatal DA levels in vivo were estimated by comparing the neostriatal DA D(2) receptor binding potential (D(2)RBP) before and after catecholamine depletion using PET and the radiotracer [11C]raclopride. Six healthy subjects completed the protocol. The AMPT treatment increased D(2)RBP significantly by 13.3+/-5.9% (average+/-standard deviation) and decreased plasma levels of the DA metabolite homovanillic acid (HVA) by 62+/-17%, and levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) by 66+/-5%. Catecholamine depletion resulted in decreased happiness, euphoria, energy, talkativeness, vigor, and attentiveness, and in increased sleepiness, fatigue, sedation, and eye blink rate (EBR). These changes were not correlated with the D(2)RBP increments. The results of this study are overall consistent with previous findings by our group using the same methodology in a different cohort of six healthy subjects.

  12. Catecholamines promote Actinobacillus pleuropneumoniae growth by regulating iron metabolism.

    PubMed

    Li, Lu; Chen, Zhaohui; Bei, Weicheng; Su, Zhipeng; Huang, Qi; Zhang, Liang; Chen, Huanchun; Zhou, Rui

    2015-01-01

    Catecholamines are host stress hormones that can induce the growth of many bacteria by facilitating iron utilization and/or regulate the expression of virulence genes through specific hormone receptors. Whether these two responsive pathways are interconnected is unknown. In our previous study, it was found that catecholamines can regulate the expression of a great number of genes of Actinobacillus pleuropneumoniae, an important swine respiratory pathogen. However, bacterial growth was not affected by catecholamines in rich medium. In this study, it was discovered that catecholamines affected A. pleuropneumoniae growth in chemically defined medium (CDM). We found that serum inhibited A. pleuropneumoniae growth in CDM, while epinephrine, norepinephrine and dopamine promoted A. pleuropneumoniae growth in the CDM containing serum. The known bacterial hormone receptor QseC didn't play roles in this process. Ion-supplementation and transcriptome analysis indicated that serum addition resulted in iron-restricted conditions which were alleviated by the addition of catecholamines. Transferrin, one of the components in serum, inhibited the growth of A. pleuropneumoniae in CDM, an effect reversed by addition of catecholamines in a TonB2-dependent manner. Our data demonstrate that catecholamines promote A. pleuropneumoniae growth by regulating iron-acquisition and metabolism, which is independent of the adrenergic receptor QseC.

  13. Catecholamines Promote Actinobacillus pleuropneumoniae Growth by Regulating Iron Metabolism

    PubMed Central

    Li, Lu; Chen, Zhaohui; Bei, Weicheng; Su, Zhipeng; Huang, Qi; Zhang, Liang; Chen, Huanchun; Zhou, Rui

    2015-01-01

    Catecholamines are host stress hormones that can induce the growth of many bacteria by facilitating iron utilization and/or regulate the expression of virulence genes through specific hormone receptors. Whether these two responsive pathways are interconnected is unknown. In our previous study, it was found that catecholamines can regulate the expression of a great number of genes of Actinobacillus pleuropneumoniae, an important swine respiratory pathogen. However, bacterial growth was not affected by catecholamines in rich medium. In this study, it was discovered that catecholamines affected A. pleuropneumoniae growth in chemically defined medium (CDM). We found that serum inhibited A. pleuropneumoniae growth in CDM, while epinephrine, norepinephrine and dopamine promoted A. pleuropneumoniae growth in the CDM containing serum. The known bacterial hormone receptor QseC didn’t play roles in this process. Ion-supplementation and transcriptome analysis indicated that serum addition resulted in iron-restricted conditions which were alleviated by the addition of catecholamines. Transferrin, one of the components in serum, inhibited the growth of A. pleuropneumoniae in CDM, an effect reversed by addition of catecholamines in a TonB2-dependent manner. Our data demonstrate that catecholamines promote A. pleuropneumoniae growth by regulating iron-acquisition and metabolism, which is independent of the adrenergic receptor QseC. PMID:25849041

  14. Catecholamines and obesity: effects of exercise and training.

    PubMed

    Zouhal, Hassane; Lemoine-Morel, Sophie; Mathieu, Marie-Eve; Casazza, Gretchen A; Jabbour, Georges

    2013-07-01

    Excess body fat in obese individuals can affect the catecholamine response to various stimuli. Indeed, several studies report lower plasma catecholamine concentrations in obese subjects compared with nonobese subjects in response to submaximal or maximal exercise. This low catecholamine response reflects decreased sympathetic nervous system (SNS) activity. Although the relationship between the SNS and obesity is not well established, some authors have suggested that low SNS activity may contribute to the development of obesity. A decreased catecholamine response could affect α- and β-adrenoceptor sensitivity in adipose tissue, reducing lipolysis and increasing fat stores. Few studies have examined the effects of obesity on the plasma catecholamine response at rest and during exercise in adolescents. It is interesting to note that the effects of age, sex, and degree of obesity and the impact of very intense exercise on the catecholamine response have not yet been well examined. Moreover, the hormonal concentrations measured in the majority of obesity studies did not take into account plasma volume changes. This methodological factor can also undoubtedly influence plasma catecholamine results.

  15. Methadone-Induced Neurotoxicity in Advanced Cancer: A Case Report.

    PubMed

    Hoff, Ann M; Hartwig, Kristopher N; Rosielle, Drew A

    2017-09-01

    Methadone use as a second-line agent for severe cancer-related pain is increasing in the field of hospice and palliative care. It has a number of qualities that make its use favorable, including lack of known active metabolites and presumed relative safety from adverse effects such as opioid-induced neurotoxicity (OIN). This article describes a case of a patient undergoing treatment of severe cancer-related pain who developed OIN in the setting of oral methadone use. As the use of methadone increases, more research into its pharmacologic and pharmacokinetic properties will be necessary.

  16. Biomarkers, mechanisms, and potential prevention of catecholamine neuron loss in Parkinson disease.

    PubMed

    Goldstein, David S

    2013-01-01

    This chapter is on biomarkers, mechanisms, and potential treatment of catecholamine neuron loss in Parkinson disease (PD). PD is characterized by a movement disorder from loss of nigrostriatal dopamine neurons. An intense search is going on for biomarkers of the disease process. Theoretically, cerebrospinal fluid (CSF) levels of the deaminated DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), should be superior to other neurochemical indices of loss of central dopamine. CSF DOPAC is low in PD-even in patients with recent onset of Parkinsonism. Cardiac norepinephrine depletion is as severe as the loss of putamen dopamine. PD importantly involves nonmotor manifestations, including anosmia, dementia, REM behavior disorder, and orthostatic hypotension, and all of these nonmotor features are associated with neuroimaging evidence for cardiac sympathetic denervation, which seems to occur independently of the movement disorder and striatal dopaminergic lesion. Analogy to a bank robber's getaway car conveys the catecholaldehyde hypothesis, according to which buildup of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the immediate product of the action of monoamine oxidase on cytosolic dopamine, causes or contributes to the death of dopamine neurons. Decreased vesicular uptake of dopamine and decreased DOPAL detoxification by aldehyde dehydrogenase (ALDH) determine this buildup. Vesicular uptake is also markedly decreased in the heart in PD. Multiple factors influence vesicular uptake and ALDH activity. Evidence is accruing for aging-related induction of positive feedback loops and an autotoxic final common pathway in the death of catecholamine neurons, mediated by metabolites produced continuously in neuronal life. The catecholaldehyde hypothesis also leads to testable experimental therapeutic ideas.

  17. Cadmium and Its Neurotoxic Effects

    PubMed Central

    Wang, Bo; Du, Yanli

    2013-01-01

    Cadmium (Cd) is a heavy metal that has received considerable concern environmentally and occupationally. Cd has a long biological half-life mainly due to its low rate of excretion from the body. Thus, prolonged exposure to Cd will cause toxic effect due to its accumulation over time in a variety of tissues, including kidneys, liver, central nervous system (CNS), and peripheral neuronal systems. Cd can be uptaken from the nasal mucosa or olfactory pathways into the peripheral and central neurons; for the latter, Cd can increase the blood brain barrier (BBB) permeability. However, mechanisms underlying Cd neurotoxicity remain not completely understood. Effect of Cd neurotransmitter, oxidative damage, interaction with other metals such as cobalt and zinc, estrogen-like, effect and epigenetic modification may all be the underlying mechanisms. Here, we review the in vitro and in vivo evidence of neurotoxic effects of Cd. The available finding indicates the neurotoxic effects of Cd that was associated with both biochemical changes of the cell and functional changes of central nervous system, suggesting that neurotoxic effects may play a role in the systemic toxic effects of the exposure to Cd, particularly the long-term exposure. PMID:23997854

  18. Phenotypic screening for developmental neurotoxicity ...

    EPA Pesticide Factsheets

    There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemicals for the potential to affect the developing brain are being explored. Typically, HTP screening uses biochemical and molecular assays to detect the interaction of a chemical with a known target or molecular initiating event (e.g., the mechanism of action). For developmental neurotoxicity, however, the mechanism(s) is often unknown. Thus, we have developed assays for detecting chemical effects on the key events of neurodevelopment at the cellular level (e.g., proliferation, differentiation, neurite growth, synaptogenesis, network formation). Cell-based assays provide a test system at a level of biological complexity that encompasses many potential neurotoxic mechanisms. For example, phenotypic assessment of neurite outgrowth at the cellular level can detect chemicals that target kinases, ion channels, or esterases at the molecular level. The results from cell-based assays can be placed in a conceptual framework using an Adverse Outcome Pathway (AOP) which links molecular, cellular, and organ level effects with apical measures of developmental neurotoxicity. Testing a wide range of concentrations allows for the distinction between selective effects on neurodevelopmental and non-specific

  19. Neurotoxic thioether adducts of 3,4-methylenedioxymethamphetamine identified in human urine after ecstasy ingestion.

    PubMed

    Perfetti, Ximena; O'Mathúna, Brian; Pizarro, Nieves; Cuyàs, Elisabet; Khymenets, Olha; Almeida, Bruno; Pellegrini, Manuela; Pichini, Simona; Lau, Serrine S; Monks, Terrence J; Farré, Magí; Pascual, Jose Antonio; Joglar, Jesús; de la Torre, Rafael

    2009-07-01

    3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely misused synthetic amphetamine derivative and a serotonergic neurotoxicant in animal models and possibly humans. The underlying mechanism of neurotoxicity involves the formation of reactive oxygen species although their source remains unclear. It has been postulated that MDMA-induced neurotoxicity is mediated via the formation of bioreactive metabolites. In particular, the primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), subsequently cause the formation of glutathione and N-acetylcysteine conjugates, which retain the ability to redox cycle and are serotonergic neurotoxicants in rats. Although the presence of such metabolites has been recently demonstrated in rat brain microdialysate, their formation in humans has not been reported. The present study describes the detection of 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine (N-Ac-5-Cys-HHMA) and 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine (N-Ac-5-Cys-HHA) in human urine of 15 recreational users of MDMA (1.5 mg/kg) in a controlled setting. The results reveal that in the first 4 h after MDMA ingestion approximately 0.002% of the administered dose was recovered as thioether adducts. Genetic polymorphisms in CYP2D6 and catechol-O-methyltransferase expression, the combination of which are major determinants of steady-state levels of HHMA and 4-hydroxy-3-methoxyamphetamine, probably explain the interindividual variability seen in the recovery of N-Ac-5-Cys-HHMA and N-Ac-5-Cys-HHA. In summary, the formation of neurotoxic thioether adducts of MDMA has been demonstrated for the first time in humans. The findings lend weight to the hypothesis that the bioactivation of MDMA to neurotoxic metabolites is a relevant pathway to neurotoxicity in humans.

  20. Intra-neuronal vesicular uptake of catecholamines is decreased in patients with Lewy body diseases.

    PubMed

    Goldstein, David S; Holmes, Courtney; Kopin, Irwin J; Sharabi, Yehonatan

    2011-08-01

    Several neurodegenerative disorders, including Parkinson disease (PD), are characterized by the presence of Lewy bodies - cytoplasmic inclusions containing α-synuclein protein aggregates - in the affected neurons. A poorly understood feature of Lewy body diseases is loss of sympathetic nerves in the heart and other organs, manifesting as orthostatic hypotension (OH; also known as postural hypotension). We asked whether sympathetic denervation is associated with decreased uptake of catecholamines, such as dopamine and norepinephrine, into storage vesicles within sympathetic neurons. We used 6-[18F]-dopamine (18F-DA) to track myocardial uptake and retention of catecholamines. Concurrently, the fate of intra-neuronal 18F-DA was followed by assessment of arterial plasma levels of the 18F-DA metabolite 18F-dihydroxyphenylacetic acid (18F-DOPAC). The ratio of myocardial 18F-DA to arterial 18F-DOPAC provided an index of vesicular uptake. Tracer concentrations were measured in patients with PD with or without orthostatic hypotension (PD+OH, PD-No-OH); in patients with pure autonomic failure (PAF, a Lewy body disease without parkinsonism); in patients with multiple system atrophy (MSA, a non-Lewy body synucleinopathy); and in normal controls. Patients with PD+OH or PAF had decreased vesicular 18F-DA uptake and accelerated 18F-DA loss, compared with MSA and control subjects. PD-No-OH patients could be subtyped into one of these categories based on their initial 18F-DA uptake. We conclude that sympathetic denervation in Lewy body diseases is associated with decreased vesicular uptake of neuronal catecholamines, suggesting that vesicular monoamine transport is impaired. Vesicular uptake may constitute a novel target for diagnosis, treatment, and prevention.

  1. Autoimmune Voltage-Gated Potassium Channelopathy Presenting With Catecholamine Excess.

    PubMed

    Stepp, K Amy; Folker, Christin; Tanzer, Marie; Hayman, Jennifer; Reynolds, Thomas; Mallory, Leah

    2017-07-01

    Autoimmune voltage-gated potassium channelopathies have been associated with a range of neurological presenting symptoms, including central, peripheral, and autonomic dysfunction. We describe a 12-year-old boy who presented with nine months of pain, anxiety, and 30-pound weight loss. He was admitted for failure to thrive, then noted to be persistently hypertensive and tachycardic. Plasma metanephrines and urine metanephrines and catecholamines were elevated. Extensive investigation for causes of elevated catecholamines, such as hyperthyroidism or catecholamine-secreting tumor, was negative. A paraneoplastic panel was positive for voltage-gated potassium channel antibodies. Treatment with intravenous immunoglobulin and pulse methylprednisolone led to complete resolution of symptoms, weight gain, and normalization of vital signs and plasma metanephrines. Voltage-gated potassium channel antibodies should be considered as part of the differential in patients presenting with elevated metanephrine and catecholamine secretion. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. [Peripheral secretion and inactivation of catecholamines (adrenaline, noradrenaline, dopamine)].

    PubMed

    Peyrin, L; Dalmaz, Y

    1975-01-01

    In spite of the biochemical relationship between catecholamines (E,NE,DA), the unity of the adrenergic system is only apparent; catecholamines are present in numerous pools, which exhibit different anatomical and cellular localizations, secretory patterns, control of release, physiological functions, inactivation schemes and metabolic behaviour. The main sources of catecholamines in the periphery are the orthosympathetic nervous system, which is permanently active in maintaining homoeostasy, and the adrenal medulla, an essential element in the struggle against stress. In addition to these large pools, catecholamines are found also in extra adrenal chromaffin tissue and in sympathetic ganglions; the latter represents a potential store of amines, whilst ganglionic dopamine-rich interneurones are important links in the regulation of orthosympathetic activity. Rather than by a topographic distinction, it seems more satisfactory to classify the catecholamines spread in adrenergic fields into a small number of pools possessing their own physiological functions and inactivation patterns. Two main pools of catecholamines in the periphery may be described: The functional pool, represented by those catecholamines already released, or able to be released; in this pool are found plasma and adrenal medullary catecholamines and NE from sympathetic nerve endings. The tissue pool, consisting of the synthesis and storage compartments, which are poorly penetrated by plasma pool with respect to their high possibilities for synthesis and storage. Catecholamines from cellular bodies and axons of sympathetic neurons and a part of the adrenal medullary amines may be related to it. Two other pools of catecholamines have to be reported: a potential extrachromaffin pool, which is apparently negligible in the physiological state, but able to exhibit its synthetic and secretory capacities in particularly critical situations; an intraganglionic dopamine pool, which plays a modulator role in

  3. THE NUMBER OF CATECHOLAMINE STORAGE GRANULES IN ADRENAL MEDULLA

    DTIC Science & Technology

    A method is described for counting the catecholamine-containing heavy granules of adrenal glands. There are 5.0 ! 0.8 (S. E.) x 10 to the 12th power... granules /gram wet weight of fowl adrenal gland. Individual heavy granules contain about 8 million molecules of catecholamines (1.4 x 10 to the 17th...power mole). Reference to published electron microphotographs of adrenal medulla cells allows estimation of the average volume of heavy granules and

  4. Reversible catecholamine-induced cardiomyopathy due to pheochromocytoma: case report.

    PubMed

    Satendra, Milan; de Jesus, Cláudia; Bordalo e Sá, Armando L; Rosário, Luís; Rocha, José; Bicha Castelo, Henrique; Correia, Maria José; Nunes Diogo, António

    2014-03-01

    Pheochromocytoma is a tumor originating from chromaffin tissue. It commonly presents with symptoms and signs of catecholamine excess, such as hypertension, tachycardia, headache and sweating. Cardiovascular manifestations include catecholamine-induced cardiomyopathy, which may present as severe left ventricular dysfunction and congestive heart failure. We report a case of pheochromocytoma which was diagnosed following investigation of dilated cardiomyopathy. We highlight the dramatic symptomatic improvement and reversal of cardiomyopathy, with recovery of left ventricular function after treatment.

  5. Xylamine, a ligand for the catecholamine transporter

    SciTech Connect

    Waggaman, L.A.

    1985-01-01

    Previous studies have established xylamine (N-2'-chloro-ethyl-N-ethyl-2-methylbenzylamine) irreversibly inhibits neuronal norepinephrine uptake with no concomitant effect on other neurotransmitter systems. Since xylamine is thought to alkylate transport-associated sites in the plasma membrane of noradrenergic neurons, so the loss of endogenous norepinephrine may be a consequence of neuronal membrane damage resulting from the alkylation of membrane components. In these studies, xylamine, under in vitro conditions, irreversibly inhibited both neuronal norepinephrine and dopamine uptake in the rat cortex and striatum, respectively. The efficacy of xylamine as a neuronal dopamine uptake inhibitor appeared to depend on its ability to access dopaminergic neurons during tissue exposure to the drug. In sympathetically innervated peripheral tissues, (/sup 3/H)xylamine was accumulated in noradrenergic neurons in a carrier-dependent manner. Although the data suggested that xylamine was interacting with the norepinephrine uptake carrier, (/sup 3/H)xylamine exposure to isolated synaptic membranes from superior cervical ganglia revealed a large proportion of (/sup 3/H)xylamine binding that was not associated with the noradrenergic transporter. For a closer characterization of xylamine binding in synaptic membranes, brain tissue was chosen as a more practical source of these membranes. While these experiments did not meet with great success, xylamine remains potentially useful as a ligand for identifying the catecholamine transporter, particularly in conjunction with procedures for protein purification and reconstitution.

  6. Selective blockade of nicotinic acetylcholine receptors by pimobendan, a drug for the treatment of heart failure: reduction of catecholamine secretion and synthesis in adrenal medullary cells.

    PubMed

    Toyohira, Yumiko; Kubo, Tatsuhiko; Watanabe, Miyabi; Uezono, Yasuhito; Ueno, Susumu; Shinkai, Koji; Tsutsui, Masato; Izumi, Futoshi; Yanagihara, Nobuyuki

    2005-02-01

    Pimobendan, a Ca(2+) sensitizer, is used clinically in the treatment of chronic heart failure. Although chronic heart failure is associated with activation of the sympathetic nervous system, it remains unknown whether pimobendan affects the function of sympathetic neurons and the adrenal medulla. Here, we report the inhibitory effects of pimobendan on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Pimobendan decreased the catecholamine secretion (IC(50)=29.5 microM) elicited by carbachol, an agonist at nicotinic acetylcholine receptors, but not that elicited by veratridine, an activator of voltage-dependent Na(+) channels, or by high K(+), an activator of voltage-dependent Ca(2+) channels. Pimobendan also inhibited carbachol-induced influx of (22)Na(+) (IC(50)=25.9 microM) and (45)Ca(2+) (IC(50)=26.0 microM), but not veratridine-induced (22)Na(+) influx or high K(+)-induced (45)Ca(2+) influx. The reduction of catecholamine secretion caused by pimobendan was not overcome by increasing the concentration of carbachol. UD-CG 212, an active metabolite of pimobendan, lowered carbachol-induced catecholamine secretion with a concentration/inhibition curve similar to that of pimobendan. In experiments in situ, pimobendan suppressed both basal and carbachol-stimulated (14)C-catecholamine synthesis (IC(50)=5.3 and 4.9 microM) from [(14)C] tyrosine [but not from L: -3, 4-dihydroxyphenyl [3-(14)C] alanine ([(14)C]DOPA)], as well as tyrosine hydroxylase activity (IC(50)=3.8 and 4.3 microM). These findings suggest that pimobendan inhibits carbachol-induced catecholamines secretion and synthesis through suppression of nicotinic acetylcholine receptors.

  7. Multiple mechanisms of PCB neurotoxicity

    SciTech Connect

    Carpenter, D.O.; Stoner, C.T.; Lawrence, D.A.

    1996-12-31

    Polychlorinated biphenyls (PCBs) have been implicated in cancer, but many of the symptoms in humans exposed to PCBs are related to the nervous system and behavior. We demonstrated three different direct mechanisms whereby PCBs are neurotoxic in rats. By using flow cytometry, we demonstrated that the orthosubstituted PCB congener 2,4,4{prime}, but neither TCDD nor the coplanar PCB congener 3,4,5,3{prime},4{prime}, causes rapid death of cerebellar granule cells. The ortho-substituted congener 2,4,4{prime} reduced long-term potentiation, an indicator of cognitive potential, in hippocampal brain slices, but a similar effect was observed for the coplanar congener 3,4,3{prime},4{prime}, indicating that this effect may be caused by both ortho- and coplanar congeners by mechanisms presumably not mediated via the Ah receptor. It was previously shown that some ortho-substituted PCB congeners cause a reduction in levels of the neurotransmitter dopamine, and we present in vitro and in vivo evidence that this is due to reduction of synthesis of dopamine via inhibition of the enzyme tyrosine hydroxylase. Thus, PCBs have a variety of mechanisms of primary neurotoxicity, and neurotoxicity is a characteristic of ortho-substituted, non-dioxin-like congeners as well as some coplanar congeners. The relative contribution of each of these mechanisms to the loss of cognitive function in humans exposed to PCBs remains to be determined. 42 refs., 3 figs., 1 tab.

  8. Developmental neurotoxicity of industrial chemicals.

    PubMed

    Grandjean, P; Landrigan, P J

    2006-12-16

    Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

  9. Local Anesthetic-Induced Neurotoxicity

    PubMed Central

    Verlinde, Mark; Hollmann, Markus W.; Stevens, Markus F.; Hermanns, Henning; Werdehausen, Robert; Lirk, Philipp

    2016-01-01

    This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor. PMID:26959012

  10. Occupational neurotoxic diseases in taiwan.

    PubMed

    Liu, Chi-Hung; Huang, Chu-Yun; Huang, Chin-Chang

    2012-12-01

    Occupational neurotoxic diseases have become increasingly common in Taiwan due to industrialization. Over the past 40 years, Taiwan has transformed from an agricultural society to an industrial society. The most common neurotoxic diseases also changed from organophosphate poisoning to heavy metal intoxication, and then to organic solvent and semiconductor agent poisoning. The nervous system is particularly vulnerable to toxic agents because of its high metabolic rate. Neurological manifestations may be transient or permanent, and may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism, sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction disorders. This study attempts to provide a review of the major outbreaks of occupational neurotoxins from 1968 to 2012. A total of 16 occupational neurotoxins, including organophosphates, toxic gases, heavy metals, organic solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles related to the electrophysiology, neuroimaging, treatment and long-term follow up of these neurotoxic diseases were also obtained. The heavy metals involved consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The organic solvents included n-hexane, toluene, mixed solvents and carbon disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also included, along with toxic chemicals including polychlorinated biphenyls, tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In addition we attempted to correlate these events to the timeline of industrial development in Taiwan. By researching this topic, the hope is that it may help other developing countries to improve industrial hygiene and promote occupational safety and health care during the process of industrialization.

  11. Occupational Neurotoxic Diseases in Taiwan

    PubMed Central

    Liu, Chi-Hung; Huang, Chu-Yun

    2012-01-01

    Occupational neurotoxic diseases have become increasingly common in Taiwan due to industrialization. Over the past 40 years, Taiwan has transformed from an agricultural society to an industrial society. The most common neurotoxic diseases also changed from organophosphate poisoning to heavy metal intoxication, and then to organic solvent and semiconductor agent poisoning. The nervous system is particularly vulnerable to toxic agents because of its high metabolic rate. Neurological manifestations may be transient or permanent, and may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism, sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction disorders. This study attempts to provide a review of the major outbreaks of occupational neurotoxins from 1968 to 2012. A total of 16 occupational neurotoxins, including organophosphates, toxic gases, heavy metals, organic solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles related to the electrophysiology, neuroimaging, treatment and long-term follow up of these neurotoxic diseases were also obtained. The heavy metals involved consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The organic solvents included n-hexane, toluene, mixed solvents and carbon disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also included, along with toxic chemicals including polychlorinated biphenyls, tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In addition we attempted to correlate these events to the timeline of industrial development in Taiwan. By researching this topic, the hope is that it may help other developing countries to improve industrial hygiene and promote occupational safety and health care during the process of industrialization. PMID:23251841

  12. Assessment of O-methylated catecholamine levels in plasma and urine for diagnosis of autonomic disorders.

    PubMed

    Oeltmann, Timothy; Carson, Robert; Shannon, John R; Ketch, Terry; Robertson, David

    2004-11-30

    The term 'metanephrines' is used to indicate the two catechol 3-O-methylated metabolites of epinephrine (E) and norepinephrine (NE): metanephrine and normetanephrine (NMN). The corresponding 3-O-methylated metabolite of dopamine is usually referred to as 3-methoxytyramine rather than 3-methoxydopamine and is not generally considered a "metanephrine". O-Methylation occurs outside the sympathetic neuron and neuroeffector junction. Metanephrines are products of the enzyme catechol-O-methyltransferase (COMT). Subsequent conjugation with sulfate or deamination by monoamine oxidase (MAO) followed by reduction to vanilmandelic acid (VMA) facilitates urinary excretion. For the clinician, measurement of normetanephrine provides an index of norepinephrine released during sympathetic nervous system activity, whereas metanephrine concentration provides an indication of adrenal medullary metabolism of epinephrine prior to its discharge into the circulation. Plasma epinephrine concentration is the preferable index of adrenal medullary epinephrine discharge. Pheochromocytomas, with their protean clinical manifestations, may be diagnostic challenges, but assay of metanephrines, especially plasma metanephrine, can be particularly helpful in diagnosis. These COMT metabolites may also help in elucidation of still undiscovered genetic and acquired disorders of catecholamine metabolism.

  13. Detection of catecholamines and metanephrines by radio-immunoassay in canine plasma.

    PubMed

    Francis, Roland C E; Pickerodt, Philipp A; Salewski, Lothar; Boemke, Willehad; Höhne, Claudia

    2010-02-01

    This study investigated the applicability of two human radio-immunoassays (RIA) to detect epinephrine (EPI), norepinephrine (NE), and their O-methylated metabolites metanephrine (MN) and normetanephrine (NMN) in canine plasma. The analysis yielded a positive correlation between metabolites and their respective parent compounds: EPI and MN (r=0.63), NE and NMN (r=0.47), as well as between parent compounds, EPI and NE (r=0.48), and between metabolites MN and NMN (r=0.71). Moreover, EPI (r=0.99) and NE (r=0.77) concentrations determined by RIA did correlate positively with high pressure liquid chromatography (HPLC). However, there was limited agreement between both methods. It was concluded that complete validation tests for accuracy, precision and agreement are needed before this RIA can be applied to quantify catecholamines, metanephrine, and normetanephrine in canine plasma. The assay may prove to be a potential alternative to HPLC or tandem mass spectrometry in the work-up of pheochromocytoma and the detection of overall sympathetic activity in dogs. Copyright (c) 2008 Elsevier Ltd. All rights reserved.

  14. Correlation between catecholamine levels and outcome in patients with severe head trauma.

    PubMed

    Salehpoor, F; Bazzazi, A M; Estakhri, R; Zaheri, M; Asghari, B

    2010-08-01

    Some studies have shown that catecholamines and the changes in their levels during and after head trauma can be useful in predicting the outcome in head trauma patients. The goal of this study is to search for a probable relation between urine levels of catecholamines and prognosis in patients with severe head trauma. Fifty four patients with severe head trauma Glasgow Coma Scale (GCS < or = 8) on admission time were recruited in Imam Reza Hospital within one. These patients were included when having no major accompanying trauma in other organs. Twenty four hour urine was collected after admission and levels of metanephrine and nor-metanephrine were measured. The relation between urine levels of these metabolites with final outcome and also with GCS at admission, 24, 48 h and 1 week after admission and discharge time and Glasgow Outcome Scale (GOS) were studied. Fifty two patients, 48 males and 4 females with a mean age of 32.3 +/- 14.7 (3-72) years were included. The main underlying etiologies were motorcycle (46.2%) and car accidents (25%). Diffuse axonal injury, brain contusion and subdural hematoma were three main diagnoses (28.8, 17.3 and 15.4% of the cases, respectively). 19 (36.5%) of the patients expired within the study period. The mean level of metanephrine and normetanephrine in urine were 207.9 +/- 200.5 and 330.2 +/- 218.4 microg in 24 h, respectively. There was no meaningful relation between urine levels of these metabolites and any of GCS and GOS. There was also no meaningful relation between these parameters and final prognosis in patients.

  15. Pyrilamine inhibits nicotine-induced catecholamine secretion.

    PubMed

    Kim, Dong-Chan; Yun, So Jeong; Park, Yong-Soo; Jun, Dong-Jae; Kim, Dongjin; Jiten Singh, N; Kim, Sanguk; Kim, Kyong-Tai

    2014-07-01

    Function of nicotine, which induces activation of all parts of the body including our brain, has been receiving much attention for a long period of time and also been actively studied by researchers for its pharmacological actions in the central nervous system. The modulation of nicotine concentration and the inhibition of nicotine binding on target receptors in the brain are the key factors for smoking addiction therapy. In previous studies showed that influx of nicotine at the blood-brain barrier was through the pyrilamine-sensitive organic cation transporters. But the direct interacting mechanism of pyrilamine on the nicotine binding target receptors has not yet been clarified. The aim of the present study is to investigate the direct binding mechanisms of a pyrilamine on the nicotinic acetylcholine receptors (nAChRs). We found that pyrilamine shares the same ligand binding pocket of nicotine (NCT) on nAChRs but interacts with more amino acid residues than NCT does. The extended part of pyrilamine interacts with additional residues in the ligand binding pocket of nAChRs which are located nearby the entrance of the binding pocket. The catecholamine (CA) secretion induced by nAChR agonist (NCT') was significantly inhibited by the pyrilamine pretreatment. Real time carbon-fiber amperometry confirmed the inhibition of the NCT'-induced exocytosis by pyrilamine in a single cell level. We also found that pyrilamine inhibited the NCT'-induced [Ca(2+)]i. In contrast, pyrilamine did not affect the increase in calcium induced by high K(+). Overall, these data suggest that pyrilamine directly docks into the ligand binding site of nAChRs and specifically inhibits the nAChR-mediated effects thereby causing inhibition of CA secretion. Therefore, pyrilamine may play an important role to explore new treatments to aid smoking cessation.

  16. Stress stimulates production of catecholamines in rat adipocytes

    PubMed Central

    Kvetnansky, R.; Ukropec, J.; Laukova, M.; Manz, B.; Pacak, K.; Vargovic, P.

    2012-01-01

    The sympathoadrenal system is the main source of catecholamines (CAs) in adipose tissues and therefore plays the key role in the regulation of adipose tissue metabolism. We recently reported existence of an alternative catecholamine producing system directly in adipose tissue cells, and here we investigated effect of various stressors - physical (cold) and emotional stress (immobilization) on dynamics of this system. Acute or chronic cold exposure increased intracellular NE and EPI concentration in isolated rat mesenteric adipocytes. Gene expression of catecholamine biosynthetic enzymes did not change in adipocytes but was increased in stromal vascular fraction (SVF) after 28-day cold. Exposure of rats to a single immobilization stress caused increases in NE and EPI levels, and also gene expression of catecholamine biosynthetic enzymes in adipocytes. In SVF changes were similar but more pronounced. Animals adapted to a long-term cold exposure (28 days, 4°C) did not show those responses found after a single immobilization stress either in adipocytes or SVF. Our data indicate that gene machinery accommodated in adipocytes, which is able to synthesize NE and EPI de novo, is significantly activated by stress. Cold-adapted animals keep their adaptation even after an exposure to a novel stressor (immobilization). These findings suggest the functionality of CAs produced endogenously in adipocytes. Taken together, the newly discovered catecholamine synthesizing system in adipocytes is activated in stress situations and might significantly contribute to regulation of lipolysis and other metabolic or thermogenetic processes. PMID:22402834

  17. Catecholamines for inflammatory shock: a Jekyll-and-Hyde conundrum.

    PubMed

    Andreis, Davide Tommaso; Singer, Mervyn

    2016-09-01

    Catecholamines are endogenous neurosignalling mediators and hormones. They are integral in maintaining homeostasis by promptly responding to any stressor. Their synthetic equivalents are the current mainstay of treatment in shock states to counteract myocardial depression and/or vasoplegia. These phenomena are related in large part to decreased adrenoreceptor sensitivity and altered adrenergic signalling, with resultant vascular and cardiomyocyte hyporeactivity. Catecholamines are predominantly used in supraphysiological doses to overcome these pathological consequences. However, these adrenergic agents cause direct organ damage and have multiple 'off-target' biological effects on immune, metabolic and coagulation pathways, most of which are not monitored or recognised at the bedside. Such detrimental consequences may contribute negatively to patient outcomes. This review explores the schizophrenic 'Jekyll-and-Hyde' characteristics of catecholamines in critical illness, as they are both necessary for survival yet detrimental in excess. This article covers catecholamine physiology, the pleiotropic effects of catecholamines on various body systems and pathways, and potential alternatives for haemodynamic support and adrenergic modulation in the critically ill.

  18. Immobilized Catecholamine and Cocaine Effects on Contractility of Cardiac Muscle

    PubMed Central

    Venter, J. Craig; Ross, John; Dixon, Jack E.; Mayer, Steven E.; Kaplan, Nathan O.

    1973-01-01

    Isoproterenol, norepinephrine, and epinephrine covalently bound to glass beads exert a positive inotropic effect on isometrically contracting papillary muscles from cats. Immobilized isoproterenol maintains increases in force and velocity of contraction for more than 5 hr. 1 μM Cocaine potentiates the action of immobilized norepinephrine, isoproterenol, and epinephrine, but not of isoproterenol in solution. The data presented indicate that the effects of immobilized catecholamines are not due to their coming off the glass. The effects observed with cocaine and immobilized catecholamines are not altered by prior treatment of the muscle with reserpine. These results suggest that the major site of catecholamine action is on receptors located on the extended surface of myocardial cells and a post-junctional site for cocaine potentiation. Images PMID:4515619

  19. Blood and urine catecholamine concentrations after implantation of artificial heart.

    PubMed

    Stanley, T H; Kennard, L; Isern-Amaral, J; Olsen, D; Lunn, J

    1976-05-01

    Plasma and urine epinephrine and norepinephrine concentrations were measured before and after implantation of an artificial heart in 20 calves and before and after thoracotomy in 3 control calves. All animals had similar preoperative plasma and urine catecholamine concentrations. During the first 4 postoperative days, plasma and urine epinephrine and norepinephrine concentrations were markedly elevated in all animals. However, calves with an artificial heart had significantly higher concentrations than control calves. Thereafter, catecholamine levels in control animals returned to preoperative levels, whereas epinephrine concentrations in artificial heart recipients remained elevated for 2 weeks and norepinephrine concentrations remained elevated for over a month. Two artifical heart recipeints survived longer than 2 months and had normal plasma and urine catecholamine concentrations from day 32 until a few days before being put to death. Although the mechanism in unclear, these findings suggest that early artificial heart function is associated with a significant metabolic stress which slowly disappears or becomes tolerable after one month.

  20. [Catecholamine response to the Wingate test in untrained women].

    PubMed

    Vincent, Sophie; Gratas-Delamarche, Arlette; Berthon, Phanélie Marie; Zouhal, Hassane; Jacob, Christophe; Bentue-Ferrer, Danièle; Delamarche, Paul

    2003-10-01

    Supramaximal exercises are well known to induce a severe stress on the adrenal medulla and nervous sympathetic system. This stress induces increased plasma catecholamines concentrations. The responses of catecholamines to supramaximal exercises in women are still not well characterized and have been studied mostly in trained subjects. Hence the aim of the present study was to evaluate plasma catecholamine responses to a Wingate test in young and untrained women (n = 6) and men (n = 7). Venous plasma catecholamine concentrations were determined by HPLC, at rest, at the end of the warm-up and of the exercise, and during recovery (5, 10, 20, and 30 mn). Our results failed to show any significant difference in resting catecholamine concentrations ([A]p: 0.41 +/- 0.05 vs. 0.45 +/- 0.05 nmol. L-1; [NA]p: 3.28 +/- 0.68 vs. 2.58 +/- 0.26 nmol.L-1), kinetics, and maximal plasma catecholamine concentrations (Amax: 4.47 +/- 1.08 vs. 3.31 +/- 0.63 nmol.L-1; NAmax: 18.05 +/- 1.11 vs. 14.01 +/- 2.02 nmol.L-1) in response to the Wingate test between women and men, respectively. The Amax/NAmax ratio used as an index of adrenal medulla sensitivity to sympathetic input was also similar between genders. In conclusion, this study was able to demonstrate, in untrained subjects, that gender did not alder the sympatho-adrenergic response induced by a severe stress.

  1. Catecholamines: Mediator of the Hypermetabolic Response to Thermal Injury

    PubMed Central

    Wilmore, Douglas W.; Long, James M.; Mason, Arthur D.; Skreen, Robert W.; Pruitt, Basil A.

    1974-01-01

    Hypermetabolism characterizes the metabolic response to thermal injury and the extent of energy production is positively related to the rate of urinary catecholamine excretion. Alpha and beta adrenergic blockade decreased metabolism from 69.6 ± 5.3 Kcal/m2/hr to 57.4 ± 5.2 (p < 0.01), and infusion of 6 µgm epinephrine/minute in normal man significantly increased metabolic rate. Twenty noninfected burned adults with a mean burn size of 45% total body surface (range 7-84%) and four normal controls were studied in an environmental chamber at two or more temperatures between 19 and 33 C with vapor pressure constant at 11.88 mm Hg. All burn patients were hypermetabolic at all temperatures studied and their core and mean skin temperatures were significantly elevated above control values. Between 25 and 33 C ambient, metabolism was unchanged in controls and burns of less than 40% total body surface (48.9 ± 4.6 Kcal/m2/hr vs. 48.9 ± 4.5), but metabolic rate decreased in larger burns in the warmer environment (72.0 ± 1.9 vs. 65.8 ± 1.7, p < 0.001). At 21 C, metabolism and catecholamines increased, except in four nonsurvivors who became hypothermic with decreased catechol elaboration. Metabolic rate in ten patients with bacteremia was below predicted levels while catecholamines were markedly elevated suggesting interference with tissue uptake of the neurohormonal transmitters. Feeding burn patients or administering glucose and insulin improved nitrogen retention and altered substrate flow but did not significantly reduce urinary catecholamines or metabolic rate. Burned patients are internally warm, not externally cold, and catecholamines appear to mediate their increased heat production. Hypermetabolism may be modified by ambient temperature, infection, and pharmacologic means. Alterations in hypothalamic function due to injury, resulting in increased catecholamine elaboration, would explain the metabolic response to thermal injury. PMID:4412350

  2. RISK CHARACTERIZATION OF PERSISTENT NEUROTOXIC CONTAMINANTS

    EPA Science Inventory

    Neurotoxicity is an adverse change in structure or function of the central and/or peripheral nervous system following exposure to a chemical, physical, or biological agent. Thousands of chemicals have been estimated to have neurotoxic potential. Many persistent and bioaccumulat...

  3. RISK CHARACTERIZATION OF PERSISTENT NEUROTOXIC CONTAMINANTS

    EPA Science Inventory

    Neurotoxicity is an adverse change in structure or function of the central and/or peripheral nervous system following exposure to a chemical, physical, or biological agent. Thousands of chemicals have been estimated to have neurotoxic potential. Many persistent and bioaccumulat...

  4. Catecholamine toxicity in aromatic L-amino acid decarboxylase deficiency.

    PubMed

    Anselm, Irina A; Darras, Basil T

    2006-08-01

    This report presents the case of an adult male with aromatic L-amino acid decarboxylase deficiency who developed serious cardiac rhythm disturbances during treatment with intravenous dopamine and norepinephrine for severe hypotension. Three weeks later, he spontaneously developed atrial fibrillation while not receiving exogenous catecholamines. He died suddenly after several months. We presume cardiac arrhythmia was the most likely cause of his death. Patients with aromatic L-amino acid decarboxylase deficiency may be prone to cardiac arrhythmias at rest and also may be exceptionally sensitive to exogenous catecholamines. Therefore, close cardiac monitoring is indicated at baseline and during treatment with pressors.

  5. Effect of clonidine on adrenal medulla catecholamine levels in rats.

    PubMed

    Gaillard, G; Tran, M A; Rostin, M; Salvayre, R; Montastruc, J L

    1987-01-01

    The effects of clonidine on adrenal medulla catecholamines levels were studied in normotensive rats. Intraperitoneal injections (50,100 micrograms/kg) of clonidine caused a dose-dependent decrease in adrenaline content of the gland. This effect was suppressed by denervation of the adrenal medulla, i.e. unilateral section of splanchnic fibers performed 5 days before. These results demonstrate that clonidine decreases the catecholamine content of the adrenal medulla only through a central action. They suggest that the adrenal medulla is involved in the hypotensive effect of clonidine.

  6. Studies on the metabolism of catecholamines in the central nervous system of the mouse

    PubMed Central

    Ceasar, P.M.; Hague, P.; Sharman, D.F.; Werdinius, B.

    1974-01-01

    1 The distribution of the metabolites of noradrenaline, 1-(3,4-dihydroxyphenyl)ethane-1,2-diol (DOPEG) and 1-(4-hydroxy-3-methoxyphenyl)ethane-1,2-diol (MOPEG), in the brain of the mouse has been investigated. 2 The rate of disappearance of the metabolites after inhibition of the enzyme monoamine oxidase has been used to estimate their turnover rates in the mouse hypothalamus. It was concluded that the turnover of DOPEG was much faster than that of MOPEG. 3 When mice were treated with reserpine dissolved in 5% ascorbic acid solution there was an increase in the hypothalamic concentration of both MOPEG and DOPEG. However, similar increases in the concentrations of the two metabolites were seen when the animals were treated with 5% ascorbic acid solution alone. 4 The administration of tropolone, an inhibitor of the enzyme catechol-O-methyl transferase, resulted in an increase in the concentration of DOPEG. 5 Mice, exposed to a temperature of -15° C showed increased hypothalamic concentrations of both DOPEG and MOPEG. 6 The rates of formation in the mouse striatum of 3,4-dihydroxyphenylacetic acid (DOPAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA), acidic metabolites of dopamine, were compared with the turnover rate of dopamine, estimated from the rate at which this catecholamine disappears after treatment with α-methyl-p-tyrosine. It was concluded that the estimate of dopamine turnover obtained by this method is likely to be too large because of the compensatory feedback mechanism which is thought to play a role in the metabolism of dopamine in the brain. PMID:4141637

  7. Neurotoxicity

    MedlinePlus

    ... Strategy Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ... Resources Current Research Research Funded by NINDS Basic Neuroscience Clinical Research Translational Research Research at NINDS Focus ...

  8. Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity.

    PubMed

    Bai, F; Lau, S S; Monks, T J

    1999-12-01

    Direct injection of either 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) or 3,4-(+/-)-methylenedioxyamphetamine (MDA) into the brain fails to reproduce the serotonergic neurotoxicity seen following peripheral administration. The serotonergic neurotoxicity of MDA and MDMA therefore appears to be dependent upon the generation of a neurotoxic metabolite, or metabolites, the identity of which remains unclear. alpha-Methyldopamine (alpha-MeDA) is a major metabolite of both MDA and MDMA. We have shown that intracerebroventricular (icv) injection of 2,5-bis(glutathion-S-yl)-alpha-methyldopamine [2, 5-bis(glutathion-S-yl)-alpha-MeDA] causes decreases in serotonin concentrations in the striatum, cortex, and hippocampus, and neurobehavioral effects similar to those seen following MDA and MDMA administration. In contrast, although 5-(glutathion-S-yl)-alpha-methyldopamine [5-(glutathion-S-yl)-alpha-MeDA] and 5-(N-acetylcystein-S-yl)-alpha-methyldopamine [5-(N-acetylcystein-S-yl)-alpha-MeDA] produce neurobehavioral changes similar to those seen with MDA and MDMA, and acute changes in brain 5-HT and dopamine concentrations, neither conjugate caused long-term decreases in 5-HT concentrations. We now report that direct intrastriatal or intracortical administration of 5-(glutathion-S-yl)-alpha-MeDA (4 x 200 or 4 x 400 nmol), 5-(N-acetylcystein-S-yl)-alpha-MeDA (4 x 7 or 4 x 20 nmol), and 2, 5-bis(glutathion-S-yl)-alpha-MeDA (4 x 150 or 4 x 300 nmol) causes significant decreases in striatal and cortical 5-HT concentrations (7 days following the last injection). Interestingly, intrastriatal injection of 5-(glutathion-S-yl)-alpha-MeDA or 2, 5-bis(glutathion-S-yl)-alpha-MeDA, but not 5-(N-acetylcystein-S-yl)-alpha-methyldopamine, also caused decreases in 5-HT concentrations in the ipsilateral cortex. The same pattern of changes was seen when the conjugates were injected into the cortex. The effects of the thioether conjugates of alpha-MeDA were confined to 5-HT nerve terminal fields

  9. Methodological approach to the evaluation of neurotoxicity data and the classification of neurotoxic chemicals.

    PubMed

    Simonsen, L; Johnsen, H; Lund, S P; Matikainen, E; Midtgård, U; Wennberg, A

    1994-02-01

    This text is the result of the authors' involvement in a working group on criteria for the identification and classification of neurotoxic chemicals. (The work of the group does not necessarily represent the official stand of the affiliated institutes.) A definition of neurotoxicity and criteria for evaluating studies dealing with neurotoxicology are presented. The evaluation is a stepwise process that ends with assigning the chemicals to groups depending on the available evidence for neurotoxicity (ie, neurotoxic, probably neurotoxic, possibly neurotoxic, probably not neurotoxic, or not classifiable). Finally, the description of the potency of neurotoxic chemicals is briefly discussed. The model has been tested by evaluating selected research papers on the following 10 chemicals: manganese, aluminum, tetrahydrofuran, cyclohexanone, dichlorvos, trichloroethylene, formaldehyde, tri-ortho-cresyl phosphate, n-hexane, and vinyl chloride. There was sufficient evidence for classifying five of the ten chemicals (aluminum, manganese, n-hexane, trichloroethylene, tri-ortho-cresyl phosphate) as definitely neurotoxic to humans, and three were considered to be possibly neurotoxic to humans (dichlorvos, tetrahydrofuran, vinyl chloride). Cyclohexanone and formaldehyde were not classifiable according to the model.

  10. Neurophysiological studies on the relation between the structural properties and neurotoxicity of aliphatic hydrocarbon compounds in rats.

    PubMed Central

    Misumi, J; Nagano, M

    1984-01-01

    In order to determine the specific structural properties responsible for neurotoxic activity, the comparative neurotoxicity of n-hexane, methyl n-butyl ketone, 2,5-hexanedione, and their relatives was investigated in the peripheral nerves of rats. The maximum conduction velocity of motor and sensory fibres and the motor distal latency of the tail nerves of rats were periodically examined in animals receiving repeated subcutaneous injections of 11 aliphatic monoketone or diketone compounds and their relatives for prolonged periods. A study of the comparative neurotoxicity of n-hexane, methyl n-butyl ketone, and their metabolites showed that 2,5-hexanedione was the most actively neurotoxic. Furthermore, a study of other symmetrical diketones with different carbon numbers showed that 2,4-pentanedione, which is structurally similar to 2,5-hexanedione, possessed a different type of neurotoxic activity than 2,5-hexanedione. Regarding aliphatic monoketone compounds, acetone, 2-pentanone, 2-heptanone, and 2-octanone were confirmed non-neurotoxic for the peripheral nervous system. Evidence from some previous reports, however, suggested that 3-heptanone, 4-octanone, and 5-nonanone might produce neuropathies by being converted to 2,5-diketones under specific conditions. PMID:6093852

  11. Molecular Profiling: Catecholamine Modulation of Gene Expression in Enteropathogenic Bacteria

    USDA-ARS?s Scientific Manuscript database

    Investigations of the enteric pathogens Escherichia coli O157:H7, Salmonella enterica serovar Typhimurium and Vibrio parahaemolyticus have demonstrated that these bacteria can respond to the presence of catecholamines, including norepinephrine and/or epinephrine, in their environment by modulating g...

  12. Reduced catecholamine response to exercise in amenorrheic athletes

    USDA-ARS?s Scientific Manuscript database

    Studies have found an array of endocrine disturbances related to energy deprivation in women with functional hypothalamic amenorrhea. Purpose: We examined the catecholamine response to exercise in five eumenorrheic (EU) and five amenorrheic (AM) athletes, matched by age (mean T SEM: EU = 29.8 T 2.5 ...

  13. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  14. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  15. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  16. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  17. 21 CFR 862.1165 - Catecholamines (total) test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Catecholamines (total) test system. 862.1165 Section 862.1165 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test...

  18. Survey of the use of catecholamines by French physicians.

    PubMed

    Leone, Marc; Vallet, Benoit; Teboul, Jean-Louis; Mateo, Joachim; Bastien, Olivier; Martin, Claude

    2004-05-01

    The objective of the study was to perform a descriptive approach of the current use of catecholamines by French physicians. A questionnaire of 12 questions with 4 items established by a group of French intensivists. French physicians from 433 departments working in the following practicing areas: intensive care unit (ICU), emergency department, and pre-hospital setting. Responding physicians were asked about the catecholamine that they would select in various clinical settings. The response rate was 82%. Of the responding physicians, 277 (78%) worked in an ICU, 28 (8%) in an emergency department, and 21 (6%) in a pre-hospital setting. Dobutamine was chosen for patients with cardiogenic shock by 90% of the respondents. Norepinephrine was the first choice agent as vasopressor in patients with septic shock in 52% of the cases. Dopamine was selected in a clinical setting requiring an optimization of regional blood flow, as in the concept of high-risk surgical patients. Dopexamine was used as a second or third choice agent to improve regional blood flow and cardiac output. The indications of epinephrine for anaphylactic shock and cardio-circulatory arrest were obvious for more than 90% of responding physicians. A lack of standardization appears in the use of catecholamines by French physicians, particularly for improvement of regional circulation and management of high-risk surgical patients. Guidelines that define the place of each catecholamine in these settings are required to improve the quality of prescription.

  19. Kynurenine pathway inhibition reduces neurotoxicity of HIV-1-infected macrophages.

    PubMed

    Kerr, S J; Armati, P J; Pemberton, L A; Smythe, G; Tattam, B; Brew, B J

    1997-12-01

    The AIDS dementia complex (ADC) is a consequence of excessive immune activation driven at least in part by systemic HIV infection and probably brain infection. Quinolinic acid (QUIN) is a neurotoxic tryptophan metabolite produced by macrophages in response to stimulation with cytokines or infection with HIV-1. Consequently it has been implicated in ADC pathogenesis. However, macrophages infected with HIV-1 synthesize numerous neurotoxic substances. Therefore we conducted experiments using human fetal brain tissue to determine the relative importance of QUIN as a neurotoxin in ADC. Human macrophages were infected with HIV-1 in vitro using a viral isolate from a demented patient. 6-Chloro-D-tryptophan, an inhibitor of QUIN biosynthesis, was added to half the macrophage cultures to block formation of QUIN. Supernatants containing QUIN (SQpos) or in which QUIN biosynthesis had been inhibited (SQneg) were then added to human fetal brain aggregate cultures. Toxicity was evaluated using lactate dehydrogenase efflux, trypan blue exclusion, immunohistochemistry, image analysis, and electron microscopy. Each technique showed a reduction of toxicity in SQneg-treated cultures. These studies confirm the significance of QUIN as a neurotoxin in ADC and suggest that neuroprotective strategies may have a place in the treatment of this disease.

  20. Catecholamines and related o-diphenols in cockroach hemolymph and cuticle during sclerotization and melanization: comparative studies on the order Dictyoptera.

    PubMed

    Czapla, T H; Hopkins, T L; Kramer, K J

    1990-01-01

    Catecholamines and related o-diphenols extracted from the cuticle and hemolymph of adult cockroaches during sclerotization and pigmentation of the cuticle were analyzed by reverse phase HPLC with electrochemical detection. At ecdysis, dopamine (DA) o-conjugates predominated in the hemolymph of Periplaneta americana, P. australasiae, P. fuliginosa, P. brunnea, and Blatta orientalis (Blattidae); Blattella germanica (Blattellidae); and Gromphadorhina portentosa and Blaberus craniifer (Blaberidae). N-Acetyldopamine (NADA) conjugates were second in abundance in these species, but were major in the hemolymph of the other blaberoid species, Leucophaea maderae and Nauphoeta cinerea. After ecdysis NADA became the major hemolymph catecholamine in all species as DA decreased rapidly. N-beta-Alanyldopamine (NBAD) concentrations in the hemolymph remained low in all species, although NBAD and its metabolite, N-beta-alanylnorepinephrine (NBANE), were generally the major catecholamines in tanning cuticle. Catechol (1,2-dihydroxybenzene) occurred mainly as a conjugate(s) at high levels in the hemolymph of nymphs and adults of all blattid species. Only trace amounts were detected in B. germanica and Cryptocercus punctulatus (Cryptocercidae), and none was found in any of the blaberoid species. High concentrations of NBANE and NBAD accumulated in tanning cuticle of B. germanica, G. portentosa, and all blattid species, whereas NADA and DA predominated in cuticle from the other blaberoid species, particularly L. maderae and N. cinerea. However, cockroaches as a group appear to utilize both the N-acetyl and N-beta-alanyl catecholamines for stabilization of the exoskeleton. The Blattidae differed most from the other families in having considerably higher concentrations of catecholamines in hemolymph and cuticle, as well as the large amounts of catechol conjugates in the hemolymph.

  1. Inverse relationship between cardiac accumulation of meta-(/sup 131/I)iodobenzylguanidine (I-131 MIBG) and circulation catecholamines in suspected pheochromocytoma

    SciTech Connect

    Nakajo, M.; Shapiro, B.; Glowniak, J.; Sisson, J.C.; Beierwaltes, W.H.

    1983-12-01

    Heart intensity (HI) in the 24- and 48-hr images of meta-(/sup 131/I)iodobenzylguanidine (I-131 MIBG), a pheochromocytoma-seeking guanethidine analog, were compared with concentrations of plasma and urinary catecholamines and their metabolites in nonpheochromocytoma and pheochromocytoma patients. HI was inversely related to plasma concentrations and urinary excretion rates of the hormones. Plasma norepinephrine had the highest inverse correlation with HI (r = -0.73 at 24 hr, -0.63 at 48 hr) and urinary metanephrine the lowest (r = -0.23 at 24 hr, -0.28 at 48 hr). A similar relationship was observed in the intensity of salivary-gland visualization, but with less marked variations. HI was much higher in ninpheochromocytoma patients than in pheochromocytoma patients. HI in an I-131 MIGB image provides useful information in the diagnosis of pheochromocytoma, and may provide a tool for the study of the influence of catecholamines on the heart.

  2. Biomarkers of adult and developmental neurotoxicity

    SciTech Connect

    Slikker, William

    2005-08-07

    Neurotoxicity may be defined as any adverse effect on the structure or function of the central and/or peripheral nervous system by a biological, chemical, or physical agent. A multidisciplinary approach is necessary to assess adult and developmental neurotoxicity due to the complex and diverse functions of the nervous system. The overall strategy for understanding developmental neurotoxicity is based on two assumptions: (1) significant differences in the adult versus the developing nervous system susceptibility to neurotoxicity exist and they are often developmental stage dependent; (2) a multidisciplinary approach using neurobiological, including gene expression assays, neurophysiological, neuropathological, and behavioral function is necessary for a precise assessment of neurotoxicity. Application of genomic approaches to developmental studies must use the same criteria for evaluating microarray studies as those in adults including consideration of reproducibility, statistical analysis, homogenous cell populations, and confirmation with non-array methods. A study using amphetamine to induce neurotoxicity supports the following: (1) gene expression data can help define neurotoxic mechanism(s) (2) gene expression changes can be useful biomarkers of effect, and (3) the site-selective nature of gene expression in the nervous system may mandate assessment of selective cell populations.

  3. Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations

    PubMed Central

    Bohár, Zsuzsanna; Toldi, József; Fülöp, Ferenc; Vécsei, László

    2015-01-01

    Kynurenines are the products of tryptophan metabolism. Among them, kynurenine and kynurenic acid are generally thought to have neuroprotective properties, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid are considered neurotoxic. They participate in immunoregulation and inflammation and possess pro- or anti-excitotoxic properties, and their involvement in oxidative stress has also been suggested. Consequently, it is not surprising that kynurenines have been closely related to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. More information about the less-known metabolites, picolinic and cinnabarinic acid, evaluation of new receptorial targets, such as aryl-hydrocarbon receptors, and intensive research on the field of the immunomodulatory function of kynurenines delineated the high importance of this pathway in general homeostasis. Emerging knowledge about the kynurenine pathway provides new target points for the development of therapeutical solutions against neurodegenerative diseases. PMID:25938971

  4. Neurotoxicity of manganese oxide nanomaterials

    NASA Astrophysics Data System (ADS)

    Stefanescu, Diana M.; Khoshnan, Ali; Patterson, Paul H.; Hering, Janet G.

    2009-11-01

    Manganese (Mn) toxicity in humans has been observed as manganism, a disease that resembles Parkinson's disease. The mechanism of Mn toxicity and the chemical forms that may be responsible for its neurotoxicity are not well understood. We examined the toxicity of Mn oxide nanomaterials in a neuronal precursor cell model, using the MTS assay to evaluate mitochondrial function in living cells and the LDH assay to quantify the release of the enzyme lactate dehydrogenase as a result of damage to the cell membrane. Both assays show that the toxicity of Mn is dependent on the type of Mn oxide nanomaterial and its concentration as well as on the state of cell differentiation. Following exposure to Mn oxide nanomaterials, reactive oxygen species (ROS) are generated, and flow cytometry experiments suggest that cell death occurred through apoptosis. During exposure to Mn oxide nanomaterials, increased levels of the transcription factor NF-κB (which mediates the cellular inflammatory response) were observed.

  5. Articaine and neurotoxicity - a review.

    PubMed

    Hopman, A J G; Baart, J A; Brand, H S

    2017-10-03

    The biochemical composition of articaine differs from other amide anaesthetics. The lipophilic part of articaine consists of a thiophene ring, whereas other amide anaesthetics contain a benzene ring. When used correctly, local anaesthetics are remarkably safe. However, all local anaesthetics are potentially neurotoxic. In rare cases a prolonged abnormal perception/sensation may be present after the expected duration of action (paraesthesia). In several countries retrospective studies have been conducted that examined the incidence of persistent paraesthesia after the use of local anaesthetics. In most studies the number of paraesthesia cases after the use of articaine was higher than the market share of this anaesthetic. In animal studies and in cell culture experiments, however, articaine did not have a higher toxicity compared to other amide anaesthetics. Further studies of the cause of paraesthesia after administration of local anaesthetics seem to be warranted.

  6. Neurotoxic Thioether Adducts of 3,4-Methylenedioxymethamphetamine Identified in Human Urine After Ecstasy IngestionS⃞

    PubMed Central

    Perfetti, Ximena; O'Mathúna, Brian; Pizarro, Nieves; Cuyàs, Elisabet; Khymenets, Olha; Almeida, Bruno; Pellegrini, Manuela; Pichini, Simona; Lau, Serrine S.; Monks, Terrence J.; Farré, Magí; Pascual, Jose Antonio; Joglar, Jesús; de la Torre, Rafael

    2009-01-01

    3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a widely misused synthetic amphetamine derivative and a serotonergic neurotoxicant in animal models and possibly humans. The underlying mechanism of neurotoxicity involves the formation of reactive oxygen species although their source remains unclear. It has been postulated that MDMA-induced neurotoxicity is mediated via the formation of bioreactive metabolites. In particular, the primary catechol metabolites, 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA), subsequently cause the formation of glutathione and N-acetylcysteine conjugates, which retain the ability to redox cycle and are serotonergic neurotoxicants in rats. Although the presence of such metabolites has been recently demonstrated in rat brain microdialysate, their formation in humans has not been reported. The present study describes the detection of 5-(N-acetylcystein-S-yl)-3,4-dihydroxymethamphetamine (N-Ac-5-Cys-HHMA) and 5-(N-acetylcystein-S-yl)-3,4-dihydroxyamphetamine (N-Ac-5-Cys-HHA) in human urine of 15 recreational users of MDMA (1.5 mg/kg) in a controlled setting. The results reveal that in the first 4 h after MDMA ingestion ∼0.002% of the administered dose was recovered as thioether adducts. Genetic polymorphisms in CYP2D6 and catechol-O-methyltransferase expression, the combination of which are major determinants of steady-state levels of HHMA and 4-hydroxy-3-methoxyamphetamine, probably explain the interindividual variability seen in the recovery of N-Ac-5-Cys-HHMA and N-Ac-5-Cys-HHA. In summary, the formation of neurotoxic thioether adducts of MDMA has been demonstrated for the first time in humans. The findings lend weight to the hypothesis that the bioactivation of MDMA to neurotoxic metabolites is a relevant pathway to neurotoxicity in humans. PMID:19349378

  7. A vicious cycle of acute catecholamine cardiomyopathy and circulatory collapse secondary to pheochromocytoma.

    PubMed

    Otusanya, Olufisayo; Goraya, Harmeen; Iyer, Priyanka; Landi, Kristen; Tibb, Amit; Msaouel, Pavlos

    2015-10-01

    Acute catecholamine cardiomyopathy is an uncommon, life-threatening manifestation of pheochromocytoma. The massive release of catecholamines from the adrenal medulla and their toxic effects on the coronary vessels and the cardiac myocytes play a significant role in the pathogenesis of cardiomyopathy in patients with pheochromocytoma. Severe manifestations, such as acute catecholamine cardiomyopathy, may be the initial presentation, especially in unsuspected and untreated pheochromocytoma cases. The clinical course of catecholamine-induced cardiomyopathy is unpredictable as patients may rapidly deteriorate into circulatory collapse and multisystem crisis. We report a case of a 25-year-old man who presented with catecholamine-induced cardiomyopathy.

  8. Age at Diagnosis of Pheochromocytoma Differs According to Catecholamine Phenotype and Tumor Location

    PubMed Central

    Timmers, Henri J.; Lenders, Jacques W.M.; Bornstein, Stefan R.; Tiebel, Oliver; Mannelli, Massimo; King, Kathryn S.; Vocke, Cathy D.; Linehan, W. Marston; Bratslavsky, Gennady; Pacak, Karel

    2011-01-01

    Context: Pheochromocytomas and paragangliomas (PPGLs) are diagnosed earlier in patients with hereditary than sporadic disease. Whether other factors influence age at diagnosis is unclear. Objective: We examined ages at which PPGLs were diagnosed according to different catecholamine phenotypes and locations of tumors. Design & Setting: Retrospective multicenter study. Patients: Patients with PPGLs included 172 with and 183 without identified germline mutations or hereditary syndromes. Biochemical Measurements: Differences in plasma concentrations of metanephrine, a metabolite of epinephrine, were used to distinguish epinephrine-producing tumors from those lacking epinephrine production. Results: Patients with epinephrine-producing tumors were diagnosed 11 yr later (P < 0.001) than those with tumors lacking appreciable epinephrine production. Among patients without evidence of a hereditary condition, those with and without epinephrine-producing tumors had respective mean ± se ages of 50 ± 2 and 42 ± 2 yr (P < 0.001) at diagnosis. Patients with multiple endocrine neoplasia type 2 and neurofibromatosis type 1, all with epinephrine-producing tumors, were similarly diagnosed with disease at a later age than patients with tumors that lacked appreciable epinephrine production secondary to mutations of von Hippel-Lindau and succinate dehydrogenase genes (40 ± 2 vs. 31 ± 1 yr, P < 0.001). Among the latter patients, those with multifocal tumors were diagnosed earlier than those with solitary tumors (19 ± 3 vs. 34 ± 2 yr, P < 0.001). Conclusions: The variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of PPGLs from different chromaffin progenitor cells with variable susceptibility to disease causing mutations. Different optimal age cut-offs for mutation testing are indicated for patients with and without epinephrine-producing tumors (44–49 vs. 30–35 yr, respectively). PMID:21147885

  9. Delayed treatment of hemoglobin neurotoxicity.

    PubMed

    Regan, Raymond F; Rogers, Bret

    2003-01-01

    Hemoglobin is an oxidative neurotoxin that may contribute to cell injury after CNS trauma and hemorrhagic stroke. Prior studies have demonstrated that concomitant treatment with iron-chelating antioxidants prevents its neurotoxicity. However, the efficacy of these agents when applied hours after hemoglobin has not been determined, and is the subject of the present investigation. Consistent with prior observations, an increase in reactive oxygen species generation, detected by 2',7'-dichlorofluorescin oxidation, was observed when mixed neuronal/astrocyte cultures prepared from mouse cortex were exposed to hemoglobin alone. However, this oxidative stress developed slowly. A significant increase in the dichlorofluorescein signal compared with control, untreated cultures was not observed until four hours after addition of hemoglobin, and was followed by loss of membrane integrity and propidium iodide staining. Treating cultures with the 21-aminosteroid U74500A or the ferric iron chelator deferoxamine four hours after initiating hemoglobin treatment markedly attenuated reactive oxygen species production within 2 h. Continuous exposure to 5 micro M hemoglobin for 24 h resulted in death of about three-quarters of neurons, without injuring astrocytes. Most neuronal loss was prevented by concomitant treatment with U74500A; its effect was not significantly attenuated if treatment was delayed for 2-4 h, and it still prevented over half of neuronal death if treatment was delayed for 8 h. Similar neuroprotection was produced by delayed treatment with deferoxamine or the lipid-soluble iron chelator phenanthroline. None of these agents had any effect on neuronal death when added to cultures 12 h after hemoglobin. These results suggest that hemoglobin is a potent but slowly-acting neurotoxin. The delayed onset of hemoglobin neurotoxicity may make it an attractive target for therapeutic intervention.

  10. Reversible Lithium Neurotoxicity: Review of the Literature

    PubMed Central

    Netto, Ivan

    2012-01-01

    Objective: Lithium neurotoxicity may be reversible or irreversible. Reversible lithium neurotoxicity has been defined as cases of lithium neurotoxicity in which patients recovered without any permanent neurologic sequelae, even after 2 months of an episode of lithium toxicity. Cases of reversible lithium neurotoxicity differ in clinical presentation from those of irreversible lithium neurotoxicity and have important implications in clinical practice. This review aims to study the clinical presentation of cases of reversible lithium neurotoxicity. Data Sources: A comprehensive electronic search was conducted in the following databases: MEDLINE (PubMed), 1950 to November 2010; PsycINFO, 1967 to November 2010; and SCOPUS (EMBASE), 1950 to November 2010. MEDLINE and PsycINFO were searched by using the OvidSP interface. Study Selection: A combination of the following search terms was used: lithium AND adverse effects AND central nervous system OR neurologic manifestation. Publications cited include articles concerned with reversible lithium neurotoxicity. Data Extraction: The age, sex, clinical features, diagnostic categories, lithium doses, serum lithium levels, precipitating factors, and preventive measures of 52 cases of reversible lithium neurotoxicity were extracted. Data Synthesis: Among the 52 cases of reversible lithium neurotoxicity, patients ranged in age from 10 to 80 years and a greater number were female (P = .008). Most patients had affective disorders, schizoaffective disorders, and/or depression (P < .001) and presented mainly with acute organic brain syndrome. In most cases, the therapeutic serum lithium levels were less than or equal to 1.5 mEq/L (P < .001), and dosage regimens were less than 2,000 mg/day. Specific drug combinations with lithium, underlying brain pathology, abnormal tissue levels, specific diagnostic categories, and elderly populations were some of the precipitating factors reported for reversible lithium neurotoxicity. The

  11. Strategies for enhancing catecholamine-mediated neurotransmission

    NASA Technical Reports Server (NTRS)

    Wurtman, Richard J.

    1992-01-01

    Major findings made during this project period included the following observations: changes in tyrosine availability do affect brain dopamine release, as assessed by in vivo microdialysis, but that neuronal feedback mechanisms limit the durations of this effect except when dopaminergic neurotransmission has been deficient; the circulating hormone TRH markedly stimulates brain dopamine release, an effect probably mediated by its diketopiperazine metabolite; the amount of circulating L-dopa which enters the brain is both enhanced by carbohydrate consumption and suppressed by protein intake (both nutritional effects can be damaging, inasmuch as a sudden rush of L-dopa into the brain can facilitate dyskinesias, while the inhibition of brain L-dopa uptake by proteins suppresses its conversion to brain dopamine; an appropriate mixture of dietary proteins and carbohydrates can obviate both effects); serotonin release from superfused hypothalamic slices is a linear function of available tryptophan levels throughout the normal dynamic range; the daily rhythm in plasma melatonin levels is abnormal both in the sudden infant death syndrome and in women with secondary amenorrhea; tyrosine can potentiate the anorectic effects of widely-used sympathomimetic drugs; newly-described COMT inhibitors can enhance brain dopamine release in vivo; and a cell culture system, based on Y-79 (retinoblast) cells, exists in which melatonin reliably suppresses dopamine release.

  12. EVALUATION OF POTENTIAL DEVELOPMENTAL NEUROTOXICITY OF ORGANOTINS.

    EPA Science Inventory

    Organotins, including monomethyltin (MMT), dimethyltin (DMT), and dibutyltin (DBT), are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for developmental neurotoxic effects were raised by published findi...

  13. ASSESSING HIPPOCAMPAL CHANGES INDICATIVE OF NEUROTOXIC EFFECTS.

    EPA Science Inventory

    Subtle changes in cognitive function are often the earliest indication of neurotoxic effects in humans. The hippocampus is a large forebrain structure subserving specific kinds of information encoding and consolidation in humans and other animals. Because of it laminar structur...

  14. EVALUATION OF POTENTIAL DEVELOPMENTAL NEUROTOXICITY OF ORGANOTINS.

    EPA Science Inventory

    Organotins, including monomethyltin (MMT), dimethyltin (DMT), and dibutyltin (DBT), are widely used as heat stabilizers in PVC and CPVC piping, which results in their presence in drinking water supplies. Concern for developmental neurotoxic effects were raised by published findi...

  15. ASSESSING HIPPOCAMPAL CHANGES INDICATIVE OF NEUROTOXIC EFFECTS.

    EPA Science Inventory

    Subtle changes in cognitive function are often the earliest indication of neurotoxic effects in humans. The hippocampus is a large forebrain structure subserving specific kinds of information encoding and consolidation in humans and other animals. Because of it laminar structur...

  16. Hypercalcemic effect of catecholamines and its prevention by thyrocalcitonin.

    PubMed

    Hsu, W H; Cooper, C W

    1975-12-18

    Earlier work by others has shown that the catecholamines, epinephrine and isoproterenol, can raise blood calcium levels in parathyroidectomized but not intact rats, and can restrict the hypocalcemic effect of injected thyrocalcitonin (TCT). The present findings support this earlier work, further showing that such catecholamines can produce hypercalcemia in rats after removal of the thyroid gland by acute thyroparathyroidectomy (TPTX) and indicating that these drugs may raise blood calcium by mobilizing calcium from bone. Rats were fasted overnight, subjected to TPTX and concurrently injected with adrenergic agonist or antagonist drugs alone or in combination. Epinephrine, isoproterenol, and the beta-2 adrenergic agonist, salbutamol, in doses greater than or equal to 1 mg/kg raised blood calcium from low normal levels (approximately 9-10 mg/100 ml) by 1.5 to 2 mg/100 ml (p less than 0.01). Hypercalcemia was apparent by 1 hour after injection and lasted for 1-4 hours. The extent of Ca elevation was dose-related. Pretreatment of rats with the alpha-adrenergic antagonist, phenoxybenzamine, enhanced the effect of epinephrine while pretreatment with the beta-antagonist, propranolol, reduced the effect of isoproterenol. The more selective beta-2 antagonist, butoxamine, but not the beta-1 antagonist, practolol, also reduced the hypercalcemic effect of isoproterenol in TPTX rats. These results suggest that catecholamine-induced hypercalcemia in TPTX rats is mediated by beta-2 adrenergic receptors. Related studies using rats prelabeled with 45Ca further suggest that the catecholamines, like parathyroid hormone, may act to raise blood calcium by mobilizing calcium from bone. The fact that these catecholamines could induce marked hypercalcemia in acutely TPTX rats but not in intact rats indicated that endogenous TCT protects the thyroid intact rat against hypercalcemia. The present findings support this idea in showing that isoproterenol and salbutamol raised levels of

  17. Plasma catecholamine metabolites in schizophrenics: evidence for the two-subtype concept.

    PubMed

    Chang, W H; Chen, T Y; Lin, S K; Lung, F W; Lin, W L; Hu, W H; Yeh, E K

    1990-03-01

    Plasma homovanillic acid (pHVA) and plasma methoxyhydroxyphenyl glycol (pMHPG), as well as plasma haloperidol, were measured in 33 schizophrenic patients before and during 6 weeks of haloperidol treatment. Good responders had higher baseline pHVA values compared with poor responders (17.4 +/- 8.8 ng/ml, n = 22 versus 11.4 +/- 5.0 ng/ml, n = 11, p less than 0.05). A higher than 15 ng/ml pretreatment pHVA level was associated with a more consistent clinical response to the subsequent treatment. Differential pHVA changes during treatment were also found between good and poor responders. Within the good responder group, a significant decline in pHVA over time was found. By contrast, pHVA showed a transient increase in the poor responder group. Plasma MHPG changes showed a similar pattern during treatment in good responders, although no significant differences in baseline values were found between the good (n = 13) and poor (n = 9) responders, and pMHPG showed no change during treatment in poor responders. Significant correlations between baseline pHVA and pMHPG values were found in 22 patients. Good responders and poor responders did not differ significantly in terms of age, duration of illness, severity of presenting symptoms, haloperidol dose, or plasma drug concentration. Two hypothetical subtypes of schizophrenia and both dopamine and norepinephrine systems involved in schizophrenic psychopathology are proposed.

  18. Cocaine treatment increases expression of a 40 kDa catecholamine-regulated protein in discrete brain regions.

    PubMed

    Sharan, Niki; Chong, Victor Z; Nair, Venugopalan D; Mishra, Ram K; Hayes, Robert J; Gardner, Eliot L

    2003-01-01

    Previous reports from our laboratory have described brain-specific catecholamine-regulated proteins, which bind dopamine and related catecholamines. Evidence from the molecular cloning of a 40 kDa catecholamine-regulated protein (CRP40) revealed that CRP40 is dopamine-inducible and has properties similar to those of the 70 kDa heat shock protein (HSP70) family. The present study investigates the effects of acute and chronic cocaine treatment on CRP40 expression in the striatum, nucleus accumbens, prefrontal cortex, and medulla. Acute treatment with cocaine increased CRP40 expression in the nucleus accumbens and striatum, whereas chronic treatment with cocaine increased CRP40 expression in the nucleus accumbens only. Neither of these treatments affected CRP40 levels in the prefrontal cortex or medulla. In addition, pretreatment with the spin-trapping agent alpha-phenyl-tert-butylnitrone did not attenuate cocaine-induced expression of CRP40, suggesting that the observed increases in CRP40 levels were not caused by free radicals. On the other hand, pretreatment with anisomycin, a protein synthesis inhibitor, blocked the cocaine-induced expression of CRP40. Thus, protein synthesis may be involved in the observed CRP40 level increases. Furthermore, neither acute nor chronic cocaine treatment affected levels of inducible or constitutively expressed HSP70, which indicates a specificity of cocaine's effects on CRP40. Since cocaine has been shown to increase extracellular dopamine levels, these findings suggest that increased expression of CRP40 is associated with high extracellular levels of dopamine (or its metabolites). Elevated levels of CRP40 could play a protective role for dopamine neurons in response to increased oxidative stress that has been shown to be induced by cocaine and that can lead to apoptosis and neurodegeneration.

  19. Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson's disease and other synucleinopathies.

    PubMed

    Goldstein, David S; Holmes, Courtney; Sharabi, Yehonatan

    2012-06-01

    Central catecholamine deficiency characterizes α-synucleinopathies such as Parkinson's disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson's disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects-108 synucleinopathy patients (34 Parkinson's disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson's disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86 ± 0.09 (SEM), 1.00 ± 0.09, 1.32 ± 0.12 nmol/l] than controls (2.15 ± 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 ± 0.44, 7.75 ± 0.42, 5.82 ± 0.65 nmol/l) than controls (11.0 ± 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson's disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson's disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson's disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid

  20. Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson’s disease and other synucleinopathies

    PubMed Central

    Holmes, Courtney; Sharabi, Yehonatan

    2012-01-01

    Central catecholamine deficiency characterizes α-synucleinopathies such as Parkinson’s disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson’s disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects—108 synucleinopathy patients (34 Parkinson’s disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson’s disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid [0.86 ± 0.09 (SEM), 1.00 ± 0.09, 1.32 ± 0.12 nmol/l] than controls (2.15 ± 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 ± 0.44, 7.75 ± 0.42, 5.82 ± 0.65 nmol/l) than controls (11.0 ± 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson’s disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson’s disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson’s disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid

  1. Spectrophotometric determination of some catecholamine drugs using sodium bismuthate.

    PubMed

    Sorouraddin, M H; Manzoori, J L; Kargarzadeh, E; Haji Shabani, A M

    1998-12-01

    A novel spectrophotometric method is described for the determination of epinephrine (EP) and norepinephrine (NE). The method is based on the development of a red colour with sodium bismuthate, as a sensitive chromogenic reagent, in aqueous medium at pH 3. Oxidation of these catecholamines produces aminochrome derivatives which can be measured spectrophotometrically at 486.0 nm. Calibration graphs are linear in the range 4.8-800 (micromol l(-1)) for epinephrine bitartarate and 4.8-600 (micromol l(-1)) for norepinephrine bitartarate with detection limits of 0.26 (micromol l(-1)) and 2.46 (micromol l(-1)) for epinephrine and norepinephrine bitartarate salts, respectively. The method has successfully been applied to determination of these catecholamines in pharmaceutical preparations.

  2. Microfluorometric Detection of Catecholamines with Multiphoton-Excited Fluorescence

    NASA Astrophysics Data System (ADS)

    Balaji, J.; Reddy, Chandra S.; Kaushalya, S. K.; Maiti, Sudipta

    2004-04-01

    We demonstrate sensitive spatially resolved detection of physiological chromophores that emit in the ultraviolet (less than 330 nm). An atypical laser source (a visible wavelength femtosecond optical parametric oscillator), and an unconventional collection geometry (a lensless detector that detects the forward-emitted fluorescence) enable this detection. We report the excitation spectra of the catecholamines dopamine and norepinephrine, together with near-UV emitters serotonin and tryptophan, in the range of 550-595 nm. We estimate the molecular two-photon action cross section of dopamine, norepinephrine, and serotonin to be 1.2 mGM (1 GM, or Goppert Mayor, is equal to 10^-58 m^4 s^-1 photon^-1), 2 mGM, and 43 mGM, respectively, at 560 nm. The sensitivity achieved by this method holds promise for the microscopic imaging of vesicular catecholamines in live cells.

  3. Predictors of plasma and urinary catecholamine levels in normotensive and hypertensive men and women.

    PubMed

    Saxena, A R; Chamarthi, B; Williams, G H; Hopkins, P N; Seely, E W

    2014-05-01

    Age, sex, hypertension and dietary sodium are proposed to affect plasma and urinary catecholamines. Yet no prior study has examined the simultaneous effects of these factors within the same study population. So results may have been confounded by factors not determined. We investigate, for the first time, the impact of simultaneously determined predictors of plasma and urinary catecholamines and the relationship of catecholamines with the diagnosis of hypertension. Hypertensive and normotensive subjects (n=308) were studied off antihypertensives in liberal and low sodium balance. 24 h urinary catecholamines (norepinephrine and epinephrine) were measured. Plasma catecholamines were measured supine after overnight fast. Repeated measures multivariate linear regression models examined the effect of sex, race, age, body mass index (BMI), dietary salt (liberal salt vs low salt), hypertension status and mean arterial pressure (MAP) on plasma and urinary catecholamines. Logistic regression determined the relationship of catecholamines with diagnosis of hypertension. Dietary sodium restriction and increasing age predicted increased plasma and urinary norepinephrine, with sodium restriction having the greatest effect. Female sex predicted lower urinary and plasma epinephrine. Neither plasma nor urinary catecholamines predicted the diagnosis of hypertension. In summary, specific demographic factors variably impact catecholamines and should be considered when assessing catecholamines in research and clinical settings.

  4. Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin.

    PubMed

    Mahata, Manjula; Zhang, Kuizing; Gayen, Jiaur R; Nandi, Suvobroto; Brar, Bhawanjit K; Ghosh, Sajalendu; Mahapatra, Nitish R; Taupenot, Laurent; O'Connor, Daniel T; Mahata, Sushil K

    2011-07-01

    Pituitary adenylyl cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) augment the biosynthesis of tyrosine hydroxylase (TH). We tested whether secretin belonging to the glucagon/PACAP/VIP superfamily would increase transcription of the tyrosine hydroxylase (Th) gene and modulate catecholamine secretion. Secretin activated transcription of the endogenous Th gene and its transfected promoter (EC(50) ∼4.6 nM) in pheochromocytoma (PC12) cells. This was abolished by pre-treatment with a secretin receptor (SCTR) antagonist and by inhibition of protein kinase A (PKA), mitogen-activated protein kinase, or CREB (cAMP response element-binding protein). In agreement, secretin increased PKA activity and induced phosphorylation of CREB and binding to Th CRE, suggesting secretin signaling to transcription via a PKA-CREB pathway. Secretin stimulated catecholamine secretion (EC(50) ∼3.5 μM) from PC12 cells, but this was inhibited by pre-treatment with VIP-preferring receptor (VPAC1)/PACAP-preferring receptor (PAC1) antagonists. Secretin-evoked secretion occurred without extracellular Ca(2+) and was abolished by intracellular Ca(2+) chelation. Secretin augmented phospholipase C (PLC) activity and increased inositol-1,4,5-triphosphate (IP(3)) levels in PC12 cells; PLC-β inhibition blocked secretin-induced catecholamine secretion, indicating the participation of intracellular Ca(2+) from a phospholipase pathway in secretion. Like PACAP, secretin evoked long-lasting catecholamine secretion, even after only a transient exposure. Thus, transcription is triggered by nanomolar concentrations of the peptide through SCTR, with signaling along the cAMP-PKA and extracellular-signal-regulated kinase 1/2 pathways and through CREB. By contrast, secretion is triggered only by micromolar concentrations of peptide through PAC1/VPAC receptors and by utilizing a PLC/intracellular Ca(2+) pathway.

  5. Urinary catecholamine levels in children with and without dental caries.

    PubMed

    Vanderas, A P; Manetas, C; Papagiannoulis, L

    1995-10-01

    Urinary catecholamines have been used to measure emotionally stressful states which may affect the development of dental caries. This study investigates the hypothesis that children with and without dental caries do not differ significantly in the mean values of urinary catecholamines such as epinephrine, norepinephrine, and dopamine. As a test of this hypothesis, 314 children, males and females, aged from 6 to 8 years, were included in the study. Dental caries were recorded clinically and radiographically, and oral hygiene was evaluated by the recording of dental plaque. A 24-hour urine sample was collected for each subject, and a representative sample (25 mL) was analyzed by the HPLC technique to assay the catecholamine content. Socioeconomic factors such as parental age, education, and profession were recorded by a questionnaire distributed to the parents. Of the examined children, 38 (14 males and 24 females) were free of dental caries and constituted the case group. Two control groups, A and B, of 38 children each (14 males and 24 females) with dental caries were matched by age and gender. Differences in the quantitative and qualitative data were tested by the paired t test and the X2-test, respectively, while a regression analysis was applied to measure the effects of norepinephrine and dopamine on epinephrine. The logistic multiple-regression analysis was used to test, in the entire population, the impact of catecholamines and other related factors on the probability of subjects' developing dental caries. The 95% probability was used. The results showed statistically significant differences in epinephrine values between the case group and control groups A and B. The data suggest, therefore, that children with emotionally stressful states have higher probability of developing dental caries.

  6. Chronic hyperoxic effects on cat carotid body catecholamines and structure.

    PubMed

    Mokashi, A; Di Guilio, C; Morelli, L; Lahiri, S

    1994-06-01

    To account for the loss of O2 chemoreception in the cat carotid body during chronic hyperoxia, we studied the putative neurotransmitter correlates. Also, we studied the structural aspect of the carotid body tissues. We found that catecholamine concentrations increased and that the densecored vesicles in the glomus cells were not depleted, indicating that a lack of transmitters was not the cause for the loss of O2 chemoreception.

  7. Volatile Metabolites

    PubMed Central

    Rowan, Daryl D.

    2011-01-01

    Volatile organic compounds (volatiles) comprise a chemically diverse class of low molecular weight organic compounds having an appreciable vapor pressure under ambient conditions. Volatiles produced by plants attract pollinators and seed dispersers, and provide defense against pests and pathogens. For insects, volatiles may act as pheromones directing social behavior or as cues for finding hosts or prey. For humans, volatiles are important as flavorants and as possible disease biomarkers. The marine environment is also a major source of halogenated and sulfur-containing volatiles which participate in the global cycling of these elements. While volatile analysis commonly measures a rather restricted set of analytes, the diverse and extreme physical properties of volatiles provide unique analytical challenges. Volatiles constitute only a small proportion of the total number of metabolites produced by living organisms, however, because of their roles as signaling molecules (semiochemicals) both within and between organisms, accurately measuring and determining the roles of these compounds is crucial to an integrated understanding of living systems. This review summarizes recent developments in volatile research from a metabolomics perspective with a focus on the role of recent technical innovation in developing new areas of volatile research and expanding the range of ecological interactions which may be mediated by volatile organic metabolites. PMID:24957243

  8. Copper deficiency in neonatal mice alters brain catecholamine levels

    SciTech Connect

    Bailey, W.R.; Prohaska, J.R. )

    1991-03-15

    Copper (Cu) deficiency was investigated in Swiss albino mice to develop a model that alters brain catecholamine metabolism without serious growth impairment. Cu deficiency was induced by feeding a diet low in Cu to dams beginning either 7 days (d) prior, 4d prior, 4d after, or on the day of parturition. All 4-week-old male Cu-deficient ({minus}Cu) offspring were anemic and exhibited biochemical characteristics of Cu deficiency when compared to their respective +Cu control mice. However, the best model, which resulted in altered catecholamine metabolism characterized by elevation of dopamine (DA) and depression in norepinephrine (NE) in brain, heart, and spleen, was when treatment began 4d prior to birth. Body and brain weight were not altered. However, levels of Cu in brain and liver of {minus}Cu mice were markedly reduced to 21% and 31% of those measured in +Cu controls, respectively. Furthermore, brain NE and DA concentrations of {minus}Cu mice were 72% and 132% of those quantified in +Cu offspring, respectively. A plausible explanation is that dietary Cu deficiency results in lower activity of brain dopamine-{beta}-monooxygenase, the Cu dependent enzyme that catalyzes conversion of DA to NE. It is not yet known if these changes in Ne and DA pool size altered the quantity or characteristics of the neuronal catecholamine receptors, and more importantly, whether or not the observed changes are reversible by nutritional intervention.

  9. Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal.

    PubMed

    Fox, Megan E; Rodeberg, Nathan T; Wightman, R Mark

    2017-02-01

    Dysregulated catecholamine signaling has long been implicated in drug abuse. Although much is known about adaptations following chronic drug administration, little work has investigated how a single drug exposure paired with withdrawal influences catecholamine signaling in vivo. We used fast-scan cyclic voltammetry in freely moving rats to measure real-time catecholamine overflow during acute morphine exposure and naloxone-precipitated withdrawal in two regions associated with the addiction cycle: the dopamine-dense nucleus accumbens (NAc) and norepinephrine-rich ventral bed nucleus of the stria terminalis (vBNST). We compared dopamine transients in the NAc with norepinephrine concentration changes in the vBNST, and correlated release with specific withdrawal-related behaviors. Morphine increased dopamine transients in the NAc, but did not elicit norepinephrine responses in the vBNST. Conversely, dopamine output was decreased during withdrawal, while norepinephrine was released in the vBNST during specific withdrawal symptoms. Both norepinephrine and withdrawal symptoms could be elicited in the absence of morphine by administering naloxone with an α2 antagonist. The data support reciprocal roles for dopamine and norepinephrine signaling during drug exposure and withdrawal. The data also support the allostasis model and show that negative-reinforcement may begin working after a single exposure/withdrawal episode.

  10. PGE2, PGF2 alpha and catecholamines in pheochromocytoma.

    PubMed

    Ignatowska-Switalska, H; Wocial, B; Januszewicz, W; Filipecki, S

    1982-01-01

    In order to relate urinary prostaglandin excretion in pheochromocytoma (Ph) to the pattern of noradrenaline (NA), adrenaline (A) and dopamine (D), 14 patients with this disease were investigated during normal sodium intake. 20 healthy volunteers served as controls (C). Urinary PGs were determined by RIA; NA, A and D were measured fluorometrically. In patients with elevated excretion of NA + A (n=3), NA alone (n=6) and D (n=5), urinary PGE2 was significantly (p less than 0.01) diminished respectively 367,4 +/- 143,6; 445 +/- 104; 440,4 +/- 125,2 pmol/24h in comparison to C/1075 +/- 165,4 pmol/24 h. On the other hand urinary excretion of PGF2 alpha was distinctly increased in patients with elevated NA + A, normal NA + A and elevated D respectively 6375 +/- 1697, 1035 +/- 217,8, 5070 + 1225 pmol/24 h and decreased in patients with elevated A 989 +/- 217,5 pmol/24 h in comparison to C/1886 +/- 255,7 pmol/24 h. It is concluded, that in patients with Ph PGs excretion is related to the pattern of catecholamines excretion. Low PGE2 excretion in most patients with Ph suggests that the physiological interrelationship between catecholamines and PGs is disturbed in this disease. High PGF2 alpha excretion may reflect enhanced activity of 9-ketoreductase PGE2 probably caused by an excess of catecholamines.

  11. Leisure Activities, Caregiving Demands, and Catecholamine Levels in Dementia Caregivers

    PubMed Central

    Chattillion, Elizabeth A.; Mausbach, Brent T.; Roepke, Susan K.; von Känel, Roland; Mills, Paul J.; Dimsdale, Joel E.; Allison, Matthew; Ziegler, Michael G.; Patterson, Thomas L.; Ancoli-Israel, Sonia; Grant, Igor

    2012-01-01

    This study examined whether satisfaction from leisure activities moderates the relationship between caregiving demands (i.e., hours per day spent caring for a spouse with dementia) and resting levels of the catecholamines norepinephrine (NE) and epinephrine (EPI). Spousal caregivers (N=107; mean age 73.95±8.12 years) were assessed in home for plasma levels of NE and EPI, amount of care provided, and leisure satisfaction. Regression was used to determine whether leisure satisfaction moderated the relationship between hours providing care per day and catecholamine levels. A significant interaction was found between hours caregiving and leisure satisfaction for NE, but not for EPI. Post hoc regressions were conducted for both NE and EPI. At low leisure satisfaction, time spent caring for a spouse was positively associated with plasma NE (β = .41; p = .005) and EPI (β = .44; p = .003). In contrast, at high levels of satisfaction, time caregiving was not significantly associated with plasma NE (β = −.08; p = .57) or EPI (β = .23; p = .12). These findings suggest that leisure satisfaction may protect caregivers from increases in catecholamines, which have been implicated in cardiovascular risk. Further support for these findings may impact psychological treatments for distressed caregivers. PMID:22149759

  12. Pendrin localizes to the adrenal medulla and modulates catecholamine release

    PubMed Central

    Lazo-Fernandez, Yoskaly; Aguilera, Greti; Pham, Truyen D.; Park, Annie Y.; Beierwaltes, William H.; Sutliff, Roy L.; Verlander, Jill W.; Pacak, Karel; Osunkoya, Adeboye O.; Ellis, Carla L.; Kim, Young Hee; Shipley, Gregory L.; Wynne, Brandi M.; Hoover, Robert S.; Sen, Shurjo K.; Plotsky, Paul M.

    2015-01-01

    Pendrin (Slc26a4) is a Cl−/HCO3− exchanger expressed in renal intercalated cells and mediates renal Cl− absorption. With pendrin gene ablation, blood pressure and vascular volume fall, which increases plasma renin concentration. However, serum aldosterone does not significantly increase in pendrin-null mice, suggesting that pendrin regulates adrenal zona glomerulosa aldosterone production. Therefore, we examined pendrin expression in the adrenal gland using PCR, immunoblots, and immunohistochemistry. Pendrin protein was detected in adrenal lysates from wild-type but not pendrin-null mice. However, immunohistochemistry and qPCR of microdissected adrenal zones showed that pendrin was expressed in the adrenal medulla, rather than in cortex. Within the adrenal medulla, pendrin localizes to both epinephrine- and norepinephrine-producing chromaffin cells. Therefore, we examined plasma catecholamine concentration and blood pressure in wild-type and pendrin-null mice under basal conditions and then after 5 and 20 min of immobilization stress. Under basal conditions, blood pressure was lower in the mutant than in the wild-type mice, although epinephrine and norepinephrine concentrations were similar. Catecholamine concentration and blood pressure increased markedly in both groups with stress. With 20 min of immobilization stress, epinephrine and norepinephrine concentrations increased more in pendrin-null than in wild-type mice, although stress produced a similar increase in blood pressure in both groups. We conclude that pendrin is expressed in the adrenal medulla, where it blunts stress-induced catecholamine release. PMID:26173457

  13. Hypotension and reduced catecholamines in neuropeptide Y transgenic rats.

    PubMed

    Michalkiewicz, Mieczyslaw; Knestaut, Kriss M; Bytchkova, Elena Yu; Michalkiewicz, Teresa

    2003-05-01

    The neurons that control blood pressure express neuropeptide Y. Administered centrally, this neuropeptide reduces blood pressure and anxiety, together with lowering sympathetic outflow. The generation of neuropeptide Y transgenic rats overexpressing this peptide, under its natural promoter, has allowed us to examine the role of endogenous neuropeptide Y in the long-term control of blood pressure by the sympathetic nervous system. This study tested a hypothesis that endogenous neuropeptide Y acts to reduce blood pressure and catecholamine release. Blood pressure was measured by radiotelemetry in conscious male transgenic and nontransgenic littermates (control). Novel cage with cold water and forced swimming were used as stressors. Catecholamines were determined in 24-hour urine (baseline) and plasma (cold water stress) by a radioenzymatic assay. Blood pressures in baseline and during the stresses were significantly reduced in the transgenic rats. The lower blood pressure was associated with reduced catecholamines, lower decrease in pressure after autonomic ganglionic blockade, and increased longevity. Data obtained through the use of this transgenic rat model support and extend the evidence for the previously postulated sympatholytic and hypotensive effects of neuropeptide Y and provide novel evidence for an important physiological role of endogenous peptide in blood pressure regulation. As indicated by the increased longevity of these rats, in long-term regulation, these buffering actions of neuropeptide Y may have important cardiovascular protective effects against sympathetic hyperexcitation.

  14. Prevention moderates associations between family risks and youth catecholamine levels.

    PubMed

    Brody, Gene H; Yu, Tianyi; Chen, Edith; Miller, Gregory E

    2014-11-01

    The purpose of this study was to establish, using a quasi-experimental design, whether 2 family risk factors, parental psychological dysfunction and nonsupportive parenting, during preadolescence could longitudinally predict elevated sympathetic nervous system (SNS) activity 9 years later, and to determine whether participation in an efficacious family centered prevention program could moderate these associations if they emerged. Rural African American preadolescents (N = 476) were assigned randomly to the Strong African American Families (SAAF) program or to a control condition. When youths were 11 years of age (M = 11.2 years), primary caregivers provided data on their own depressive symptoms and self-esteem, and youths provided data on their receipt of nonsupportive parenting. When the youths were 20 years of age, indicators of SNS activity, the catecholamines epinephrine and norepinephrine, were assayed from their overnight urine voids. Parental psychological dysfunction and nonsupportive parenting forecast elevated catecholamine levels for youths in the control condition, but not for those in the SAAF condition. The demonstration that a prevention program can induce reduction of catecholamine levels is important from both theoretical and public health perspectives, because it shows that the developmental progression from family risk factors to heightened sympathetic nervous system activity is not immutable. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  15. Pendrin localizes to the adrenal medulla and modulates catecholamine release.

    PubMed

    Lazo-Fernandez, Yoskaly; Aguilera, Greti; Pham, Truyen D; Park, Annie Y; Beierwaltes, William H; Sutliff, Roy L; Verlander, Jill W; Pacak, Karel; Osunkoya, Adeboye O; Ellis, Carla L; Kim, Young Hee; Shipley, Gregory L; Wynne, Brandi M; Hoover, Robert S; Sen, Shurjo K; Plotsky, Paul M; Wall, Susan M

    2015-09-15

    Pendrin (Slc26a4) is a Cl(-)/HCO3 (-) exchanger expressed in renal intercalated cells and mediates renal Cl(-) absorption. With pendrin gene ablation, blood pressure and vascular volume fall, which increases plasma renin concentration. However, serum aldosterone does not significantly increase in pendrin-null mice, suggesting that pendrin regulates adrenal zona glomerulosa aldosterone production. Therefore, we examined pendrin expression in the adrenal gland using PCR, immunoblots, and immunohistochemistry. Pendrin protein was detected in adrenal lysates from wild-type but not pendrin-null mice. However, immunohistochemistry and qPCR of microdissected adrenal zones showed that pendrin was expressed in the adrenal medulla, rather than in cortex. Within the adrenal medulla, pendrin localizes to both epinephrine- and norepinephrine-producing chromaffin cells. Therefore, we examined plasma catecholamine concentration and blood pressure in wild-type and pendrin-null mice under basal conditions and then after 5 and 20 min of immobilization stress. Under basal conditions, blood pressure was lower in the mutant than in the wild-type mice, although epinephrine and norepinephrine concentrations were similar. Catecholamine concentration and blood pressure increased markedly in both groups with stress. With 20 min of immobilization stress, epinephrine and norepinephrine concentrations increased more in pendrin-null than in wild-type mice, although stress produced a similar increase in blood pressure in both groups. We conclude that pendrin is expressed in the adrenal medulla, where it blunts stress-induced catecholamine release.

  16. Catecholamine differential modulation of PMA and superantigen stimulated lymphocytes

    SciTech Connect

    Downs, M.O.; Johnson, H.M. )

    1991-03-15

    Neurotransmitters have been demonstrated to be important modulators of immune regulation. The authors have previously demonstrated that the catecholamine agonists isoproterenol (Iso), epinephrine (Epi), and norepinephrine (Nor) are potent inhibitors of IFN{gamma} production by phorbol myristate acetate (PMA) stimulated T-cell lymphoma cell line (L12-R4) with the order of potency being Iso > Epi > Nor. Herein, they describe a differential effect of catecholamine influence on staphylococcal enterotoxin A (SEA) stimulated murine splenic cell cultures. Norepinephrine and to a lesser extent Epi can cause a biphasic modulation of IFN{gamma} production. Inhibition of INF{gamma}was seen in the micromolar range while augmentation occurred at the nanomolar range. In light of previous work, these data suggest that {beta}-adrenergic agonist stimulation of antigen presenting cells (APC) may be immunosuppressive while {alpha}-agonist stimulation immunopotentiating. Further, APC may play a central role in determining the net outcome of catecholamine stimulation by being able to mediate signals from both pathways. This response may represent a peripheral neurotransmitter mediated mechanism for fine tuning' immunoreactivity.

  17. Rutin attenuates ethanol-induced neurotoxicity in hippocampal neuronal cells by increasing aldehyde dehydrogenase 2.

    PubMed

    Song, Kibbeum; Kim, Sokho; Na, Ji-Young; Park, Jong-Heum; Kim, Jae-Kyung; Kim, Jae-Hun; Kwon, Jungkee

    2014-10-01

    Rutin is derived from buckwheat, apples, and black tea. It has been shown to have beneficial anti-inflammatory and antioxidant effects. Ethanol is a central nervous system depressant and neurotoxin. Its metabolite, acetaldehyde, is critically toxic. Aldehyde dehydrogenase 2 (ALDH2) metabolizes acetaldehyde into nontoxic acetate. This study examined rutin's effects on ALDH2 activity in hippocampal neuronal cells (HT22 cells). Rutin's protective effects against acetaldehyde-based ethanol neurotoxicity were confirmed. Daidzin, an ALDH2 inhibitor, was used to clarify the mechanisms of rutin's protective effects. Cell viability was significantly increased after rutin treatment. Rutin significantly reversed ethanol-increased Bax, cytochrome c expression and caspase 3 activity, and decreased Bcl-2 and Bcl-xL protein expression in HT22 cells. Interestingly, rutin increased ALDH2 expression, while daidzin reversed this beneficial effect. Thus, this study demonstrates rutin protects HT22 cells against ethanol-induced neurotoxicity by increasing ALDH2 activity.

  18. Mechanisms of Mycotoxin-Induced Neurotoxicity through Oxidative Stress-Associated Pathways

    PubMed Central

    Doi, Kunio; Uetsuka, Koji

    2011-01-01

    Among many mycotoxins, T-2 toxin, macrocyclic trichothecenes, fumonisin B1 (FB1) and ochratochin A (OTA) are known to have the potential to induce neurotoxicity in rodent models. T-2 toxin induces neuronal cell apoptosis in the fetal and adult brain. Macrocyclic trichothecenes bring about neuronal cell apoptosis and inflammation in the olfactory epithelium and olfactory bulb. FB1 induces neuronal degeneration in the cerebral cortex, concurrent with disruption of de novo ceramide synthesis. OTA causes acute depletion of striatal dopamine and its metabolites, accompanying evidence of neuronal cell apoptosis in the substantia nigra, striatum and hippocampus. This paper reviews the mechanisms of neurotoxicity induced by these mycotoxins especially from the viewpoint of oxidative stress-associated pathways. PMID:21954354

  19. Novel free radical spin traps protect against malonate and MPTP neurotoxicity.

    PubMed

    Matthews, R T; Klivenyi, P; Mueller, G; Yang, L; Wermer, M; Thomas, C E; Beal, M F

    1999-05-01

    Both malonate and 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) are neurotoxins which cause energy depletion, secondary excitotoxicity, and free radical generation. Malonate is a reversible inhibitor of succinate dehydrogenase, while MPTP is metabolized to 1-methyl-4-phenylpyridinium, an inhibitor of mitochondrial complex I. We examined the effects of pretreatment with the cyclic nitrone free radical spin trap MDL 101,002 on malonate and MPTP neurotoxicity. MDL 101,002 produced dose-dependent neuroprotection against malonate-induced striatal lesions. MDL 101, 002 produced significant protection against MPTP induced depletions of dopamine and its metabolites. MDL 101,002 also significantly attenuated MPTP-induced increases in striatal 3-nitrotyrosine concentrations. The free radical spin trap tempol also produced significant protection against MPTP neurotoxicity. These findings provide further evidence that free radical spin traps produce neuroprotective effects in vivo and suggest that they may be useful in the treatment of neurodegenerative diseases.

  20. Serum Catecholamines and Dysautonomia in Diabetic Gastroparesis and Liver Cirrhosis

    PubMed Central

    Aslam, Naeem; Kedar, Archana; Nagarajarao, Harsha S.; Reddy, Kartika; Rashed, Hani; Cutts, Teresa; Riely, Caroline; Abell, Thomas L.

    2016-01-01

    Background Plasma catecholamine influences autonomic function and control, but there are few reports correlating them. In this study, 47 individuals (mean age, 38 years) were studied: 19 diabetes mellitus (DM) patients with gastroparesis, 16 with liver disease and 12 control subjects. Methods Noninvasive autonomic function was assessed for sympathetic adrenergic functions as peripheral vasoconstriction in response to cold stress test and postural adjustment ratio (PAR) and cholinergic function as Valsalva ratio, represented by change in R-R intervals. Measurements were compared by analysis of variance and Spearman’s correlation, and results were reported as mean ± standard error. Results Plasma norepinephrine (1902.7 ± 263.3; P = 0.001) and epinephrine (224.5 ± 66.5; P = 0.008) levels, as well as plasma dopamine levels (861.3 ± 381.7), and total plasma catecholamine levels were highest for patients with liver disease, who also had significant negative correlation between norepinephrine level and vasoconstriction (P = 0.01; r = −0.5), PAR1 (P = 0.01; r = −0.5), sympathetic adrenergic functions (P = 0.005; r = −0.6), total autonomic index (P = 0.01–0.5) and total autonomic function (P = 0.01; r = −0.2) and also negative correlation between epinephrine plasma level and total autonomic function (P = 0.04; r = 0.4). DM patients were next highest in norepinephrine level (133.26 ± 7.43), but lowest for plasma catecholamine; a positive correlation between dopamine level and PAR1 (P = 0.008; r = 0.6) was also seen in this group. Plasma dopamine levels and spider score correlated negatively (P = 0.04; r = −0.5) and total plasma catecholamine positively with encephalopathy (P = 0.04; r = 0.5) in patients with liver disease. Conclusions Plasma catecholamine levels correlated with adrenergic functions in control subjects and patients with DM and liver disease, with no significant correlation seen for cholinergic function. PMID:26181082

  1. An integrated liquid chromatography-tandem mass spectrometry approach for the ultra-sensitive determination of catecholamines in human peripheral blood mononuclear cells to assess neural-immune communication.

    PubMed

    Li, Xiaoguang Sunny; Li, Shu; Kellermann, Gottfried

    2016-06-03

    Catecholamines play a vital role in the interactions between the nervous and immune systems and their dysfunctions are implicated in various autoimmune and neurological diseases. However, accurate quantitation of catecholamines in the immune system presents a special analytical challenge. We proposed the first LC-MS/MS method for the determination of catecholamines in human peripheral blood mononuclear cells (PBMC) with significantly improved sensitivity, selectivity and throughput without requiring derivatization, evaporation and ion-pairing reagent. PBMC were separated by density gradient centrifugation and lysed with 0.2M acetic acid. The analytical novelty includes the first solid phase extraction on a 96-well hydrophilic-lipophilic-balanced (HLB) μElution plate upon complexation with phenylboronic acid (PBA), enabling specific clean-up and fivefold pre-concentration of catecholamines in a single extraction. LC chromatographic separation was obtained on a PFP column with 0.01% HCOOH as additive with enhanced signal response. Summation of five MRM transitions yielded three-four fold rise in sensitivity. The lower limit of quantification of 1pg/mL for epinephrine (E) and 5pg/mL for norepinephrine (NE) and dopamine (DA) represents a considerable sensitivity improvement over available methods. Less than 8.7% of intraday and interday precision, 91.8-111.3% of accuracy and successful assessment of reference intervals for 40 healthy donors suggested good reproducibility and reliability of the assay. The novel PBA-HLB-PFP-MRM summation approach allows rapid, sensitive and reliable determination of catecholamines in PBMC, which will facilitate better understanding of the new arena of neural-immune network. Additionally, the substantially improved method can be modified to quantify catecholamines and metabolites in other biological matrices.

  2. Ca/sup 2 +/-stimulated catecholamine release from. cap alpha. -toxin-permeabilized PC12 cells: biochemical evidence for exocytosis and its modulation by protein kinase C and G protein

    SciTech Connect

    Ahnert-Hilger, G.; Braeutigam, M.; Gratzl, M.

    1987-12-01

    Two possible cellular pathways of catecholamines from the chromaffin vesicles of PC12 cells to the surrounding medium are explored in this study. The direct one circumventing the cytoplasm can be activated in ..cap alpha..-toxin-permeabilized cells with micromolar levels of free Ca/sup 2 +/. Catecholamine metabolites formed in the cytoplasm (i.e., 3,4-dihydroxyphenylacetic acid and 3,4-dihydroxyphenylethanol) are neither formed nor released from the cells under these conditions. However, when vesicular catecholamines were discharged into the cytoplasm by addition of the ionophore nigericin, such metabolites are formed and released into the medium independent of Ca/sup 2 +/. Both types of experiments provide direct evidence for the operation of Ca/sup 2 +/-induced exocytosis of dopamine and noradrenaline in permeabilized PC12 cells. The Ca/sup 2 +/ dependence of dopamine or noradrenaline release, as measured by the determination of the endogenous catecholamines using the high-performance liquid chromatography technique, exhibits two different phases. One is already activated below ..mu..M free Ca/sup 2 +/ and plateaus at 1-5 ..mu..M free Ca/sup 2 +/, while a second occurs in the presence of larger amounts of free Ca/sup 2 +/ (10-100 ..mu..M). Ca/sup 2 +/-induced catecholamine release from the permeabilized cells can be modulated in different ways: It is enhanced by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate and the diacylglycerol 1-oleyl-2-acetylglycerol provided Mg/sup 2 +//ATP is present, and it is inhibited by guanosine 5'-O-(3-thiotriphosphate). The latter effect is abolished by pretreatment of the cells with pertussis toxin but not by cholera toxin. Thus, it appears that Ca/sup 2 +/-induced exocytosis can be modulated via the protein kinase C system, as well as via GTP binding proteins.

  3. In vitro neurotoxic hazard characterization of different tricresyl phosphate (TCP) isomers and mixtures.

    PubMed

    Duarte, Daniel J; Rutten, Joost M M; van den Berg, Martin; Westerink, Remco H S

    2016-02-03

    Exposure to tricresyl phosphates (TCPs), via for example contaminated cabin air, has been associated with health effects including the so-called aerotoxic syndrome. While TCP neurotoxicity is mainly attributed to ortho-isomers like tri-ortho-cresyl phosphate (ToCP), recent exposure and risk assessments indicate that ToCP levels in cabin air are very low. However, the neurotoxic potential of non-ortho TCP isomers and TCP mixtures is largely unknown. We therefore measured effects of exposure (up to 48h) to different TCP isomers, mixtures and the metabolite of ToCP (CBDP: cresyl saligenin phosphate) on cell viability and mitochondrial activity, spontaneous neuronal electrical activity, and neurite outgrowth in primary rat cortical neurons. The results demonstrate that exposure to TCPs (24-48h, up to 10μM) increases mitochondrial activity, without affecting cell viability. Effects of acute TCP exposure (30min) on neuronal electrical activity are limited. However, electrical activity is markedly decreased for the majority of TCPs (10μM) following 48h exposure. Additional preliminary data indicate that exposure to TCPs (48h, 10μM) did not affect the number of neurites per cell or average neurite length, except for TmCP and the analytical TCP mixture (Sigma) that induced a reduction of average neurite length. The combined neurotoxicity data demonstrate that the different TCPs, including ToCP, are roughly equipotent and a clear structure-activity relation is not apparent for the studied endpoints. The no-observed-effect-concentrations (1μM) are well above current exposure levels indicating limited neurotoxic health risk, although exposures may have been higher in the past. Moreover, prolonged and/or repeated exposure to TCPs may exacerbate the observed neurotoxic effects, which argues for additional research.

  4. Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin.

    PubMed Central

    Screnci, D.; Er, H. M.; Hambley, T. W.; Galettis, P.; Brouwer, W.; McKeage, M. J.

    1997-01-01

    The diaminocyclohexane platinum (Pt(DACH)) derivatives ormaplatin and oxaliplatin have caused severe and dose-limiting peripheral sensory neurotoxicity in a clinical trial. We hypothesized that this toxicity could vary in relation to the biotransformation and stereochemistry of these Pt(DACH) derivatives. We prepared pure R,R and S,S enantiomers of ormaplatin (Pt(DACH)Cl4), oxaliplatin (Pt(DACH)oxalato) and their metabolites (Pt(DACH)Cl2 and Pt(DACH)methionine) and assessed their peripheral sensory neurotoxicity and tissue distribution in the rat and in vitro anti-tumour activity in human ovarian carcinoma cell lines. The R,R enantiomers of Pt(DACH)Cl4, Pt(DACH)oxalato and Pt(DACH)Cl2, induced peripheral sensory neurotoxicity at significantly lower cumulative doses (18 +/- 5.7 vs 32 +/- 2.3 micromol kg(-1); P < 0.01) and at earlier times (4 +/- 1 vs 6.7 +/- 0.6 weeks; P = 0.016) during repeat-dose treatment than the S,S enantiomers. Pt(DACH)methionine enantiomers showed no biological activity. There was no difference between Pt(DACH) enantiomers in the platinum concentration in sciatic nerve, dorsal root ganglia, spinal cord, brain or blood at the end of each experiment. Three human ovarian carcinoma cell lines (41 M, 41 McisR and SKOV-3) showed no (or inconsistent) chiral discrimination in their sensitivity to Pt(DACH) enantiomers, whereas two cell lines (CH-1 and CH-1cisR) showed modest enantiomeric selectivity favouring the R,R isomer (more active). In conclusion, Pt(DACH) derivatives exhibit enantiomeric-selective peripheral sensory neurotoxicity during repeated dosing in rats favouring S,S isomers (less neurotoxic). They exhibited less chiral discrimination in their accumulation within peripheral nerves and in vitro anti-tumour activity. PMID:9275028

  5. Current Challenges in Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    Neurotoxicity risk assessment must continue to evolve in parallel with advances in basic research. Along with this evolution is an expansion in the scope of neurotoxicity assessments of environmental health risks. Examples of this expansion include an increasing emphasis on complex animal models that better replicate human behavior and a wider array of molecular and mechanistic data relevant to interpreting the underlying cause(s) of toxicity. However, modern neurotoxicology studies are often more nuanced and complicated than traditional studies, and they often vary considerably in evaluation methods from one study to the next, impeding comparisons. This can pose particular difficulties for risk assessors, especially given the recent demand for chemical risk assessments to be more systematic and transparent. This presentation will introduce and provide some examples of specific challenges in neurotoxicity assessments of environmental chemicals. Some of these challenges are relatively new to the field, such as the incorporation of data on neuron-supportive glial cells into hazard characterization, while other challenges have persisted for several decades, but only recently are studies being designed to evaluate them, including analyses of latent neurotoxicity. The examples provided illustrate some future research areas of interest for scientists and risk assessors examining human neurotoxicity risk. This abstract will be presented to internal U.S. Food and Drug A

  6. Current Challenges in Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    Neurotoxicity risk assessment must continue to evolve in parallel with advances in basic research. Along with this evolution is an expansion in the scope of neurotoxicity assessments of environmental health risks. Examples of this expansion include an increasing emphasis on complex animal models that better replicate human behavior and a wider array of molecular and mechanistic data relevant to interpreting the underlying cause(s) of toxicity. However, modern neurotoxicology studies are often more nuanced and complicated than traditional studies, and they often vary considerably in evaluation methods from one study to the next, impeding comparisons. This can pose particular difficulties for risk assessors, especially given the recent demand for chemical risk assessments to be more systematic and transparent. This presentation will introduce and provide some examples of specific challenges in neurotoxicity assessments of environmental chemicals. Some of these challenges are relatively new to the field, such as the incorporation of data on neuron-supportive glial cells into hazard characterization, while other challenges have persisted for several decades, but only recently are studies being designed to evaluate them, including analyses of latent neurotoxicity. The examples provided illustrate some future research areas of interest for scientists and risk assessors examining human neurotoxicity risk. This abstract will be presented to internal U.S. Food and Drug A

  7. Simultaneous measurement of L-dopa, its metabolites and carbidopa in plasma of parkinsonian patients by improved sample pretreatment and high-performance liquid chromatographic determination.

    PubMed

    Lucarelli, C; Betto, P; Ricciarello, G; Giambenedetti, M; Corradini, C; Stocchi, F; Belliardo, F

    1990-07-06

    A procedure is described for the determination of L-3,4-dihydroxyphenylalanine (L-DOPA), its metabolites and carbidopa (CD) in plasma of Parkinsonian patients by high-performance liquid chromatography with dual working-electrode coulometric electrochemical detection. An efficient sample preparation scheme is presented for the isolation of L-DOPA, its metabolites and the catecholamines from the same plasma aliquot. After a simple deproteinization with methanol containing 2% of 0.5 M perchloric acid and evaporation of the solvent, L-DOPA, its metabolites and CD were separated with a 5-micron Nucleosil C18 column. Catecholamines were extracted from the supernatant of the deproteinized plasma by ion exchange on small columns and adsorption on alumina. Recoveries were close to 100% for L-DOPA, its metabolites and CD and 70% for catecholamines. The use of the same mobile phase for the concurrent assay of L-DOPA, its metabolites and catecholamines considerably increased the throughput of samples in the chromatographic system. The dual-electrode coulometric detector afforded peak identification by comparing current ratios. Monitoring of data from patients under L-DOPA therapy is reported.

  8. Life Change as a Predictor of Catecholamines, Cortisol, Anxiety and Depressive Symptoms

    DTIC Science & Technology

    1994-08-05

    APPROVAL SHEET Title of Thesis: "Life Change as a Predictor of Catecholamines, Cortisol, Anxiety and Depressive Symptoms" Name of Candidate: Sara...34Life Change as a Predictor of Catecholamines, Cortisol, Anxiety and Depressive symptoms" beyond brief excerpts is with the permission of the...University of the Health Sciences Abstract LIFE CHANGE AS A PREDICTOR OF CATECHOLAMINES, CORTISOL, ANXIETY AND DEPRESSIVE SYMPTOMS Sara Cohen Garson

  9. Plasma and urine catecholamine levels in cosmonauts during long-term stay on Space Station Salyut-7

    NASA Astrophysics Data System (ADS)

    Kvetn̆anský, R.; Davydova, N. A.; Noskov, V. B.; Vigas̆, M.; Popova, I. A.; Us̆akov, A. C.; Macho, L.; Grigoriev, A. I.

    The activity of the sympathetic adrenal system in cosmonauts exposed to a stay in space lasting for about half a year has so far been studied only by measuring catecholamine levels in plasma and urine samples taken before space flight and after landing. The device "Plasma 01", specially designed for collecting and processing venous blood from subjects during space flight on board the station Salyut-7 rendered it possible for the first time to collect and freeze samples of blood from cosmonauts in the course of a long-term 237-day space flight. A physician-cosmonaut collected samples of blood and urine from two cosmonauts over the period of days 217-219 of their stay in space. The samples were transported to Earth frozen. As indicators of the sympathetic adrenal system activity, plasma and urine concentrations of epinephrine and norepinephrine as well as urine levels of the catecholamine metabolites metanephrine, normetanephrine, and vanillylmandelic acid were determined before, during and after space flight. On days 217-219 of space flight plasma epinephrine and norepinephrine levels were slightly increased, yet not substantially different from normal. During stress situations plasma norepinephrine and epinephrine levels usually exhibit a manifold increase. On days 217-219 of space flight norepinephrine and epinephrine levels in urine were comparable with pre-flight values and the levels of their metabolites were even significantly decreased. All the parameters studied, particularly plasma norepinephrine as well as urine norepinephrine, normetanephrine, and vanillylmandelic acid, reached the highest values 8 days after landing. The results obtained suggest that, in the period of days 217-219 of the cosmonauts' stay in space in the state of weightlessness, the sympathetic adrenal system is either not activated at all or there is but a slight activation induced by specific activities of the cosmonauts, whereas in the process of re-adaptation after space flight on

  10. A 21st Century Update on Neurotoxicity Risk Assessment

    EPA Science Inventory

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing ...

  11. A 21st Century Update on Neurotoxicity Risk Assessment

    EPA Science Inventory

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing ...

  12. Can Zebrafish be used to Identify Developmentally Neurotoxic Chemicals

    EPA Science Inventory

    Can Zebrafish be Used to Identify Developmentally Neurotoxic Chemicals? The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental neurotoxicity. We are exploring behavioral methods using zebrafish by desig...

  13. Can Zebrafish be used to Identify Developmentally Neurotoxic Chemicals

    EPA Science Inventory

    Can Zebrafish be Used to Identify Developmentally Neurotoxic Chemicals? The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental neurotoxicity. We are exploring behavioral methods using zebrafish by desig...

  14. Neurotoxicity of heroin-cocaine combinations in rat cortical neurons.

    PubMed

    Cunha-Oliveira, Teresa; Rego, A Cristina; Garrido, Jorge; Borges, Fernanda; Macedo, Tice; Oliveira, Catarina R

    2010-09-30

    Cocaine and heroin are frequently co-abused by humans, in a combination known as speedball. Recently, chemical interactions between heroin (Her) or its metabolite morphine (Mor) and cocaine (Coc) were described, resulting in the formation of strong adducts. In this work, we evaluated whether combinations of Coc and Her affect the neurotoxicity of these drugs, using rat cortical neurons incubated with Coc, Her, Her followed by Coc (Her+Coc) and Her plus Coc (Her:Coc, 1:1). Neurons exposed to Her, Her+Coc and Her:Coc exhibited a decrease in cell viability, which was more pronounced in neurons exposed to Her and Her+Coc, in comparison with neurons exposed to the mixture (Her:Coc). Cells exposed to the mixture showed increased intracellular calcium and mitochondrial dysfunction, as determined by a decrease in intracellular ATP levels and in mitochondrial membrane potential, displaying both apoptotic and necrotic characteristics. Conversely, a major increase in cytochrome c release, caspase 3-dependent apoptosis, and decreased metabolic neuronal viability were observed upon sequential exposure to Her and Coc. The data show that drug combinations potentiate cortical neurotoxicity and that the mode of co-exposure changes cellular death pathways activated by the drugs, strongly suggesting that chemical interactions occurring in Her:Coc, such as adduct formation, shift cell death mechanisms towards necrosis. Since impairment of the prefrontal cortex is involved in the loss of impulse control observed in drug addicts, the data presented here may contribute to explain the increase in treatment failure observed in speedball abusers.

  15. Nucleus Accumbens Invulnerability to Methamphetamine Neurotoxicity

    PubMed Central

    Kuhn, Donald M.; Angoa-Pérez, Mariana; Thomas, David M.

    2016-01-01

    Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure. PMID:23382149

  16. Nucleus accumbens invulnerability to methamphetamine neurotoxicity.

    PubMed

    Kuhn, Donald M; Angoa-Pérez, Mariana; Thomas, David M

    2011-01-01

    Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure.

  17. A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine.

    PubMed

    van Vliet, Erwin; Morath, Siegfried; Eskes, Chantra; Linge, Jens; Rappsilber, Juri; Honegger, Paul; Hartung, Thomas; Coecke, Sandra

    2008-01-01

    There is a need for more efficient methods giving insight into the complex mechanisms of neurotoxicity. Testing strategies including in vitro methods have been proposed to comply with this requirement. With the present study we aimed to develop a novel in vitro approach which mimics in vivo complexity, detects neurotoxicity comprehensively, and provides mechanistic insight. For this purpose we combined rat primary re-aggregating brain cell cultures with a mass spectrometry (MS)-based metabolomics approach. For the proof of principle we treated developing re-aggregating brain cell cultures for 48 h with the neurotoxicant methyl mercury chloride (0.1-100 microM) and the brain stimulant caffeine (1-100 microM) and acquired cellular metabolic profiles. To detect toxicant-induced metabolic alterations the profiles were analysed using commercial software which revealed patterns in the multi-parametric dataset by principal component analyses (PCA), and recognised the most significantly altered metabolites. PCA revealed concentration-dependent cluster formations for methyl mercury chloride (0.1-1 microM), and treatment-dependent cluster formations for caffeine (1-100 microM) at sub-cytotoxic concentrations. Four relevant metabolites responsible for the concentration-dependent alterations following methyl mercury chloride treatment could be identified using MS-MS fragmentation analysis. These were gamma-aminobutyric acid, choline, glutamine, creatine and spermine. Their respective mass ion intensities demonstrated metabolic alterations in line with the literature and suggest that the metabolites could be biomarkers for mechanisms of neurotoxicity or neuroprotection. In addition, we evaluated whether the approach could identify neurotoxic potential by testing eight compounds which have target organ toxicity in the liver, kidney or brain at sub-cytotoxic concentrations. PCA revealed cluster formations largely dependent on target organ toxicity indicating possible potential

  18. Pb neurotoxicity: neuropsychological effects of lead toxicity.

    PubMed

    Mason, Lisa H; Harp, Jordan P; Han, Dong Y

    2014-01-01

    Neurotoxicity is a term used to describe neurophysiological changes caused by exposure to toxic agents. Such exposure can result in neurocognitive symptoms and/or psychiatric disturbances. Common toxic agents include heavy metals, drugs, organophosphates, bacterial, and animal neurotoxins. Among heavy metal exposures, lead exposure is one of the most common exposures that can lead to significant neuropsychological and functional decline in humans. In this review, neurotoxic lead exposure's pathophysiology, etiology, and epidemiology are explored. In addition, commonly associated neuropsychological difficulties in intelligence, memory, executive functioning, attention, processing speed, language, visuospatial skills, motor skills, and affect/mood are explored.

  19. Neurotoxicity of fragrance compounds: A review.

    PubMed

    Pinkas, Adi; Gonçalves, Cinara Ludvig; Aschner, Michael

    2017-10-01

    Fragrance compounds are chemicals belonging to one of several families, which are used frequently and globally in cosmetics, household products, foods and beverages. A complete list of such compounds is rarely found on the ingredients-list of such products, as "fragrance mixtures" are defined as "trade secrets" and thus protected by law. While some information regarding the general toxicity of some of these compounds is available, their neurotoxicity is known to a lesser extent. Here, we discuss the prevalence and neurotoxicity of fragrance compounds belonging to the three most common groups: phthalates, synthetic musks and chemical sensitizers. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. The catecholamine response to spaceflight: role of diet and gender

    NASA Technical Reports Server (NTRS)

    Stein, T. P.; Wade, C. E.

    2001-01-01

    Compared with men, women appear to have a decreased sympathetic nervous system (SNS) response to stress. The two manifestations where the sexual dimorphism has been the most pronounced involve the response of the SNS to fluid shifts and fuel metabolism during exercise. The objectives of this study were to investigate whether a similar sexual dimorphism was found in the response to spaceflight. To do so, we compared catecholamine excretion by male and female astronauts from two similar shuttle missions, Spacelab Life Sciences 1 (SLS1, 1991) and 2 (SLS2, 1993) for evidence of sexual dimorphism. To evaluate the variability of the catecholamine response in men, we compared catecholamine excretion from the two SLS missions against the 1996 Life and Microgravity Sciences Mission (LMS) and the 1973 Skylab missions. RESULTS: No gender- or mission-dependent changes were found with epinephrine. Separating out the SLS1/2 data by gender shows that norepinephrine excretion was essentially unchanged with spaceflight in women (98 +/- 10%; n = 3) and substantially decreased with the men (41 +/- 9%; n = 4, P < 0.05). Data are a percentage of mean preflight value +/- SE. Comparisons among males demonstrated significant mission effects on norepinephrine excretion. After flight, there was a transient increase in norepinephrine but no evidence of any gender-specific effects. We conclude that norepinephrine excretion during spaceflight is both mission and gender dependent. Men show the greater response, with at least three factors being involved, a response to microgravity, energy balance, and the ratio of carbohydrate to fat in the diet.

  1. Interspecies variations in Bordetella catecholamine receptor gene regulation and function.

    PubMed

    Brickman, Timothy J; Suhadolc, Ryan J; Armstrong, Sandra K

    2015-12-01

    Bordetella bronchiseptica can use catecholamines to obtain iron from transferrin and lactoferrin via uptake pathways involving the BfrA, BfrD, and BfrE outer membrane receptor proteins, and although Bordetella pertussis has the bfrD and bfrE genes, the role of these genes in iron uptake has not been demonstrated. In this study, the bfrD and bfrE genes of B. pertussis were shown to be functional in B. bronchiseptica, but neither B. bronchiseptica bfrD nor bfrE imparted catecholamine utilization to B. pertussis. Gene fusion analyses found that expression of B. bronchiseptica bfrA was increased during iron starvation, as is common for iron receptor genes, but that expression of the bfrD and bfrE genes of both species was decreased during iron limitation. As shown previously for B. pertussis, bfrD expression in B. bronchiseptica was also dependent on the BvgAS virulence regulatory system; however, in contrast to the case in B. pertussis, the known modulators nicotinic acid and sulfate, which silence Bvg-activated genes, did not silence expression of bfrD in B. bronchiseptica. Further studies using a B. bronchiseptica bvgAS mutant expressing the B. pertussis bvgAS genes revealed that the interspecies differences in bfrD modulation are partly due to BvgAS differences. Mouse respiratory infection experiments determined that catecholamine utilization contributes to the in vivo fitness of B. bronchiseptica and B. pertussis. Additional evidence of the in vivo importance of the B. pertussis receptors was obtained from serologic studies demonstrating pertussis patient serum reactivity with the B. pertussis BfrD and BfrE proteins.

  2. Lorry drivers' work stress evaluated by catecholamines excreted in urine.

    PubMed Central

    van der Beek, A J; Meijman, T F; Frings-Dresen, M H; Kuiper, J I; Kuiper, S

    1995-01-01

    OBJECTIVES--To evaluate lorry drivers' work stress by measurement of adrenaline and noradrenaline excreted in the urine, and to find out which factors in their working situation are related to the excretion rates of these catecholamines. METHODS--The urinary excretion of adrenaline and noradrenaline of 32 lorry drivers, who also had loading and unloading activities to perform, was studied for one working day and one rest day. Each driver was asked to provide six urine samples on both days. RESULTS--For all samples, except the first (overnight) sample, the excretion rates of both catecholamines on the working day were higher than those on the rest day. Hierarchical multiple regression analyses were carried out to find out which factors in the drivers' working situation were related to the excretion rate of the working day. The excretion rate of adrenaline on the rest day, age, and psychosomatic complaints were positively related to the excretion rate on the working day (all P < 0.05). Body mass index and physical workload during loading and unloading were positively related to noradrenaline excretion rate (both P < 0.01). Psychosocial job strain did not significantly contribute to the proportion of variance explained in the excretion rates of both catecholamines. CONCLUSIONS--The excretion rates of adrenaline and, especially, noradrenaline on the working day were higher than those found in earlier studies among professional drivers and insufficient recovery took place after the work was ended. The only association between excretion rate on the working day and work stressors was found for noradrenaline and physical workload. The drivers' sympathoadrenal medullary reactivity to everyday work demands shows the characteristics of sustained activation. PMID:7670621

  3. Global Effects of Catecholamines on Actinobacillus pleuropneumoniae Gene Expression

    PubMed Central

    Li, Lu; Xu, Zhuofei; Zhou, Yang; Sun, Lili; Liu, Ziduo; Chen, Huanchun; Zhou, Rui

    2012-01-01

    Bacteria can use mammalian hormones to modulate pathogenic processes that play essential roles in disease development. Actinobacillus pleuropneumoniae is an important porcine respiratory pathogen causing great economic losses in the pig industry globally. Stress is known to contribute to the outcome of A. pleuropneumoniae infection. To test whether A. pleuropneumoniae could respond to stress hormone catecholamines, gene expression profiles after epinephrine (Epi) and norepinephrine (NE) treatment were compared with those from untreated bacteria. The microarray results showed that 158 and 105 genes were differentially expressed in the presence of Epi and NE, respectively. These genes were assigned to various functional categories including many virulence factors. Only 18 genes were regulated by both hormones. These genes included apxIA (the ApxI toxin structural gene), pgaB (involved in biofilm formation), APL_0443 (an autotransporter adhesin) and genes encoding potential hormone receptors such as tyrP2, the ygiY-ygiX (qseC-qseB) operon and narQ-narP (involved in nitrate metabolism). Further investigations demonstrated that cytotoxic activity was enhanced by Epi but repressed by NE in accordance with apxIA gene expression changes. Biofilm formation was not affected by either of the two hormones despite pgaB expression being affected. Adhesion to host cells was induced by NE but not by Epi, suggesting that the hormones affect other putative adhesins in addition to APL_0443. This study revealed that A. pleuropneumoniae gene expression, including those encoding virulence factors, was altered in response to both catecholamines. The differential regulation of A. pleuropneumoniae gene expression by the two hormones suggests that this pathogen may have multiple responsive systems for the two catecholamines. PMID:22347439

  4. Interspecies Variations in Bordetella Catecholamine Receptor Gene Regulation and Function

    PubMed Central

    Brickman, Timothy J.; Suhadolc, Ryan J.

    2015-01-01

    Bordetella bronchiseptica can use catecholamines to obtain iron from transferrin and lactoferrin via uptake pathways involving the BfrA, BfrD, and BfrE outer membrane receptor proteins, and although Bordetella pertussis has the bfrD and bfrE genes, the role of these genes in iron uptake has not been demonstrated. In this study, the bfrD and bfrE genes of B. pertussis were shown to be functional in B. bronchiseptica, but neither B. bronchiseptica bfrD nor bfrE imparted catecholamine utilization to B. pertussis. Gene fusion analyses found that expression of B. bronchiseptica bfrA was increased during iron starvation, as is common for iron receptor genes, but that expression of the bfrD and bfrE genes of both species was decreased during iron limitation. As shown previously for B. pertussis, bfrD expression in B. bronchiseptica was also dependent on the BvgAS virulence regulatory system; however, in contrast to the case in B. pertussis, the known modulators nicotinic acid and sulfate, which silence Bvg-activated genes, did not silence expression of bfrD in B. bronchiseptica. Further studies using a B. bronchiseptica bvgAS mutant expressing the B. pertussis bvgAS genes revealed that the interspecies differences in bfrD modulation are partly due to BvgAS differences. Mouse respiratory infection experiments determined that catecholamine utilization contributes to the in vivo fitness of B. bronchiseptica and B. pertussis. Additional evidence of the in vivo importance of the B. pertussis receptors was obtained from serologic studies demonstrating pertussis patient serum reactivity with the B. pertussis BfrD and BfrE proteins. PMID:26371128

  5. Catecholamine-containing nerve fibres in the human abdominal vagus.

    PubMed

    Lundberg, J; Ahlman, H; Dahlström, A; Kewenter, J

    1976-03-01

    The vagal nerve of man has been investigated for the presence of adrenergic nerve fibres using the histochemical fluorescence method of Hillarp and Falck. Following 30-60 min of nerve ligation during surgical operations, the right anterior main trunk (subdiafragmatic level) from one patient, and the anterior nerve of Latarget of 5 patients were found to contain unmyelinated nerve fibres with accumulations of green fluorescent material representing a catecholamine. The observations indicate the presence of adrenergic nerve fibres running caudally in the human vagal nerve, in accordance with similar findings in other mammals, e.g. cats and dogs.

  6. Plasma catecholamines in the lamprey: intrinsic cardiovascular messengers?

    PubMed

    Dashow, L; Epple, A

    1985-01-01

    The widely scattered cardiovascular chromaffin cells of Petromyzon marinus appear to form an intrinsic control system of circulatory function. In response to blood-borne stimuli, a checkpoint-like accumulation of epinephrine cells in the heart releases its hormone; epinephrine, in turn, stimulates the release of norepinephrine, and probably also of dopamine, from other cardiovascular chromaffin cells. The myocardium seems to be a major target of norepinephrine. On the other hand, high disappearance rates of epinephrine and dopamine in the gills point to these organs as possible major targets of the latter two secretions. Carbon dioxide and hypovolemia are strong stimuli of catecholamine release.

  7. Studies of (±)-3,4-methylenedioxymethamphetamine (MDMA) metabolism and disposition in rats and mice: relationship to neuroprotection and neurotoxicity profile.

    PubMed

    Mueller, Melanie; Maldonado-Adrian, Concepcion; Yuan, Jie; McCann, Una D; Ricaurte, George A

    2013-02-01

    The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition.

  8. MANAGING EXPOSURES TO NEUROTOXIC AIR POLLUTANTS.

    EPA Science Inventory

    Researchers at EPA's National Health and Environmental Effects Research Laboratory are developing a biologically-based dose-response model to describe the neurotoxic effects of exposure to volatile organic compounds (VOCs). The model is being developed to improve risk assessment...

  9. MANAGING EXPOSURES TO NEUROTOXIC AIR POLLUTANTS.

    EPA Science Inventory

    Researchers at EPA's National Health and Environmental Effects Research Laboratory are developing a biologically-based dose-response model to describe the neurotoxic effects of exposure to volatile organic compounds (VOCs). The model is being developed to improve risk assessment...

  10. DEVELOPMENTAL NEUROTOXICITY OF PYRETHROID INSECTICIDES: CRITICAL REVIEW.

    EPA Science Inventory

    Pyrethroids are widely utilized insecticides whose primary action is the disruption of voltage-sensitive sodium channels (VSSC). Although these compounds have been in use for over 30 years and their acute neurotoxicity has been well characterized, there is considerably less info...

  11. NEUROTOXICITY OF TETRACHLOROETHYLENE (PERCHLOROETHYLENE): DISCUSSION PAPER

    EPA Science Inventory

    This paper is a background document for a meeting of neurotoxicity experts to discuss the central nervous system effects of exposure to perchloroethylene (perc). The document reviews the literature on neurological testing of people exposed to perc occupationally in dry cleanin...

  12. NEUROTOXICITY OF TETRACHLOROETHYLENE (PERCHLOROETHYLENE): DISCUSSION PAPER

    EPA Science Inventory

    This paper is a background document for a meeting of neurotoxicity experts to discuss the central nervous system effects of exposure to perchloroethylene (perc). The document reviews the literature on neurological testing of people exposed to perc occupationally in dry cleanin...

  13. Neurotoxicity versus Neuroprotection of Anesthetics: Young Children on the Ropes?

    PubMed

    Eizaga Rebollar, Ramón; García Palacios, María V; Morales Guerrero, Javier; Torres Morera, Luis M

    2017-08-01

    Normal brain development in young children depends on a balance between excitation and inhibition of neurons, and alterations to this balance may cause apoptosis. During the perioperative period, both surgical stimuli and anesthetics can induce neurotoxicity. This article attempts to expand the perspective of a topical issue-anesthetic-induced neurotoxicity-by also considering the protective effect of general anesthetics against surgery-induced neurotoxicity, all of which may generate some controversy in the current literature. The "new" major factor influencing neurotoxicity-nociceptive stimulus-is discussed together with other factors to develop clinical and research strategies to obtain a balance between neurotoxicity and neuroprotection.

  14. Hypersensitivity of lung vessels to catecholamines in systemic hypertension.

    PubMed

    Guazzi, M D; Alimento, M; Fiorentini, C; Pepi, M; Polese, A

    1986-08-02

    Among patients with primary systemic hypertension pressure and arteriolar resistance in the pulmonary circulation exceed normal values and are hyper-reactive to sympathetic stimulation. A study was therefore carried out in 16 patients with uncomplicated essential hypertension and nine healthy subjects to compare the pulmonary vascular reactivity to exogenous catecholamines. In the normotensive group the dose response relation to adrenaline (microgram: dyn) was 1 = -4, 2 = -9, 3 = -9, and 4 = -10 and to noradrenaline 2 = +3, 4 = /8, 6 = +4, and 8 = +3. The relations in the hypertensive subjects were 1 = +18, 2 = +42, 3 = +59, and 4 = +77 and 2 = +39, 4 = +54, 6 = +76, and 8 = +100, respectively. Group differences were highly significant. Cardiac output (blood flow through the lungs) was raised by adrenaline and reduced by noradrenaline. In either case the driving pressure across the lungs was significantly augmented in the hypertensive patients but not in the normotensive group. Both catecholamines had a vasoconstrictor effect on the pulmonary circulation as a result of vascular over-reactivity. The opposite changes in resistance between normal and hypertensive subjects produced by adrenaline suggest that a constrictor vascular hypersensitivity occurs in the pulmonary circulation with the development of systemic high blood pressure.

  15. Hypersensitivity of lung vessels to catecholamines in systemic hypertension.

    PubMed Central

    Guazzi, M D; Alimento, M; Fiorentini, C; Pepi, M; Polese, A

    1986-01-01

    Among patients with primary systemic hypertension pressure and arteriolar resistance in the pulmonary circulation exceed normal values and are hyper-reactive to sympathetic stimulation. A study was therefore carried out in 16 patients with uncomplicated essential hypertension and nine healthy subjects to compare the pulmonary vascular reactivity to exogenous catecholamines. In the normotensive group the dose response relation to adrenaline (microgram: dyn) was 1 = -4, 2 = -9, 3 = -9, and 4 = -10 and to noradrenaline 2 = +3, 4 = /8, 6 = +4, and 8 = +3. The relations in the hypertensive subjects were 1 = +18, 2 = +42, 3 = +59, and 4 = +77 and 2 = +39, 4 = +54, 6 = +76, and 8 = +100, respectively. Group differences were highly significant. Cardiac output (blood flow through the lungs) was raised by adrenaline and reduced by noradrenaline. In either case the driving pressure across the lungs was significantly augmented in the hypertensive patients but not in the normotensive group. Both catecholamines had a vasoconstrictor effect on the pulmonary circulation as a result of vascular over-reactivity. The opposite changes in resistance between normal and hypertensive subjects produced by adrenaline suggest that a constrictor vascular hypersensitivity occurs in the pulmonary circulation with the development of systemic high blood pressure. PMID:3089490

  16. Catecholamine-Based Treatment in AD Patients: Expectations and Delusions

    PubMed Central

    Stefani, Alessandro; Olivola, Enrica; Liguori, Claudio; Hainsworth, Atticus H.; Saviozzi, Valentina; Angileri, Giacoma; D’Angelo, Vincenza; Galati, Salvatore; Pierantozzi, Mariangela

    2015-01-01

    In Alzheimer disease, the gap between excellence of diagnostics and efficacy of therapy is wide. Despite sophisticated imaging and biochemical markers, the efficacy of available therapeutic options is limited. Here we examine the possibility that assessment of endogenous catecholamine levels in cerebrospinal fluid (CSF) may fuel new therapeutic strategies. In reviewing the available literature, we consider the effects of levodopa, monoamine oxidase inhibitors, and noradrenaline (NE) modulators, showing disparate results. We present a preliminary assessment of CSF concentrations of dopamine (DA) and NE, determined by HPLC, in a small dementia cohort of either Alzheimer’s disease (AD) or frontotemporal dementia patients, compared to control subjects. Our data reveal detectable levels of DA, NE in CSF, though we found no significant alterations in the dementia population as a whole. AD patients exhibit a small impairment of the DA axis and a larger increase of NE concentration, likely to represent a compensatory mechanism. While waiting for preventive strategies, a pragmatic approach to AD may re-evaluate catecholamine modulation, possibly stratified to dementia subtypes, as part of the therapeutic armamentarium. PMID:25999852

  17. Direct effects of recurrent hypoglycaemia on adrenal catecholamine release.

    PubMed

    Orban, Branly O; Routh, Vanessa H; Levin, Barry E; Berlin, Joshua R

    2015-01-01

    In Type 1 and advanced Type 2 diabetes mellitus, elevation of plasma epinephrine plays a key role in normalizing plasma glucose during hypoglycaemia. However, recurrent hypoglycaemia blunts this elevation of plasma epinephrine. To determine whether recurrent hypoglycaemia affects peripheral components of the sympatho-adrenal system responsible for epinephrine release, male rats were administered subcutaneous insulin daily for 3 days. These recurrent hypoglycaemic animals showed a smaller elevation of plasma epinephrine than saline-injected controls when subjected to insulin-induced hypoglycaemia. Electrical stimulation of an adrenal branch of the splanchnic nerve in recurrent hypoglycaemic animals elicited less release of epinephrine and norepinephrine than in controls, without a change in adrenal catecholamine content. Responsiveness of isolated, perfused adrenal glands to acetylcholine and other acetylcholine receptor agonists was also unchanged. These results indicate that recurrent hypoglycaemia compromised the efficacy with which peripheral neuronal activity stimulates adrenal catecholamine release and demonstrate that peripheral components of the sympatho-adrenal system were directly affected by recurrent hypoglycaemia. © The Author(s) 2014.

  18. Time control, catecholamines and back pain among young nurses.

    PubMed

    Elfering, Achim; Grebner, Simone; Semmer, Norbert K; Gerber, Hans

    2002-12-01

    This study had two objectives. First, it addressed concern with the contribution of work stressors and resources to the development of back pain, over and above the influence of biomechanical work factors. Second, using recent models about the role of the sympathetic-adrenal medullar system in musculoskeletal problems as its basis, it tested whether low-back pain is associated with higher levels of catecholamines. Altogether 114 nurses filled out a questionnaire in their first year of practice and again one year later. In addition, in a subsample of 24 nurses studied intensively at follow-up, urinary catecholamines were assessed at noon, before the end of work, in the evening, and at corresponding times on a day off. Daily stressful experiences and daily mood were also recorded. With control for baseline pain, biomechanical workload, and other potentially confounding variables, time control at the beginning of the study predicted low-back pain a year later. In the subsample, the epinephrine and norepinephrine levels were higher in those reporting more frequent episodes of back pain, the largest differences occurring at the end of work. In addition, control over stressful events at work was lower in this group. Time control is a risk factor for low-back pain among nurses beyond the influence of physical work load. Low control at work may increase the activity of the sympathetic-adrenal medullar system, which seems to play an important role in the development of musculoskeletal pain.

  19. Chronic catecholamine depletion switches myocardium from carbohydrate to lipid utilisation.

    PubMed

    Drake-Holland, A J; Van der Vusse, G J; Roemen, T H; Hynd, J W; Mansaray, M; Wright, Z M; Noble, M I

    2001-03-01

    Chronic cardiac transplantation denervation (i.e., global sympathetic denervation with myocardial catecholamine depletion, plus parasympathetic denervation) is known to inhibit myocardial oxidation of glucose. It is not known whether this is due to increased utilization of lactate, lipid or ketone bodies. The purpose of the present study was to test the hypothesis that the extraction and contribution of blood-borne fatty acids (FA) to overall oxidative energy conversion is increased. In anaesthetised dogs (control n = 6, cardiac denervated n = 6), we investigated fatty acid (FA) utilization. The studies were made at least four weeks after surgical cardiac denervation. Measurements were made of total FAs and with a radio-labelled tracer (U-14C palmitate). The contribution of FA utilisation to overall substrate oxidation rose from 31% (control) to 48% (cardiac denervated). The increase in the ratio (%) of CO2 production from palmitate oxidation to total CO2 production increased from 4.0 +/- 1.8 (control) to 10.6 +/- 5.8 (denervated, p = 0.04). The time from uptake of FA to release of CO2 product was unaltered. We conclude that the contribution of FA oxidation to overall energy conversion is increased in chronically denervated hearts, which is postulated to result from a decline in the active form of pyruvate dehydrogenase. This would appear to be a result of chronic catecholamine depletion.

  20. Stress, Allostatic Load, Catecholamines, and Other Neurotransmitters in Neurodegenerative Diseases

    PubMed Central

    2016-01-01

    As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators—“homeostats.” Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. “Allostatic load” refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholaminergic neurons leak vesicular contents into the cytoplasm continuously during life and that catecholamines in the neuronal cytoplasm are autotoxic. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time. PMID:22297542

  1. Stress, Allostatic Load, Catecholamines, and Other Neurotransmitters in Neurodegenerative Diseases

    PubMed Central

    2017-01-01

    As populations age, the prevalence of geriatric neurodegenerative diseases will increase. These diseases generally are multifactorial, arising from complex interactions among genes, environment, concurrent morbidities, treatments, and time. This essay provides a concept for the pathogenesis of Lewy body diseases such as Parkinson disease, by considering them in the context of allostasis and allostatic load. Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators—“homeostats.” Stress can be defined as a condition or state in which a sensed discrepancy between afferent information and a setpoint for response leads to activation of effectors, reducing the discrepancy. “Allostatic load” refers to the consequences of sustained or repeated activation of mediators of allostasis. From the analogy of an idling car, the revolutions per minute of the engine can be maintained at any of a variety of levels (allostatic states). Just as allostatic load (cumulative wear and tear) reflects design and manufacturing variations, byproducts of combustion, and time, eventually leading to engine breakdown, allostatic load in catecholaminergic neurons might eventually lead to Lewy body diseases. Central to the argument is that catecholaminergic neurons leak vesicular contents into the cytoplasm continuously during life and that catecholamines in the neuronal cytoplasm are autotoxic. These neurons therefore depend on vesicular sequestration to limit autotoxicity of cytosolic transmitter. Parkinson disease might be a disease of the elderly because of allostatic load, which depends on genetic predispositions, environmental exposures, repeated stress-related catecholamine release, and time. PMID:21615193

  2. Corneal neurotoxicity due to topical benzalkonium chloride.

    PubMed

    Sarkar, Joy; Chaudhary, Shweta; Namavari, Abed; Ozturk, Okan; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Hallak, Joelle; Jain, Sandeep

    2012-04-06

    The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro. Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Wide-field stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth. BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001). Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous tear production.

  3. Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

    PubMed Central

    Sarkar, Joy; Chaudhary, Shweta; Namavari, Abed; Ozturk, Okan; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Hallak, Joelle; Jain, Sandeep

    2012-01-01

    Purpose. The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro. Methods. Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Wide-field stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth. Results. BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001). Conclusion. Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous

  4. Clarithromycin-induced neurotoxicity in adults.

    PubMed

    Bandettini di Poggio, M; Anfosso, Sandra; Audenino, Daniela; Primavera, Alberto

    2011-03-01

    Clarithromycin is a relatively new antibiotic of the macrolide family heralded for an improved side effect profile, dosing schedule, and microbiological activity relative to its parent compound, erythromycin. We review the literature on clarithromycin-induced neurotoxicity in adults and present an illustrative case. A total of 38 patients with clarithromycin-induced neurotoxicity have been reported. The average age of patients was 51.3 years (range: 19-87 years) with females comprising 52.6% of patients. Psychiatric illness was the most common comorbidity, while only two patients had renal failure. Clarithromycin had been prescribed for respiratory infections in most patients, and only two patients were receiving more than 1000 mg/day of antibiotic. The symptoms started 1 day to 10 days after starting clarithromycin (mean: 5 days). A total of 71% of patients were under treatment with concomitant medication, and eight patients were undergoing treatment with psychoactive drugs. Patients had a very good outcome after clarithromycin was discontinued, but medication with neuroleptics or benzodiazepine was required for 58% of patients in the acute phase. Only four patients underwent an electroencephalogram (EEG). Our illustrative patient was a 74-year-old woman with clarithromycin-induced delirium due to non-convulsive status epilepticus (NCSE). Her clinical symptoms and electroencephalogram (EEG) readings dramatically improved after discontinuation of clarithromycin. The mechanism underlying the central nervous system side effects remains unclear. We suggest including an EEG in the diagnostic procedures of patients under treatment with clarithromycin who develop features of neurotoxicity because an EEG can help to differentiate patients with psychiatric illness from those with encephalopathy or epilepsy. Because of the widespread use of clarithromycin, clinicians should be aware of its neurotoxicity. Early detection of clarithromycin-induced neurotoxicity and

  5. Neurotoxicity of general anesthetics: an update.

    PubMed

    Vlisides, Phillip; Xie, Zhongcong

    2012-01-01

    Though general anesthetics have now been used clinically for well over a century, both their mechanisms of action as well as the nature of any potentially neurotoxic side effects remain elusive. With roughly 234 million people undergoing surgery each year worldwide, it remains imperative that any potentially deleterious effects of anesthetics be investigated and addressed. The issue of anesthetic- induced neurotoxicity in certain subsets of patients has continued to garner attention over the past decade, as more pre-clinical and clinical studies released are suggesting that inhalational and intravenous anesthetics may both cause and mitigate existing significant neuropathology. Pre-clinically, both cell-culture and animal studies suggest that anesthetics may cause neuroapoptosis, caspase activation, neurodegeneration, β-amyloid protein (Aβ) accumulation and oligomerization, and ultimately, deficits in neurocognition. Interestingly, however, newer data suggest that certain volatile anesthetics, such as desflurane, may have a less harmful neurotoxic profile compared to others in the pre-clinical and clinical settings. Continued pre-clinical investigation may have significant impact on clinical practice in the near future. Clinically, recent studies have raised awareness that exposure to general anesthetics during childhood may be associated with an increased risk for subsequent deficits in learning, memory, and cognition. Furthermore, retrospective studies continue to allude to the potential effects of surgery and anesthesia on cognitive trajectory, and more specifically, post-operative cognitive dysfunction (POCD) in the elderly. Studies to date regarding both of these clinical topics, however, are fraught with confounders, and many are underpowered statistically. The aim of this review is to examine the current data (both pre-clinical and clinical) on anesthetic-induced neurotoxicity and argue that further data are needed to either support or refute the potential

  6. THC Prevents MDMA Neurotoxicity in Mice

    PubMed Central

    Touriño, Clara; Zimmer, Andreas; Valverde, Olga

    2010-01-01

    The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg ×4) were pretreated with THC (3 mg/kg ×4) at room (21°C) and at warm (26°C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB1 receptor antagonist AM251 and the CB2 receptor antagonist AM630, as well as in CB1, CB2 and CB1/CB2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB1 receptor antagonist AM251, neither in CB1 and CB1/CB2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB2 cannabinoid antagonist and in CB2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB1 receptor, although CB2 receptors may also contribute to attenuate neuroinflammation in this

  7. Is the deficiency of vitamin B12 related to oxidative stress and neurotoxicity in Parkinson's patients?

    PubMed

    Qureshi, G Ali; Qureshi, Aftab A; Devrajani, Bika Ram; Chippa, M A; Syed, S Ali

    2008-02-01

    This review deals with the results showing the relation between vitamin B(12) deficiency and neurotoxicity of homocysteine and nitrite (a metabolite of nitric oxide) in Parkinson's patients treated with levodopa (L-Dopa). We have already reported a linear relationship between the CSF levels of nitrite with glutamic acid and homocysteine suggesting that the production of nitrite is interrelated with the neurotoxic level of homocysteine. The levels of nitrite and homocysteine resulting in the deficiency of vitamin B(12) are some of the factors promoting degeneration in Parkinson's disease. This review emphasizes the importance of these parameters in designing suitable drug therapy for Parkinson disease. Additionally, there is evidence that increased homocysteine levels might accelerate dopaminergic cell death in Parkinson disease (PD), through neurotoxic effects. Furthermore, levodopa (L-Dopa) treatment of PD results in hyperhomocysteinemia as a consequence of L-Dopa methylation by catechol-O-methyltransferase (COMT). Therefore, higher dietary intakes of folate, vitamin B12, and vitamin B6 might decrease the risk of PD through decreasing plasma homocysteine.

  8. Selective 5-hydroxytryptamine2 receptor antagonists protect against the neurotoxicity of methylenedioxymethamphetamine in rats.

    PubMed

    Schmidt, C J; Abbate, G M; Black, C K; Taylor, V L

    1990-11-01

    The serotonergic deficits resulting from methylenedioxymethamphetamine (MDMA)-induced neurotoxicity were prevented by the simultaneous administration of 5-hydroxytryptamine2 (5-HT2) receptor antagonists such as MDL 11,939 or ritanserin. This effect was not region specific as protection was observed in the cortex, hippocampus and striatum 1 week after the administration of a single dose of MDMA. MDL 11,939 also showed some efficacy at reducing the deficits in 5-HT concentrations and tryptophan hydroxylase activity produced by multiple administrations of MDMA. Protection against the neurotoxicity required the administration of MDL 11,939 within 1 hr of MDMA indicating 5-HT2 receptor activation was an early event in the process leading to terminal damage. Examination of the effect of the 5-HT2 receptor blockade on the early neurochemical alterations induced by MDMA revealed an inhibitory effect on MDMA-stimulated dopamine synthesis. Analysis of these data and the associated changes in dopamine metabolites indicates that 5-HT2 receptor antagonists block MDMA-induced neurotoxicity by interfering with the ability of the dopamine neuron to maintain its cytoplasmic pool of transmitter and thereby sustain carrier-mediated dopamine release.

  9. DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats.

    PubMed

    Li, Zhen; Cui, Shengzhong; Zhang, Zhuo; Zhou, Rong; Ge, Yingbin; Sokabe, Masahiro; Chen, Ling

    2009-02-01

    Dehydroepiandrosterone (DHEA) has been implicated not only to prevent N-methyl-D-aspartate (NMDA)-induced neurotoxicity but also to enhance Ca(2+) influx through NMDA receptor (NMDAr). However, these DHEA effects, which would produce inconsistent outcomes about neuronal damages, are not well studied in ischemia-induced cerebral damages. Herein, we report that a single administration of DHEA (20 mg/kg) during 3 to 48 h after transient global cerebral ischemia in rats exerted neuroprotective effects such as reduction of ischemia-induced neuronal death in the hippocampal CA1 and improvement of ischemia-induced deficits in spatial learning. By contrast, at 1 h before or after ischemia, the administration of DHEA exacerbated the ischemia-induced neuronal death and learning impairment. This DHEA neurotoxicity appeared to be caused by DHEA itself, but not through its metabolite testosterone, and was inhibited by a pretreatment with the NMDAr blocker MK801 or the sigma-1 (sigma(1)) receptor antagonist NE100. However, the DHEA neuroprotection was blocked by NE100. These results show that DHEA not only provides robust ischemic neuroprotection with a long therapeutic opportunity but also exerts neurotoxicity when administered during ischemia and early reperfusion, which points to the importance of administration timing of DHEA in the clinical treatment of brain damages by the transient brain ischemia including stroke.

  10. Plasma catecholamine levels and cardiac rhythm before and after cardiac catheterisation.

    PubMed Central

    Turton, M B; Deegan, T; Coulshed, N

    1977-01-01

    Plasma catecholamine concentrations were estimated in a group of 17 fasting patients immediately before and 3 days after cardiac catheterisation. At both times electrocardiograms were recorded and blood pressures, heart rates, and respiration rates measured. Control catecholamine values were established in a group of 10 male and 10 female volunteers, bled at the same time of day under the same conditions of nutrition and posture. Levels of adrenaline and noradrenaline were increased substantially before catheterisation; 3 days later, the values were comparable to those of the control group, though still marginally higher. The increments in catecholamine levels were independent of sex and of the presence or otherwise of persistent supraventricular arrhythmias. In spite of the considerably raised catecholamine levels, electrocardiographic patterns remained unchanged, as did the other physiological values. The absence of any relation between enhanced catecholamine secretion and physiological effects is considered to be the result either of enhanced parasympathetic activity or of adaptation to a prolonged period of stress. PMID:603731

  11. A calcium ionophore stimulating the secretion of catecholamines from the cat adrenal.

    PubMed Central

    Garcia, A G; Kirpekar, S M; Prat, J C

    1975-01-01

    1. Experiments were performed on perfused cat adrenal glands to examine the effect of a calcium ionophore A-23187 in the secretion of catecholamines. 2. Ionophore (1-10 muM) caused a dose-dependent release of catecholamines and the output was about 100-fold greater at 10 mum than at 1 mum. 3. Release of catecholamines by the ionophore was dependent on the calcium concentration of the perfusion medium. Omission of calcium blocked the response to the ionophore while excess calcium facilitated it. 4. Magnesium antagonized the secretory response to the ionophore. Excess calcium overcame the inhibitory effect of magnesium. 5. The ionophore did not modify release of catecholamines by induced splanchnic nerve stimulation. 6. The results suggest that the ionophore, like depolarization, introduces calcium into the chromaffin cell to cause release of catecholamines. PMID:1091727

  12. The enteric parasite Entamoeba uses an autocrine catecholamine system during differentiation into the infectious cyst stage.

    PubMed

    Coppi, Alida; Merali, Salim; Eichinger, Daniel

    2002-03-08

    Enteric amoebae of the genus Entamoeba travel from host to host in an encysted form. We previously showed that in vitro cyst development of Entamoeba invadens requires the addition of defined amounts of multivalent galactose-terminated molecules, such as mucin, to the cultures. The amoeba surface lectin that binds mucin is presumed to convey transmembrane signals when clustered by the ligand, but the signaling molecules that function downstream of the lectin are not known. We report here that Entamoeba encystation was induced in the absence of galactose ligand when catecholamines were added to the encystation medium. Micromolar amounts of both epinephrine and norepinephrine induced encystation. Of a variety of synthetic catecholamine agonists tested, only beta(1)-adrenergic receptor agonists supported encystation, whereas alpha- and beta(2)-adrenergic receptor agonists did not. Only beta(1)-adrenergic receptor antagonists inhibited encystation, and did so even when exogenous catecholamines were not added, indicating that catecholamine binding is required for encystation and suggesting an endogenous source of the ligand. High performance liquid chromatography analysis of Entamoeba extracts showed that the amoebae themselves contain catecholamines and at least one of these is released when the cells are stimulated to encyst with galactose-terminated ligands. The presence of catecholamine binding sites on the surface of amoeba trophozoites was confirmed using radiolabeled catecholamine antagonist. Amoeba encystment was inhibited by addition of beta(1)-adrenergic receptor antagonist to cells that were stimulated to differentiate with either galactose ligand or catecholamines, but not with dibutyryl cAMP. This suggests that the amoeba catecholamine receptor functions downstream of the galactose lectin and upstream of adenylyl cyclase. This enteric protozoan parasite, therefore, contains the components of an autocrine catecholamine ligand-receptor system that may act in

  13. Relationship between Urinary Pesticide Residue Levels and Neurotoxic Symptoms among Women on Farms in the Western Cape, South Africa

    PubMed Central

    Motsoeneng, Portia M.; Dalvie, Mohamed A.

    2015-01-01

    Background: This cross-sectional study aimed to investigate the relationship between urinary pesticide residue levels and neurotoxic symptoms amongst women working on Western Cape farms in South Africa. Method: A total of 211 women were recruited from farms (n = 121) and neighbouring towns (n = 90). Participant assessment was via a Q16 questionnaire, reporting on pesticide exposures and measurement of urinary OP metabolite concentrations of dialkyl phosphates (DAP) and chlorpyriphos, 3,5,6-trichloropyridinol (TCPY) and of pyrethroid (PYR) metabolite concentrations (3- phenoxybenzoic acid (3PBA), 4-fluoro-3-phenoxybenzoic acid (4F3PBA), cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA), and the cis- and trans isomers of 2,2-dichlorovinyl-2,2-dimethylcyclopropane-1-carboxylic acid. Results: Median urinary pesticide metabolites were slightly (6%–49%) elevated in the farm group compared to the town group, with 2 metabolites significantly higher and some lower in the farm group. The prevalence of all Q16 symptoms was higher amongst farm women compared to town women. Three Q16 symptoms (problems with buttoning, reading and notes) were significantly positively associated with three pyrethroid metabolites (cis- and trans-DCCA and DBCA), although associations may due to chance as multiple comparisons were made. The strongest association for a pyrethroid metabolite was between problems with buttoning and DBCA (odds ratio (OR) = 8.93, 95% confidence interval (CI):1.71–46.5. There was no association between Q16 symptoms and OP metabolites. Conclusions: Women farm residents and rural women from neighbouring towns in the Western Cape are exposed to OP and PYR pesticides. The study did not provide strong evidence that pesticides are associated with neurotoxic symptoms but associations found could be explored further. PMID:26042367

  14. Metabolism of 3H-catecholamines in the heart and adrenals of spontaneously hypertensive rats (SHR) after running stress.

    PubMed

    Zukowska-Grójec, Z; Wocial, B; Chodakowska, J; Januszewicz, W; Rutczyński, M

    1981-01-01

    The metabolism of 3H-catecholamines after i.p. injection of 3H-tyrosine was studied in the heart and adrenals of spontaneously hypertensive (SHR) and normotensive Wistar (NCR) rats at rest and following running stress. In the heart of 8-week-old NCR a sharp stress-induced increase of the levels of 3H-A and 3H-DA with an elevation of the levels of their metabolites was observed. In contrast, there was no stress-related change in the levels of 3H-NA, 3H-A and 3H-VMA in the hearts of young SHR, while the 3H-DA level, though increased after stress, remained still lower than in the age-matched NCR. In the phase of established hypertension (24 weeks) lower levels of 3H-NA and 3H-A in the heart already present at rest, as compared with NCR, remained lower after stress but the elevation of the level of their metabolites 3H-VMA and 3H-MA, was similar in both strains. In the adrenals of 8-week-old SHR the basal 3H-A level was already higher than in NCR. Stress provoked a marked decrease of adrenal 3H-A accompanied by increased formation of 3H-MA and an increase in the levels of 3H-NA and 3H-DA, more pronounced in SHR than NCR. In the phase of advanced hypertension a further elevation of 3H-A and 3H-MA and an increase of basal 3H-DA level in the adrenals were found at rest. The decreased levels of 3H-catecholamines in the heart of stressed young and non-stressed older SHR may indicate an increase in their rate of release and/or their impaired synthesis. An increased basal level of 3H-A in the adrenals of SHR concomitant with the development of hypertension, may reflect an increased synthesis and/or decreased release, as evidenced by the proportionally lower increase of its extraneuronal metabolite 3H-MA. The adrenal response to stress, more intense in SHR than in NCR, may be considered as due to enhanced release of 3H-A from the gland.

  15. 2,2′,3,5′,6-PENTACHLOROBIPHENYL (PCB 95) AND ITS HYDROXYLATED METABOLITES ARE ENANTIOMERICALLY ENRICHED IN FEMALE MICE

    PubMed Central

    Kania-Korwel, Izabela; Barnhart, Christopher D.; Stamou, Marianna; Truong, Kim M.; El-Komy, Mohammed H.M.E.; Lein, Pamela J.; Veng-Pedersen, Peter; Lehmler, Hans-Joachim

    2012-01-01

    Epidemiological and laboratory studies link polychlorinated biphenyls and their metabolites to adverse neurodevelopmental outcomes. Several neurotoxic PCB congeners are chiral and undergo enantiomeric enrichment in mammalian species, which may modulate PCB developmental neurotoxicity. This study measures levels and enantiomeric enrichment of PCB 95 and its hydroxylated metabolites (OH-PCBs) in adult female C57Bl/6 mice following subchronic exposure to racemic PCB 95. Tissue levels of PCB 95 and OH-PCBs increased with increasing dose. Dose-dependent enantiomeric enrichment of PCB 95 was observed in brain and other tissues. OH-PCBs also displayed enantiomeric enrichment in blood and liver, but were not detected in adipose and brain. In light of data suggesting enantioselective effects of chiral PCBs on molecular targets linked to PCB developmental neurotoxicity, our observations highlight the importance of accounting for PCB and OH-PCB enantiomeric enrichment in the assessment of PCB developmental neurotoxicity. PMID:22974126

  16. Gap Junction Intercellular Communication Mediates Ammonia-Induced Neurotoxicity.

    PubMed

    Bobermin, Larissa Daniele; Arús, Bernardo Assein; Leite, Marina Concli; Souza, Diogo Onofre; Gonçalves, Carlos-Alberto; Quincozes-Santos, André

    2016-02-01

    Astrocytes are important brain targets of ammonia, a neurotoxin implicated in the development of hepatic encephalopathy. During hyperammonemia, the pivotal role of astrocytes in brain function and homeostasis is impaired. These cells are abundantly interconnected by gap junctions (GJ), which are intercellular channels that allow the exchange of signaling molecules and metabolites. This communication may also increase cellular vulnerability during injuries, while GJ uncoupling could limit the extension of a lesion. Therefore, the current study was performed to investigate whether astrocyte coupling through GJ contributes to ammonia-induced cytotoxicity. We found that carbenoxolone (CBX), an effective GJ blocker, prevented the following effects induced by ammonia in astrocyte primary cultures: (1) decrease in cell viability and membrane integrity; (2) increase in reactive oxygen species production; (3) decrease in GSH intracellular levels; (4) GS activity; (5) pro-inflammatory cytokine release. On the other hand, CBX had no effect on C6 astroglial cells, which are poorly coupled via GJ. To our knowledge, this study provides the first evidence that GJ play a role in ammonia-induced cytotoxicity. Although more studies in vivo are required to confirm our hypothesis, our data suggest that GJ communication between astrocytes may transmit damage signals and excitotoxic components from unhealthy to normal cells, thereby contributing to the propagation of the neurotoxicity of ammonia.

  17. Catalytic metalloporphyrin protects against paraquat neurotoxicity in vivo.

    PubMed

    Chen, Ping; Chen, Zhen; Li, Ang; Lou, Xiao-Chu; Wu, Xiao-Kang; Zhao, Chun-Jun; Wang, Shi-Long; Liang, Li-Ping

    2008-06-01

    To examine the neuroprotective effects of a novel manganese porphyrin, manganese (III) meso-tetrakis (N,N'-diethylimidazolium-2-yl) porphyrin (MnTDM), in the mouse model of Parkinson's disease (PD) induced by paraquat (PQ). Male C57BL/6 mice were subcutaneously injected with either saline or PQ at 2-day intervals for a total of 10 doses, MnTDM was subcutaneously injected with the PQ 2 h before treatment. Performance on the pole and swim test were measured 7 days after the last injection and animals were sacrificed one day later. Levels of dopamine (DA) and its metabolites in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD). Thiobarbituric acid (TBA) method was used to assay the lipid peroxidation product, malondialdehyde (MDA), and the number of tyrosine hydroxylase (TH) positive neurons was estimated using immunohistochemistry. Pretreatment with MnTDM significantly attenuated PQ-impaired behavioral performance, depleted dopamine content in striata, increased MDA, and dopaminergic neuron loss in the substantia nigra. Oxidative stress plays an important role in PQ-induced neurotoxicity which can be potentially prevented by manganese porphyrin. These findings also propose a possible therapeutical strategy for neurodegenerative disorders associated with oxidative stress such as PD.

  18. Accumulation of neurotoxic organochlorines and trace elements in brain of female European eel (Anguilla anguilla).

    PubMed

    Bonnineau, C; Scaion, D; Lemaire, B; Belpaire, C; Thomé, J-P; Thonon, M; Leermaker, M; Gao, Y; Debier, C; Silvestre, F; Kestemont, P; Rees, J-F

    2016-07-01

    Xenobiotics such as organochlorine compounds (OCs) and metals have been suggested to play a significant role in the collapse of European eel stocks in the last decades. Several of these pollutants could affect functioning of the nervous system. Still, no information is so far available on levels of potentially neurotoxic pollutants in eel brain. In present study, carried out on female eels caught in Belgian rivers and canals, we analyzed brain levels of potentially-neurotoxic trace elements (Ag, Al, As, Cd, Co, Cr, Cu, Fe, Hg, MeHg, Mn, Ni, Pb, Sn, Sb, Zn) and OCs (Polychlorinated biphenyls, PCBs; Hexachlorocyclohexanes, HCHs; Dichlorodiphenyltrichloroethane and its metabolites, DDTs). Data were compared to levels in liver and muscle tissues. Eel brain contained very high amounts of OCs, superior to those found in the two other tissues. Interestingly, the relative abundance of PCB congeners markedly differed between tissues. In brain, a predominance of low chlorinated PCBs was noted, whereas highly chlorinated congeners prevailed in muscle and liver. HCHs were particularly abundant in brain, which contains the highest amounts of β-HCH and ϒ-HCH. p,p'-DDTs concentration was similar between brain and muscle (i.e., about twice that of liver). A higher proportion of p,p'-DDT was noticed in brain. Except for Cr and inorganic Hg, all potentially neurotoxic metals accumulated in brain to levels equal to or lower than hepatic levels. Altogether, results indicate that eel brain is an important target for organic and, to a lesser extent, for inorganic neurotoxic pollutants.

  19. Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals.

    PubMed

    Mathieu, Cécile; Bui, Linh-Chi; Petit, Emile; Haddad, Iman; Agbulut, Onnik; Vinh, Joelle; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

    2017-02-03

    Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 × 10(5) m(-1) s(-1)). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys(318)-Cys(326)), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects.

  20. A 7-day intravenous toxicity study and neurotoxicity assessment of pyridorin in Sprague-Dawley rats.

    PubMed

    Sullivan, D W; Peterson, R C; Mujer, C V; Gad, S C

    2017-07-01

    Pyridorin(®), a naturally occurring metabolite of vitamin B6 that inhibits and scavenges reactive oxygen species, is being developed as a potential therapeutic for acute kidney injury. An investigational new drug application (IND) was opened for Pyridorin in support of its ongoing oral drug clinical development program. Currently, a Pyridorin intravenous (IV) formulation is being developed for use in surgical patients. To support the IND for Pyridorin, a full battery of nonclinical Good Laboratory Practice compliant studies was performed with no neurological or behavioral signs of toxicity seen following oral or IV administration of pyridoxine dihydrochloride (the active ingredient in Pyridorin). However, excessive ingestion of vitamin B6 has been reported to cause neurotoxic syndrome in humans. Therefore, under Food and Drug Administration recommendation, a 7-day IV study in rats was conducted to further evaluate the drug's potential to cause neurotoxicity. Blood plasma samples indicated that exposure to pyridoxamine dihydrochloride and its metabolites, pyridoxal, pyridoxine, and 4-pyridoxic acid was linearly dose proportional and independent of gender. At doses of up to 200 mg/kg/day pyridoxine dihydrochloride, no treatment-related effects were seen in rats, providing further evidence for the absence of pyridoxine dihydrochloride-related changes in the nervous system. A no observed adverse effect level of 200 mg/kg/day was identified for this study.

  1. A simple and rapid analytical method based on solid-phase extraction and liquid chromatography-tandem mass spectrometry for the simultaneous determination of free catecholamines and metanephrines in urine and its application to routine clinical analysis.

    PubMed

    Woo, Hye In; Yang, Jeong Soo; Oh, Hyeon Ju; Cho, Yoon Young; Kim, Jae Hyeon; Park, Hyung-Doo; Lee, Soo-Youn

    2016-05-01

    Urinary catecholamines and metanephrines are biochemical indicators of pheochromocytoma. We developed and validated a rapid and precise analytical method based on solid-phase extraction (SPE) and liquid chromatography separation coupled to tandem mass spectrometry (LC-MS/MS) for measuring urinary free catecholamines and metanephrines in a clinical setting. Following SPE purification of catecholamines and metanephrines from urine specimens, chromatographic separation and quantitative detection were performed using LC-MS/MS. The developed method for simultaneous measurement of urinary free catecholamines and metanephrines was validated with clinical urine specimens and was compared with other clinical and biochemical results, including urinary total metanephrines, vanillylmandelic acid (VMA), and plasma free metanephrines. The performance of our newly developed method for measuring urinary free epinephrine (EPI), norepinephrine (NE), dopamine (DA), metanephrine (MN), and normetanephrine (NMN), was acceptable. The recoveries and matrix effects of analytes were 61-107% and 84.5-130.7%. The linear ranges of each analyte were 3.8-2163μg/L, 7.4-2,359μg/L, 5.4-2,825μg/L, 3.5-2,466μg/L, and 3.7-2,569μg/L, and the coefficients of variation (CV) were less than 10% with respect to imprecision. Carryover and sample stability were also validated. Validation using clinical urine specimens by comparison with various biochemical results showed that urinary free metanephrines had comparable sensitivity (100%) and superior specificity (97.1%) to urinary total and plasma free metanephrines. The facile and reliable simultaneous measurement method for urinary free catecholamines and metanephrines using LC-MS/MS developed in this study is helpful in obtaining information about multiple metabolites and is applicable to routine clinical settings for the screening of pheochromocytoma. Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights

  2. Gill damage and neurotoxicity of ammonia nitrogen on the clam Ruditapes philippinarum.

    PubMed

    Cong, Ming; Wu, Huifeng; Yang, Haiping; Zhao, Jianmin; Lv, Jiasen

    2017-04-01

    Ammonia nitrogen has been a potential menace to aquatic animals along the coastline of China. Presently, the toxicological effects of ammonia nitrogen were mainly concentrated on fishes, while little attention has been paid to molluscs. In this study, the clam Ruditapes philippinarum was used as the target animal to investigate the toxic effects of ammonia nitrogen. Our results showed that ammonia exposure could significantly reduce the integrity of lysosomes in a dose-dependent manner. Metabolite analysis revealed that exposure doses and duration time of ammonia nitrogen could affect the variation profiles of gill metabolites. In detail, branched chain amino acids, glutamate, choline and phosphocholine were significantly decreased after a one-day exposure. Inosine and phenylalanine were found significantly increased and ATP was decreased after a three-day exposure. The changes of metabolites implied that metabolisms of muscle element, neurotransmission and cell apoptosis of gill tissues would be affected by ammonia exposure. Such inferences were supported by the diminished muscle element, decreased concentrations of catecholamines and increased apoptosis rates, respectively. Therefore, we take advantage of metabolomics integrated with conventional biological assays to find out that ammonia exposure could cause lysosome instability, metabolic disturbance, aberrant gill structures and changes to neurotransmitters, and would result in mollusk gill dysfunction in feeding, respiration and immunity.

  3. Effects of water immersion on plasma catecholamines in normal humans

    NASA Technical Reports Server (NTRS)

    Epstein, M.; Johnson, G.; Denunzio, A. G.

    1983-01-01

    An investigation was conducted in order to determine whether water immersion to the neck (NI) alters plasma catecholamines in normal humans. Eight normal subjects were studied during a seated control study (C) and during 4 hr of NI, and the levels of norepinephrine (NE) and epinephrine (E) as determined by radioenzymatic assay were measured hourly. Results show that despite the induction of a marked natriuresis and diuresis indicating significant central hypervolemia, NI failed to alter plasma NE or E levels compared with those of either C or the corresponding prestudy 1.5 hr. In addition, the diuresis and natriuresis was found to vary independently of NE. These results indicate that the response of the sympathetic nervous system to acute volume alteration may differ from the reported response to chronic volume expansion.

  4. The effect of sleep apnea on plasma and urinary catecholamines.

    PubMed

    Dimsdale, J E; Coy, T; Ziegler, M G; Ancoli-Israel, S; Clausen, J

    1995-06-01

    Numerous studies have suggested an alteration of sympathetic nervous system functioning in sleep apnea. However, most of these studies did not control for confounding factors such as diet, obesity, hypertension and anti-hypertensive medications. We examined plasma and urinary catecholamines in 43 patients, including hypertensive and normotensive individuals with and without sleep apnea. Hypertensive patients were studied at least 3 weeks following tapering of anti-hypertensive medication. All patients consumed similar diets and were of similar age and level of obesity. Twenty-four-hour urinary norepinephrine levels were significantly higher in apneics (58.2 ng vs. 40.2 ng in nonapneics, p < 0.002). Urinary norepinephrine in apneics was increased during both day and night. Plasma norepinephrine levels were not significantly elevated in apneic patients but were elevated in hypertensive patients both during sleep and in the morning (p < 0.05).

  5. Plasma catecholamines during behavioral treatments for Raynaud's disease.

    PubMed

    Freedman, R R; Keegan, D; Migály, P; Galloway, M P; Mayes, M

    1991-01-01

    We have previously demonstrated that the vasospastic attacks of Raynaud's disease can be induced despite blockade of efferent digital nerves and that feedback-induced vasodilation is mediated through a non-neural, beta-adrenergic mechanism. Here, we sought to determine the role of sympathetic activity, as measured by plasma epinephrine and norepinephrine, during finger temperature feedback and autogenic training. Thirty-one female patients with idiopathic Raynaud's disease were randomly assigned to receive finger temperature feedback or autogenic training over 28 days. Half of each group began and finished training during the follicular phase of the menstrual cycle, the other half during the luteal phase. During training, significant temperature elevations were shown by feedback patients but not by autogenic patients. There were no significant effects for norepinephrine and epinephrine for either group. Cycle phase did not interact with training effects or with catecholamines. These findings do not support the role of decreased sympathetic activation in behavioral treatments for Raynaud's disease.

  6. Changes in rat adrenal catecholamines and proenkephalin metabolism after denervation.

    PubMed

    Fleminger, G; Lahm, H W; Udenfriend, S

    1984-06-01

    Adrenal enkephalin-containing peptides are known to increase 10- to 15-fold in the rat after surgical denervation of the gland. In this report we show that the increase is preceded by a lag of several hours, which is indicative of stimulation of protein synthesis at the transcriptional level. The major species of newly appearing enkephalin-containing peptide appears to be the intact precursor, proenkephalin. Processing of proenkephalin to smaller enkephalin-containing peptides in the denervated glands is slow and limited. The only product that accumulates in the process is a peptide of 3-4 kilodaltons that is derived from the carboxyl terminus of proenkephalin. An interesting observation was the dissociation between the effects of denervation on enkephalin-containing peptides and catecholamines. This is surprising because both are localized in the chromaffin granules of the gland.

  7. Changes in rat adrenal catecholamines and proenkephalin metabolism after denervation.

    PubMed Central

    Fleminger, G; Lahm, H W; Udenfriend, S

    1984-01-01

    Adrenal enkephalin-containing peptides are known to increase 10- to 15-fold in the rat after surgical denervation of the gland. In this report we show that the increase is preceded by a lag of several hours, which is indicative of stimulation of protein synthesis at the transcriptional level. The major species of newly appearing enkephalin-containing peptide appears to be the intact precursor, proenkephalin. Processing of proenkephalin to smaller enkephalin-containing peptides in the denervated glands is slow and limited. The only product that accumulates in the process is a peptide of 3-4 kilodaltons that is derived from the carboxyl terminus of proenkephalin. An interesting observation was the dissociation between the effects of denervation on enkephalin-containing peptides and catecholamines. This is surprising because both are localized in the chromaffin granules of the gland. PMID:6587373

  8. Inhibition of radioemesis by disruption of catecholamines in dogs

    SciTech Connect

    Luthra, Y.K.; Mattsson, J.L.; Yochmowitz, M.G.

    1981-03-01

    Dogs were treated 30 min to 1 h before x irradiation with ..cap alpha..-methyl-p-tyrosine or 6-hydroxydopamine. A third group of dogs was given a known antiradioemetic drug, haloperidol to verify the sensitivity of the procedure. Irradiated but untreated controls were also used. Light methoxyflurane anesthesia was used for restraint during the exposure. Exposure dose was 800 rad kerma delivered at 50 rad/min to a 10 x 10-cm area covering the abdominal area from xiphoid to pubis. Haloperidol and 6-hydroxydopamine significantly reduced the number of emetic episodes and delayed the onset time to the first episode, ..cap alpha..-Methyl-p-tyrosine caused no significant changes. The effectiveness of 6-hydroxydopamine indicates that catecholaminergic neurons are involved in radioemesis, whereas haloperidol and phenothiazine-derivative tranquilizers inhibit radiomesis by blocking catecholamine receptor neurons.

  9. Neurotoxic aspects of porphyinopathies: lead and succinylacetone

    SciTech Connect

    Silbergeld, E.K.; Hruska, R.E.; Bradley, D.; Lamon, J.M.; Frykholm, B.C.

    1982-12-01

    Neurotoxic effects of heavy metals and polyhalogenated hydrocarbons frequently occur at low levels of exposure, in some cases below those levels where direct toxic actions of these compounds have been demonstrated. Rats with acute and chronic lead exposure were compared to rats whose heme synthesis was inhibited by succinylacetone, as a semichronic model of the hereditary heme synthesis disorder, acute intermittent porphyria. Both treatments produce significant inhibition in activity of the enzyme delta-aminolevulinic acid dehydrase and elevations in the heme precursor delta-aminolevulinic acid (ALA) in tissues and urine. Associated with increased ALA is a significant inhibition of neurotransmission utilizing the amino acid ..gamma..-aminobutyric acid (GABA), expressed chemically and behaviorally. The results suggest that in addition to their direct molecular neurotoxicity, porphyrinopathic compounds such as lead may, through altering heme synthesis, adversely affect the brain at low levels of exposure.

  10. Environmental neurotoxicity of chemicals and radiation

    SciTech Connect

    Verity, M.A. )

    1993-06-01

    Epidemiologic and societal concerns continue to stimulate studies in the field of environmental neurotoxicology. Although the role of heavy metals, aluminum, and iron are unclear in the etiology of human neurodegenerative disorders, these toxins have provided fertile ground for in vivo and in vitro experimental studies to elucidate their role in neurotoxic injury. Experimental models of clinical syndromes are discussed with special relevance to developmental neurotoxicology. Cycloleucine, tellurium, and 1,3-dinitrobenzene provide models of subacute combined degeneration, primary peripheral nerve demyelination, and thiamine deficiency-like lesions, respectively. Increasing attention is being given to irradiation neurotoxicity, especially in the developing or young central nervous system. A fuller understanding of the pathogenesis of low-dose irradiation injury allows for a clearer understanding of its neurobiology and also provides a more rational approach to understanding an interventional therapy associated with brain irradiation for childhood neoplasia. 43 refs.

  11. Clinical and imaging features of fludarabine neurotoxicity.

    PubMed

    Lee, Michael S; McKinney, Alexander M; Brace, Jeffrey R; Santacruz, Karen

    2010-03-01

    Neurotoxicity from intravenous fludarabine is a rare but recognized clinical entity. Its brain imaging features have not been extensively described. Three patients received 38.5 mg or 40 mg/m per day fludarabine in a 5-day intravenous infusion before bone marrow transplantation in treatment of hematopoietic malignancies. Several weeks later, each patient developed progressive neurologic decline, including retrogeniculate blindness, leading to coma and death. Brain MRI showed progressively enlarging but mild T2/FLAIR hyperintensities in the periventricular white matter. The lesions demonstrated restricted diffusion but did not enhance. Because the neurotoxicity of fludarabine appears long after exposure, neurologic decline in this setting is likely to be attributed to opportunistic disease. However, the imaging features are distinctive in their latency and in being mild relative to the profound clinical features. The safe dose of fludarabine in this context remains controversial.

  12. Mechanisms of methamphetamine-induced dopaminergic neurotoxicity.

    PubMed

    Riddle, Evan L; Fleckenstein, Annette E; Hanson, Glen R

    2006-01-01

    Methamphetamine (METH) is a powerful stimulant of abuse with potent addictive and neurotoxic properties. More than 2.5 decades ago, METH-induced damage to dopaminergic neurons was described. Since then, numerous advancements have been made in the search for the underlying mechanisms whereby METH causes these persistent dopaminergic deficits. Although our understanding of these mechanisms remains incomplete, combinations of various complex processes have been described around a central theme involving reactive species, such as reactive oxygen and/or nitrogen species (ROS and RNS, respectively). For example, METH-induced hyperthermia, aberrant dopamine(DA), or glutamate transmission; or mitochondrial disruption leads to the generation of reactive species with neurotoxic consequences. This review will describe the current understanding of how high-dose METH administration leads to the production of these toxic reactive species and consequent permanent dopaminergic deficits.

  13. Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat

    SciTech Connect

    Szabo, S.; Horner, H.C.; Maull, H.; Schnoor, J.; Chiueh, C.C.; Palkovits, M.

    1987-03-01

    Previous structure-activity and pharmacologic studies with duodenal ulcerogens cysteamine and propionitrile implicating catecholamines in the pathogenesis of duodenal ulceration have now been followed up by dose- and time-response biochemical investigations to assess the importance of monoamines in the development of duodenal ulcers. The concentrations of norepinephrine (noradrenaline), dopamine, serotonin and their metabolites were measured in total brain, brain regions, stomach, duodenum, pancreas and adrenals in the rat. Turnover of catecholamines was determined in rats pretreated with the inhibitor of tyrosine hydroxylase alpha-methyl-p-tyrosine. The duodenal ulcerogens caused a dose- and time-dependent depletion of norepinephrine in virtually all the tissues examined. The effect was maximal 4 or 7 hr after cysteamine or propionitrile, and norepinephrine levels returned to normal in 24 hr. Dopamine changes were selective and often biphasic, e.g., elevation in adrenals, biphasic in brain cortex, hippocampus and midbrain, but uniformly decreasing in glandular stomach and duodenum. In the median eminence dopamine levels decreased by 181 and 324% at 15 and 30 min, respectively, after cysteamine, but neither dopamine nor 3,4-dihydroxyphenylacetic acid was modified in the periventricular nucleus. Serotonin levels were relatively stable, revealing slight elevations or no changes in most of the tissues. The turnover of norepinephrine was accelerated by both chemicals in virtually all brain regions, but dopamine turnover was affected only in a few areas, e.g., in the corpus striatum and medulla oblongata cysteamine decreased dopamine turnover, whereas propionitrile first (at 1 hr) accelerated then (at 8 hr) significantly suppressed it.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Plasma catecholamine levels before and after paroxetine treatment in patients with panic disorder.

    PubMed

    Oh, Jae-Young; Yu, Bum-Hee; Heo, Jung-Yoon; Yoo, Ikki; Song, Hyemin; Jeon, Hong Jin

    2015-02-28

    Catecholamines such as norepinephrine, epinephrine, and dopamine are closely related to the autonomic nervous system, suggesting that panic disorder may involve elevated catecholamine levels. This study investigated basal and posttreatment catecholamine levels in patients with panic disorder. A total of 29 patients with panic disorder and 23 healthy controls participated in the study. Panic disorder patients received paroxetine treatment for 12 weeks after clinical tests and examination had been conducted. We investigated the difference in basal levels of catecholamine and measured the changes in catecholamine levels before and after drug treatment in panic disorder patients. The basal plasma epinephrine (48.87±6.18 pg/ml) and dopamine (34.87±3.57 pg/ml) levels of panic disorder patients were significantly higher than those (34.79±4.72 pg/ml and 20.40±3.53 pg/ml) of the control group. However, basal plasma norepinephrine levels did not show statistically significant differences between patients and controls. After drug therapy, plasma catecholamine levels were nonsignificantly decreased and norepinephrine levels showed a tendency toward a decrease that did not reach significance. In conclusion, this study suggests the possibility of a baseline increase of plasma catecholamine levels and activation of sympathetic nervous systems in patients with panic disorder which may normalize after treatment with paroxetine. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Effect of heart failure on catecholamine granule morphology and storage in chromaffin cells

    PubMed Central

    Mahata, Sushil K; Zheng, Hong; Mahata, Sumana; Liu, Xuefei

    2016-01-01

    One of the key mechanisms involved in sympathoexcitation in chronic heart failure (HF) is the activation of the adrenal glands. Impact of the elevated catecholamines on the hemodynamic parameters has been previously demonstrated. However, studies linking the structural effects of such overactivation with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not been previously reported. In this study, HF was induced in male Sprague-Dawley rats by ligation of the left coronary artery. Five weeks after surgery, cardiac function was assessed by ventricular hemodynamics. HF rats showed increased adrenal weight and adrenal catecholamine levels (norepinephrine, epinephrine and dopamine) compared with sham-operated rats. Rats with HF demonstrated increased small synaptic and dense core vesicle in splanchnic–adrenal synapses indicating trans-synaptic activation of catecholamine biosynthetic enzymes, increased endoplasmic reticulum and Golgi lumen width to meet the demand of increased catecholamine synthesis and release, and more mitochondria with dilated cristae and glycogen to accommodate for the increased energy demand for the increased biogenesis and exocytosis of catecholamines from the adrenal medulla. These findings suggest that increased trans-synaptic activation of the chromaffin cells within the adrenal medulla may lead to increased catecholamines in the circulation which in turn contributes to the enhanced neurohumoral drive, providing a unique mechanistic insight for enhanced catecholamine levels in plasma commonly observed in chronic HF condition. PMID:27402067

  16. Effect of heart failure on catecholamine granule morphology and storage in chromaffin cells.

    PubMed

    Mahata, Sushil K; Zheng, Hong; Mahata, Sumana; Liu, Xuefei; Patel, Kaushik P

    2016-09-01

    One of the key mechanisms involved in sympathoexcitation in chronic heart failure (HF) is the activation of the adrenal glands. Impact of the elevated catecholamines on the hemodynamic parameters has been previously demonstrated. However, studies linking the structural effects of such overactivation with secretory performance and cell metabolism in the adrenomedullary chromaffin cells in vivo have not been previously reported. In this study, HF was induced in male Sprague-Dawley rats by ligation of the left coronary artery. Five weeks after surgery, cardiac function was assessed by ventricular hemodynamics. HF rats showed increased adrenal weight and adrenal catecholamine levels (norepinephrine, epinephrine and dopamine) compared with sham-operated rats. Rats with HF demonstrated increased small synaptic and dense core vesicle in splanchnic-adrenal synapses indicating trans-synaptic activation of catecholamine biosynthetic enzymes, increased endoplasmic reticulum and Golgi lumen width to meet the demand of increased catecholamine synthesis and release, and more mitochondria with dilated cristae and glycogen to accommodate for the increased energy demand for the increased biogenesis and exocytosis of catecholamines from the adrenal medulla. These findings suggest that increased trans-synaptic activation of the chromaffin cells within the adrenal medulla may lead to increased catecholamines in the circulation which in turn contributes to the enhanced neurohumoral drive, providing a unique mechanistic insight for enhanced catecholamine levels in plasma commonly observed in chronic HF condition.

  17. Taurine inhibition of metal-stimulated catecholamine oxidation.

    PubMed

    Dawson, R; Baker, D; Eppler, B; Tang, E; Shih, D; Hern, H; Hu, M

    2000-01-01

    Taurine is an abundant amino acid found in mammalian tissues and it has been suggested to have cytoprotective functions. The aim of the present study was to determine if taurine had the potential to reduce oxidative stress associated with metal-stimulated catecholamine oxidation. Taurine and structural analogs of taurine were tested for their ability to inhibit metal-stimulated quinone formation from dopamine or L-dopa. Oxidative damage to proteins and lipids were also assessed in vitro and the effects of taurine were determined. Taurine (20 mM) was found to decrease significantly ferric iron (50-500 microM)- and manganese (10 microM)-stimulated L-dopa or dopamine oxidation. Taurine had no effect on zinc-induced dopamine oxidation and slightly potentiated copper- and NaIO(4)-stimulated quinone formation. Ferric iron-stimulated lipid peroxidation was not affected by taurine (1-20 mM). Protein carbonyl formation induced by ferric iron (500 microM) and L-dopa (500 microM) was significantly reduced by 10 mM taurine. The cytotoxicity of L-dopa (250 microM) and ferric chloride (75 microM) to LLC-PK(1) cells was attenuated by 10 mM taurine or hypotaurine. Homotaurine alone stimulated L-dopa oxidation and potentiated the cytotoxic effects of ferric iron. Homotaurine was found to be cytotoxic when combined with L-dopa or L-dopa/iron. In contrast, hypotaurine inhibited quinone formation and protected LLC-PK(1) cells. These studies suggest that taurine may exhibit cytoprotective effects against the oxidation products of catecholamines by acting as a scavenger for free radicals and cytotoxic quinones.

  18. [Neurotoxic effects of cobalt: an open question].

    PubMed

    Catalani, S; Apostoli, P

    2011-01-01

    Increased cobalt levels have been associated with neurological diseases (hand tremor, incoordination, cognitive decline, depression, vertigo, hearing loss and visual changes) in addition to "classic" and known cardiac diseases (arrhythmias and cardiomyopathies) and allergic or endocrine symptoms. Cobalt neurotoxicity is reported in isolated cases: old occupational or iatrogenic exposures and more recent releases of metallic ions by prosthesis. The studies of these cases have revealed a typical symptomatology of cobalt probably due to its ability to induce oxidative stress and mitochondrial alterations.

  19. Iron chelation with salicylaldehyde isonicotinoyl hydrazone protects against catecholamine autoxidation and cardiotoxicity.

    PubMed

    Hašková, Pavlína; Kovaříková, Petra; Koubková, Lucie; Vávrová, Anna; Macková, Eliška; Simůnek, Tomáš

    2011-02-15

    Elevated catecholamine levels are known to induce damage of the cardiac tissue. This catecholamine cardiotoxicity may stem from their ability to undergo oxidative conversion to aminochromes and concomitant production of reactive oxygen species (ROS), which damage cardiomyocytes via the iron-catalyzed Fenton-type reaction. This suggests the possibility of cardioprotection by iron chelation. Our in vitro experiments have demonstrated a spontaneous decrease in the concentration of the catecholamines epinephrine and isoprenaline during their 24-h preincubation in buffered solution as well as their gradual conversion to oxidation products. These changes were significantly augmented by addition of iron ions and reduced by the iron-chelating agent salicylaldehyde isonicotinoyl hydrazone (SIH). Oxidized catecholamines were shown to form complexes with iron that had significant redox activity, which could be suppressed by SIH. Experiments using the H9c2 cardiomyoblast cell line revealed higher cytotoxicity of oxidized catecholamines than of the parent compounds, apparently through the induction of caspase-independent cell death, whereas co-incubation of cells with SIH was able to significantly preserve cell viability. A significant increase in intracellular ROS formation was observed after the incubation of cells with catecholamine oxidation products; this could be significantly reduced by SIH. In contrast, parent catecholamines did not increase, but rather decreased, cellular ROS production. Hence, our results demonstrate an important role for redox-active iron in catecholamine autoxidation and subsequent toxicity. The iron chelator SIH has shown considerable potential to protect cardiac cells by both inhibition of deleterious catecholamine oxidation to reactive intermediates and prevention of ROS-mediated cardiotoxicity. Copyright © 2010 Elsevier Inc. All rights reserved.

  20. In Vivo Voltammetric Monitoring of Catecholamine Release in Subterritories of the Nucleus Accumbens Shell

    PubMed Central

    Park, Jinwoo; Aragona, Brandon J.; Kile, Brian M.; Carelli, Regina M.; Wightman, R. Mark

    2010-01-01

    Fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes has been used to demonstrate that sub-second changes in catecholamine concentration occur within the nucleus accumbens (NAc) shell during motivated behaviors, and these fluctuations have been attributed to rapid dopamine signaling. However, FSCV cannot distinguish between dopamine and norepinephrine, and caudal regions of the NAc shell receive noradrenergic projections. Therefore, in the present study, we examined the degree to which norepinephrine contributes to catecholamine release within rostral and caudal portion of NAc shell. Analysis of tissue content revealed that dopamine was the major catecholamine detectable in the rostral NAc shell, whereas both dopamine and norepinephrine were found in the caudal subregion. To examine releasable catecholamines, electrical stimulation was used to evoke release in anesthetized rats with either stimulation of the medial forebrain bundle, a pathway containing both dopaminergic and noradrenergic projections to the NAc, or the ventral tegmental area/substantia nigra, the origin of dopaminergic projections. The catecholamines were distinguished by their responses to different pharmacological agents. The dopamine autoreceptor blocker, raclopride, as well as the monoamine and dopamine transporter blockers, cocaine and GBR 12909, increased evoked catecholamine overflow in both the rostral and caudal NAc shell. The norepinephrine autoreceptor blocker, yohimbine, and the norepinephrine transporter blocker, desipramine, increased catecholamine overflow in the caudal NAc shell without significant alteration of evoked responses in the rostral NAc shell. Thus, the neurochemical and pharmacological results show that norepinephrine signaling is restricted to caudal portions of the NAc shell. Following raclopride and cocaine or raclopride and GBR 12909, robust catecholamine transients were observed within the rostral shell but these were far less apparent in the caudal

  1. Assessing the Developmental Neurotoxicity of 27 ...

    EPA Pesticide Factsheets

    Assessing the Developmental Neurotoxicity of 27 Organophosphorus Pesticides Using a Zebrafish Behavioral Assay, Waalkes, M., Hunter, D.L., Jarema, K., Mundy, W., and S. Padilla. The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize organophosphorus pesticides for developmental neurotoxicity. As such, we are exploring a behavioral testing paradigm that can assess the effects of sublethal and subteratogenic concentrations of developmental neurotoxicants on zebrafish (Danio rerio). This in vivo assay quantifies the locomotor response to light stimuli under tandem light and dark conditions in a 96-well plate using a video tracking system on 6 day post fertilization zebrafish larvae. Each of twenty-seven organophosphorus pesticides was tested for their developmental neurotoxic potential by exposing zebrafish embryos/larvae to the pesticide at several concentrations (≤ 100 μM nominal concentration) during the first five days of development, followed by 24 hours of depuration and then behavioral testing. Approximately 22% of the chemicals (Acephate, Dichlorvos, Diazoxon, Bensulide,Tribufos, Tebupirimfos) did not produce any behavioral changes after developmental exposure, while many (Malaoxon Fosthiazate, Dimethoate, Dicrotophos, Ethoprop, Malathion, Naled, Diazinon, Methamidophos, Terbufos, Trichlorfon, Phorate, Pirimiphos-methyl, Profenofos, Z-Tetrachlorvinphos, Chlorpyrifos, Coumaphos, Phosmet, Omethoate) produced changes in swi

  2. Neurotoxicity of Acrylamide in Exposed Workers

    PubMed Central

    Pennisi, Manuela; Malaguarnera, Giulia; Puglisi, Valentina; Vinciguerra, Luisa; Vacante, Marco; Malaguarnera, Mariano

    2013-01-01

    Acrylamide (ACR) is a water-soluble chemical used in different industrial and laboratory processes. ACR monomer is neurotoxic in humans and laboratory animals. Subchronic exposure to this chemical causes neuropathies, hands and feet numbness, gait abnormalities, muscle weakness, ataxia, skin and in some cases, cerebellar alterations. ACR neurotoxicity involves mostly the peripheral but also the central nervous system, because of damage to the nerve terminal through membrane fusion mechanisms and tubulovescicular alterations. Nevertheless, the exact action mechanism is not completely elucidated. In this paper we have reviewed the current literature on its neurotoxicity connected to work-related ACR exposure. We have analyzed not only the different pathogenetic hypotheses focusing on possible neuropathological targets, but also the critical behavior of ACR poisoning. In addition we have evaluated the ACR-exposed workers case studies. Despite all the amount of work which have being carried out on this topic more studies are necessary to fully understand the pathogenetic mechanisms, in order to propose suitable therapies. PMID:23985770

  3. Putative adverse outcome pathways relevant to neurotoxicity

    PubMed Central

    Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

  4. Obesity-associated sympathetic overactivity in children and adolescents: the role of catecholamine resistance in lipid metabolism.

    PubMed

    Qi, Zhengtang; Ding, Shuzhe

    2016-02-01

    Obesity in children and adolescents is characterized by chronic sympathetic overdrive and reduced epinephrine-stimulated lipolysis. This resistance to catecholamines occurs during the dynamic phase of fat accumulation. This review will focus on the relationship between sympathetic-adrenal activity and lipid metabolism, thereby highlighting the role of catecholamine resistance in the development of childhood obesity. Catecholamine resistance causes lipid accumulation in adipose tissue by reducing lipolysis, increasing lipogenesis and impeding free fatty acid (FFA) transportation. Exercise improves catecholamine resistance, as evidenced by attenuated systemic sympathetic activity, reduced circulating catecholamine levels and enhanced β-adrenergic receptor signaling. Insulin resistance is mostly a casual result rather than a cause of childhood obesity. Therefore, catecholamine resistance in childhood obesity may promote insulin signaling in adipose tissue, thereby increasing lipogenesis. This review outlines a series of evidence for the role of catecholamine resistance as an upstream mechanism leading to childhood obesity.

  5. [Autonomic nervous function and plasma catecholamine levels of perioperative patients treated with antipsychotic drugs].

    PubMed

    Kudoh, A; Murakawa, T; Isihara, H; Matsuki, A

    1992-03-01

    The RR intervals on ECG and the coefficient of variation of R-R interval (CV) and perioperative plasma catecholamine levels were measured in patients receiving long-term administration of antipsychotic drugs. CV was significantly reduced (P less than 0.05) in patients on antipsychotic drugs. Preoperative plasma catecholamine levels increased significantly and elevation of plasma catecholamine levels on the first postoperative day was less than that of the control group. These findings suggest that the patients on antipsychotic drugs have disturbed autonomic nervous function. Therefore, a careful perioperative care is mandatory.

  6. Catecholamines and in vitro growth of pathogenic bacteria: enhancement of growth varies greatly among bacterial species

    NASA Technical Reports Server (NTRS)

    Belay, Tesfaye; Aviles, Hernan; Vance, Monique; Fountain, Kimberly; Sonnenfeld, Gerald

    2003-01-01

    The purpose of this study was to examine the effects of catecholamines on in vitro growth of a range of bacterial species, including anaerobes. Bacteria tested included: Porphyromonas gingivalis, Bacteriodes fragilis, Shigella boydii, Shigella sonnie, Enterobacter Sp, and Salmonella choleraesuis. The results of the current study indicated that supplementation of bacterial cultures in minimal medium with norepinephrine or epinephrine did not result in increased growth of bacteria. Positive controls involving treatment of Escherichia coli with catecholamines did result in increased growth of that bacterial species. The results of the present study extend previous observations that showed differential capability of catecholamines to enhance bacterial growth in vitro.

  7. Pheochromocytoma-induced acute pulmonary edema and reversible catecholamine cardiomyopathy mimicking acute myocardial infarction.

    PubMed

    Pineda Pompa, Luis Ramón; Barrera-Ramírez, Carlos Felipe; Martínez-Valdez, Jesús; Rodríguez, Pedro Domínguez; Guzmán, Carlos E

    2004-04-01

    Acute noncardiogenic pulmonary edema and catecholamine-induced cardiomyopathy as the first presentations of pheochromocytoma are uncommon events, but usually rapidly fatal. A 36-year-old man presented acute pulmonary edema in a setting of hypertensive emergency after arthroscopy, later developing catecholamine-induced cardiotoxicity mimicking an acute myocardial infarction, with elevation of cardiac damage markers, normal coronary arteries, and with full recovery from electrical abnormalities. Magnetic resonance imaging revealed a right adrenal mass. Elevated levels of catecholamines and metanephrines, and a positive 131I-metaiodobenzylguanidine scan confirmed a pheochromocytoma. Once the patient had been hemodynamically stabilized, he was successfully operated.

  8. Changes relevant to catecholamine metabolism in liver and brain of ascorbic acid deficient guinea-pigs.

    PubMed

    Deana, R; Bharaj, B S; Verjee, Z H; Galzigna, L

    1975-01-01

    A chronic deficiency of ascorbic acid was induced in guinea pig. The level of catecholamines, copper and the activities of ceruplasmin, catecholamine oxidase, monoamineoxidase and acetylcholinesterase were checked in brain, liver and serum. Also the levels of ascorbic acid and glutathione were measured in the organs of ascorbic acid-deficient animals. The most important changes due to the ascorbic acid deficiency were observed in the brain were monoamineoxidase, catecholamineoxidase, acetylcholinesterase and the concentration of catecholamines were altered. The statement that brain is the organ most affected by the ascorbic acid deficiency is discussed.

  9. Optical fiber biosensor based on enzymatic coating matrix for catecholamines assessment in human urine

    NASA Astrophysics Data System (ADS)

    Silva, Lurdes I. B.; Freitas, Ana C.; Rocha-Santos, Teresa A. P.; Pereira, M. E.; Duarte, Armando C.

    2010-09-01

    An optical fiber (OF) biosensor has been developed and applied for simultaneous determination of catecholamines (dopamine, norepinephrine and epinephrine) in human urine. The developed analytical device shows a high potential for catecholamines quantification with a detection limit of 2.1, 2.6 and 3.4 pg mL-1 for dopamine, norepinephrine and epinephrine, respectively. The analytical performance of the OF biosensor was found to be similar to that of the High Performance Liquid Chromatography - Electrochemical Detector (HPLC-ED) regarding catecholamines determination in samples of human urine.

  10. Catecholamines and in vitro growth of pathogenic bacteria: enhancement of growth varies greatly among bacterial species

    NASA Technical Reports Server (NTRS)

    Belay, Tesfaye; Aviles, Hernan; Vance, Monique; Fountain, Kimberly; Sonnenfeld, Gerald

    2003-01-01

    The purpose of this study was to examine the effects of catecholamines on in vitro growth of a range of bacterial species, including anaerobes. Bacteria tested included: Porphyromonas gingivalis, Bacteriodes fragilis, Shigella boydii, Shigella sonnie, Enterobacter Sp, and Salmonella choleraesuis. The results of the current study indicated that supplementation of bacterial cultures in minimal medium with norepinephrine or epinephrine did not result in increased growth of bacteria. Positive controls involving treatment of Escherichia coli with catecholamines did result in increased growth of that bacterial species. The results of the present study extend previous observations that showed differential capability of catecholamines to enhance bacterial growth in vitro.

  11. Central Neurotoxicity of Immunomodulatory Drugs in Multiple Myeloma

    PubMed Central

    Patel, Urmeel H.; Mir, Muhammad A.; Sivik, Jeffrey K.; Raheja, Divisha; Pandey, Manoj K.; Talamo, Giampaolo

    2015-01-01

    Immunomodulatory drugs (IMiDs) currently used in the treatment of multiple myeloma, are thalidomide, lenalidomide and pomalidomide. One of the most common side effects of thalidomide is neurotoxicity, predominantly in the form of peripheral neuropathy. We report 6 cases of significant central neurotoxicity associated with IMiD therapy. Treatment with thalidomide (1 patient), lenalidomide (4 patients), and pomalidomide (1 patient) was associated with various clinical manifestations of central neurotoxicity, including reversible coma, amnesia, expressive aphasia, and dysarthria. Central neurotoxicity should be recognized as an important side effect of IMiD therapy. PMID:25852850

  12. Plasma catecholamines and postoperative gastric emptying and small intestinal propulsion in the rat.

    PubMed

    Dubois, A; Henry, D P; Kopin, I J

    1975-03-01

    The role of adrenal medullary discharge of catecholamines on inhibition of gastric emptying and small intestinal propulsion after laparotomy was examined in rats. The rate of movement of a 51Cr-labeled liquid test meal, which had been introduced by gastric intubation, out of the stomach and through the small intestine, was retarded 12 hr after laparotomy. Adrenal demedullation produced a striking decrease in plasma catecholamines and abolished surgically induced elevation of the catecholamines, but had no significant effect on gastric emptying or intestinal propulsion in rats subjected to laparotomy or in the unoperated control animals. Thus circulating catecholamines play little if any role in controlling normal gastroinestinal motility or in the postoperative decrease in rate of gastric emptying and small intestinal motility.

  13. Effect of dietary copper and sucrose on catecholamine concentrations in the adrenal medulla

    SciTech Connect

    Koo, S.I.; Peterson, D.F.; Mason, P.A. KCOM, Kirksville, MO Air Force/SAM/RZP, Brooks AFB, TX )

    1991-03-11

    The severity of copper (Cu) deficiency in the rat is enhanced by dietary sucrose. Possible interactive effects of Cu status and sucrose on catecholamine concentrations in the adrenal medulla were investigated in Cu deficient rats fed a diet were investigated in Cu deficient rats fed a diet containing either glucose or sucrose, as compared with respective Cu-adequate controls. Catecholamines were analyzed by an HPLC method using 3,4-dihydroxybenxylamine as the internal standard. Cu deficiency caused pronounced decreases in norepinephrine and epinephrine, with no significant effect on dopamine, as expressed in nmoles/mg tissue. Dietary sucrose showed no appreciable effect on catecholamines in the adrenal medulla. The adrenal glands were markedly enlarged in Cu-deficient rats, whether fed glucose or sucrose. Adrenal weights were not affected by dietary sucrose. Data indicate that the increased severity of copper deficiency due to sucrose feeding is not associated with changes in adrenal catecholamine output.

  14. DISTRIBUTION OF ATRAZINE IN PC12 CELLS AND MODULATION OF CATECHOLAMINE SYNTHESIS

    EPA Science Inventory

    Previously, we reported that atrazine disrupts ovarian function by altering hypothalamic catecholamine (CA) concentrations and the consequent regulation of pituitary LH release and prolactin secretion in the young female rat. We also showed that atrazine directly interacts with t...

  15. DISTRIBUTION OF ATRAZINE IN PC12 CELLS AND MODULATION OF CATECHOLAMINE SYNTHESIS

    EPA Science Inventory

    Previously, we reported that atrazine disrupts ovarian function by altering hypothalamic catecholamine (CA) concentrations and the consequent regulation of pituitary LH release and prolactin secretion in the young female rat. We also showed that atrazine directly interacts with t...

  16. Neuroprotective effects of melatonin as evidenced by abrogation of oxaliplatin induced behavioral alterations, mitochondrial dysfunction and neurotoxicity in rat brain.

    PubMed

    Waseem, Mohammad; Tabassum, Heena; Parvez, Suhel

    2016-09-01

    Neurotoxicity is a burdensome consequence of platinum-based chemotherapy that neutralizes the administration of effective dosage and often prompts treatment withdrawal. Oxaliplatin (Oxa), a third-era platinum analogue that is active against both early-organize and progressed colorectal growth, produces critical neurotoxicity. It has been reported that the Melatonin (Mel) is a pineal hormone its metabolites display important antioxidant properties in nervous system. There is dearth of literature involving the role of mitochondria and cytosolic compartments mediated Oxa-induced neurotoxicity and its underlying mechanisms are still debatable. Rats were pre-treated with Mel (10mg/kg b.wt., i.p.) and treated with Oxa (4mg/kg b.wt. i.p.) for 5 consecutive days. For neurobehavioral performances, decreased locomotor activity and muscular strength were observed in rats. Treatment with Mel in Oxa treated rats could protect the Oxa induced alterations in motor activity and muscular strength. For painful neuropathy, thermal hyperalgesia/nociceptive tests were evaluated. In addition, pre-treatment of Mel could block or alter the inactivation of Bcl-2, caspase 3 apoptotic protein and alterations Cytochrome c (Cyt c) release in an Oxa rich environment. Pre-treatment of Mel have shown an alteration in hyperalgesia behaviour in Oxa treated rats. Oxidative stress biomarkers, levels of non-enzymatic antioxidants and mitochondrial complexes were evaluated against neurotoxicity induced by Oxa. Mel pre-treatment replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. Mel also modulated altered non-enzymatic, enzymatic antioxidants and complex enzymes of mitochondria. Futures studies are also required to identify other molecular markers involved in neurotoxicity induced by Oxa and possible action of Mel in its modulation. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  17. Determinants of catecholamine and cortisol responses to lower extremity revascularization. The PIRAT Study Group.

    PubMed

    Breslow, M J; Parker, S D; Frank, S M; Norris, E J; Yates, H; Raff, H; Rock, P; Christopherson, R; Rosenfeld, B A; Beattie, C

    1993-12-01

    Surgical trauma elicits diffuse changes in hormonal secretion and autonomic nervous system activity. Despite studies demonstrating modulation of the stress response by different anesthetic/analgesic regimens, little is known regarding the determinants of catecholamine and cortisol responses to surgery. Plasma catecholamines and cortisol secretion data were obtained from 60 patients undergoing lower extremity revascularization. Patients were randomized to receive either general anesthesia combined with patient-controlled intravenous morphine (GA) or epidural anesthesia combined with epidural fentanyl analgesia (RA). All aspects of intra- and postoperative clinical care were defined by written protocol. Plasma catecholamines were measured before induction, intraoperatively, and for the first 18 h postoperatively (by HPLC). Urine cortisol was measured intra- and postoperatively using RIA. Data were evaluated using univariate and multivariate analyses to evaluate demographic and perioperative variables as determinants of stress hormone secretion. Plasma catecholamines increased during skin closure in the GA group, and remained higher relative to the RA group in the postoperative period. Multivariate analysis indicated that age and anesthetic regimen predicted increases in catecholamines during skin closure (P < 0.005), although duration of surgery, blood loss, and body temperature were not correlated. Early postoperative norepinephrine concentrations were correlated with pain score and duration of surgery (P < 0.004), but not with anesthetic management, blood loss, or body temperature. All postoperative norepinephrine levels were highly correlated (r = 0.7) with norepinephrine levels during skin closure. Cortisol excretion was higher postoperatively than intraoperatively. No patient or perioperative variable predicted cortisol excretion, and cortisol excretion was not correlated with catecholamine levels at any time. These data indicate that patient factors, such as

  18. Radioimmunoassay of free plasma metanephrines for the diagnosis of catecholamine-producing tumors.

    PubMed

    Pussard, Eric; Chaouch, Amel; Said, Toihiri

    2014-03-01

    The determination of plasma metanephrines (MNs) provides a highly sensitive test for the diagnosis of catecholamine producing tumors. Chromatographic determinations with electrochemical or mass spectrometric detections are the methods of choice, but immunological assays have been developed. This study evaluated the clinical performances of a radioimmunoassay for free MNs in plasma. MNs, normetanephrine (NMN) and metanephrine (MN) and catecholamines, norepinephrine (NE) and epinephrine (E) were determined in plasma and urine of 533 patients suspected of catecholamine producing tumor. Urinary and plasma catecholamines and urinary MNs were determined by HPLC using amperometric detection. Plasma MNs were purified by solid phase chromatography and quantified by a specific radioimmunoassay. Fifty-nine patients had tumors (13 paraganglioma and 46 pheochromocytoma) and the diagnosis was excluded in 474 patients. Receiver operator characteristic curves have identified optimal thresholds at 100 pg/mL for plasma NMN (sensitivity 96.6% and specificity 95.8%) and 70 pg/mL for plasma MN (sensitivity 61.0% and specificity 96.8%). These cut-off values were lower than those suggested by the manufacturer (170 and 100 pg/mL, respectively). The sensitivity of combined MNs was similar in plasma (100%) and urine (98%) but higher than that of urinary catecholamines (85%, p<0.001). The specificity of combined MNs in plasma (95%) was higher than urinary MNs (85%, p<0.001) and plasma catecholamines (75%, p<0.001). Plasma-free and urinary-total MNs have a better discriminative power than catecholamines in the diagnosis of catecholamines producing tumors. Using these established cut-offs, measurement of plasma-free MN by radioimmunoassay represents an effective alternative to chromatographic methods.

  19. Electrochemical sensors and biosensors for determination of catecholamine neurotransmitters: A review.

    PubMed

    Ribeiro, José A; Fernandes, Paula M V; Pereira, Carlos M; Silva, F

    2016-11-01

    This work describes the state of the art of electrochemical devices for the detection of an important class of neurotransmitters: the catecholamines. This class of biogenic amines includes dopamine, noradrenaline (also called norepinephrine) and adrenaline (also called epinephrine). Researchers have focused on the role of catecholamine molecules within the human body because they are involved in many important biological functions and are commonly associated with several diseases, such as Alzheimer's and Parkinson. Furthermore, the release of catecholamines as a consequence of induced stimulus is an important indicator of reward-related behaviors, such as food, drink, sex and drug addiction. Thus, the development of simple, fast and sensitive electroanalytical methodologies for the determination of catecholamines is currently needed in clinical and biomedical fields, as they have the potential to serve as clinically relevant biomarkers for specific disease states or to monitor treatment efficacy. Currently, three main strategies have used by researchers to detect catecholamine molecules, namely: the use electrochemical materials in combination with, for example, HPLC or FIA, the incorporation of new materials/layers on the sensor surfaces (Tables 1-7) and in vivo detection, manly by using FSCV at CFMEs (Section 10). The developed methodologies were able not only to accurately detect catecholamines at relevant concentration levels, but to do so in the presence of co-existing interferences in samples detected (ascorbate, for example). This review examines the progress made in electrochemical sensors for the selective detection of catecholamines in the last 15 years, with special focus on highly innovative features introduced by nanotechnology. As the literature in rather extensive, we try to simplify this work by summarizing and grouping electrochemical sensors according to the manner their substrates were chemically modified. We also discuss the current and future

  20. Glial cell response to 3,4-(+/-)-methylenedioxymethamphetamine and its metabolites.

    PubMed

    Herndon, Joseph M; Cholanians, Aram B; Lau, Serrine S; Monks, Terrence J

    2014-03-01

    3,4-(±)-Methylenedioxymethamphetamine (MDMA) and 3,4-(±)-methylenedioxyamphetamine (MDA), a primary metabolite of MDMA, are phenylethylamine derivatives that cause serotonergic neurotoxicity. Although several phenylethylamine derivatives activate microglia, little is known about the effects of MDMA on glial cells, and evidence of MDMA-induced microglial activation remains ambiguous. We initially determined microglial occupancy status of the parietal cortex in rats at various time points following a single neurotoxic dose of MDMA (20mg/kg, SC). A biphasic microglial response to MDMA was observed, with peak microglial occupancy occurring 12- and 72-h post-MDMA administration. Because direct injection of MDMA into the brain does not produce neurotoxicity, the glial response to MDMA metabolites was subsequently examined in vivo and in vitro. Rats were treated with MDA (20mg/kg, SC) followed by ex vivo biopsy culture to determine the activation of quiescent microglia. A reactive microglial response was observed 72 h after MDA administration that subsided by 7 days. In contrast, intracerebroventricular (ICV) administration of MDA failed to produce a microglial response. However, thioether metabolites of MDA derived from α-methyldopamine (α-MeDA) elicited a robust microglial response following icv injection. We subsequently determined the direct effects of various MDMA metabolites on primary cultures of E18 hippocampal mixed glial and neuronal cells. 5-(Glutathion-S-yl)-α-MeDA, 2,5-bis-(glutathion-S-yl)-α-MeDA, and 5-(N-acetylcystein-S-yl)-α-MeDA all stimulated the proliferation of glial fibrillary acidic protein-positive astrocytes at a dose of 10 µM. The findings indicate that glial cells are activated in response to MDMA/MDA and support a role for thioether metabolites of α-MeDA in the neurotoxicity.

  1. Oral branched-chain amino acid supplements that reduce brain serotonin during exercise in rats also lower brain catecholamines.

    PubMed

    Choi, Sujean; Disilvio, Briana; Fernstrom, Madelyn H; Fernstrom, John D

    2013-11-01

    Exercise raises brain serotonin release and is postulated to cause fatigue in athletes; ingestion of branched-chain amino acids (BCAA), by competitively inhibiting tryptophan transport into brain, lowers brain tryptophan uptake and serotonin synthesis and release in rats, and reputedly in humans prevents exercise-induced increases in serotonin and fatigue. This latter effect in humans is disputed. But BCAA also competitively inhibit tyrosine uptake into brain, and thus catecholamine synthesis and release. Since increasing brain catecholamines enhances physical performance, BCAA ingestion could lower catecholamines, reduce performance and thus negate any serotonin-linked benefit. We therefore examined in rats whether BCAA would reduce both brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Sedentary and exercising rats received BCAA or vehicle orally; tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis rates were measured 1 h later in brain. BCAA reduced brain tryptophan and tyrosine concentrations, and serotonin and catecholamine synthesis. These reductions in tyrosine concentrations and catecholamine synthesis, but not tryptophan or serotonin synthesis, could be prevented by co-administering tyrosine with BCAA. Complete essential amino acid mixtures, used to maintain or build muscle mass, were also studied, and produced different effects on brain tryptophan and tyrosine concentrations and serotonin and catecholamine synthesis. Since pharmacologically increasing brain catecholamine function improves physical performance, the finding that BCAA reduce catecholamine synthesis may explain why this treatment does not enhance physical performance in humans, despite reducing serotonin synthesis. If so, adding tyrosine to BCAA supplements might allow a positive action on performance to emerge.

  2. Mussel-inspired catecholamine polymers as new sizing agents for fiber-reinforced composites

    NASA Astrophysics Data System (ADS)

    Lee, Wonoh; Lee, Jea Uk; Byun, Joon-Hyung

    2015-04-01

    Mussel-inspired catecholamine polymers (polydopamine and polynorepinephrine) were coated on the surface of carbon and glass fibers in order to increase the interfacial shear strength between fibers and polymer matrix, and consequently the interlaminar shear strength of fiber-reinforced composites. By utilizing adhesive characteristic of the catecholamine polymer, fiber-reinforced composites can become mechanically stronger than conventional composites. Since the catecholamine polymer is easily constructed on the surface by the simultaneous polymerization of its monomer under a weak basic circumstance, it can be readily coated on micro-fibers by a simple dipping process without any complex chemical treatments. Also, catecholamines can increase the surface free energy of micro-fibers and therefore, can give better wettability to epoxy resin. Therefore, catecholamine polymers can be used as versatile and effective surface modifiers for both carbon and glass fibers. Here, catecholamine-coated carbon and glass fibers exhibited higher interfacial shear strength (37 and 27% increases, respectively) and their plain woven composites showed improved interlaminar shear strength (13 and 9% increases, respectively) compared to non-coated fibers and composites.

  3. Valacyclovir and Acyclovir Neurotoxicity With Status Epilepticus.

    PubMed

    Hoskote, Sumedh S; Annapureddy, Narender; Ramesh, Atul K; Rose, Keith; Jones, James P

    2016-01-01

    We present the case of a 52-year-old man with hypertension, diastolic congestive heart failure, end-stage renal disease on hemodialysis 3 times a week and a remote history of a hemorrhagic stroke who presented to the emergency department with a vesicular rash on his left arm. The rash was observed to be in a dermatomal distribution, and a diagnosis of herpes zoster was made. The patient was discharged home on valacyclovir 1 g 3 times a day for a duration of 7 days. The patient took 2 doses of valacyclovir before presenting to the hospital again with irritability and hallucinations. Over the next several days, the patient's neurologic status declined and he became disoriented and increasingly somnolent. Because of a concern for varicella zoster virus (VZV) or herpes simplex virus (HSV) meningoencephalitis, acyclovir was initiated intravenously at 600 mg (10 mg/kg) for every 12 hours. Computed tomography and magnetic resonance imaging of the brain failed to reveal an acute process. Electroencephalogram was interpreted as seizure activity versus metabolic encephalopathy. Lumbar puncture was not suggestive for meningitis, subarachnoid hemorrhage, or HSV/VZV infection. The patient subsequently had a witnessed seizure during dialysis and was felt to have status epilepticus due to acyclovir and valacyclovir neurotoxicity. The patient underwent daily hemodialysis for removal of the drug and eventually made a full neurologic recovery. Our case highlights that acyclovir neurotoxicity can result in status epilepticus, hallucinations, and altered consciousness. Differentiating acyclovir neurotoxicity from HSV or VZV meningoencephalitis is of crucial importance because the symptoms are similar but the management is vastly different.

  4. Does diisocyanate exposure result in neurotoxicity?

    PubMed Central

    2014-01-01

    Context Diisocyanates have been associated with respiratory and dermal sensitization. Limited number of case reports, and a few case studies, media, and other references suggest potential neurotoxic effects from exposures to toluene diisocyanate (TDI), 1,6 hexamethylene diisocyanate (HDI), and methylene diisocyanate (MDI). However, a systematic review of the literature evaluating the causal association on humans does not exist to support this alleged association. Objective To perform systematic review examining the body of epidemiologic evidence and provide assessment of causal association based on principles of the Sir Austin Bradford Hill criteria or considerations for causal analysis. Methods A comprehensive search of public databases for published abstracts, case reports, cross-sectional surveys, and cohort studies using key search terms was conducted. Additional searches included regulatory reviews, EU IUCLID and EU Risk Assessment databases, and unpublished reports in the International Isocyanate Institute database. An expert panel consisting of physicians, toxicologists, and an epidemiologist critically reviewed accepted papers, providing examination of epidemiologic evidence of each report. Finally, the Hill criteria for causation were applied to the summative analysis of identified reports to estimate probability of causal association. Results Twelve papers reporting exposed populations with a variety of neurological symptoms or findings suitable for analysis were identified, including eleven case or case series reports, and one cross-sectional study. Three papers reported on the same population. Each of the papers was limited by paucity of diisocyanate exposure estimates, the presence of confounding exposures to known or suspected neurotoxicants, a lack of objective biological measures of exposure or neurotoxic effects, and lack of relative strength of association measures. Additionally, reported health symptoms and syndromes lacked consistency or

  5. Does diisocyanate exposure result in neurotoxicity?

    PubMed

    Hughes, M A; Carson, M; Collins, M A; Jolly, A T; Molenaar, D M; Steffens, W; Swaen, G M H

    2014-04-01

    Diisocyanates have been associated with respiratory and dermal sensitization. Limited number of case reports, and a few case studies, media, and other references suggest potential neurotoxic effects from exposures to toluene diisocyanate (TDI), 1,6 hexamethylene diisocyanate (HDI), and methylene diisocyanate (MDI). However, a systematic review of the literature evaluating the causal association on humans does not exist to support this alleged association. To perform systematic review examining the body of epidemiologic evidence and provide assessment of causal association based on principles of the Sir Austin Bradford Hill criteria or considerations for causal analysis. A comprehensive search of public databases for published abstracts, case reports, cross-sectional surveys, and cohort studies using key search terms was conducted. Additional searches included regulatory reviews, EU IUCLID and EU Risk Assessment databases, and unpublished reports in the International Isocyanate Institute database. An expert panel consisting of physicians, toxicologists, and an epidemiologist critically reviewed accepted papers, providing examination of epidemiologic evidence of each report. Finally, the Hill criteria for causation were applied to the summative analysis of identified reports to estimate probability of causal association. Twelve papers reporting exposed populations with a variety of neurological symptoms or findings suitable for analysis were identified, including eleven case or case series reports, and one cross-sectional study. Three papers reported on the same population. Each of the papers was limited by paucity of diisocyanate exposure estimates, the presence of confounding exposures to known or suspected neurotoxicants, a lack of objective biological measures of exposure or neurotoxic effects, and lack of relative strength of association measures. Additionally, reported health symptoms and syndromes lacked consistency or specificity. No plausible mechanism of

  6. Inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine apparently increases brain serotoninergic activity in the rat: no influence of previous chronic immobilization stress.

    PubMed

    Pol, O; Campmany, L; Armario, A

    1995-09-01

    The functional relationship between brain catecholamines and serotoninergic function was studied in stress-naive and chronically immobilized rats after blockade of catecholamine synthesis with alpha-methyl-p-tyrosine (alpha MpT). The levels of noradrenaline (NA), serotonin, and 5-hydroxyindole acetic acid (5-HIAA) in pons plus medulla, brainstem, hypothalamus, hippocampus, and frontal cortex, and those of 3-methoxy, 4-hydroxyphenile-tileneglicol sulphate (MHPG-SO4) in the hypothalamus were measured by HPLC. Chronic immobilization (IMO) resulted in higher NA levels in pons plus medulla and hypothalamus, the latter area (the only one in which the NA metabolite was determined) also showing slightly elevated MHPG-SO4 levels as compared to stress-naive rats. Chronic IMO did not alter either serotonin or 5-HIAA levels, but acute stress consistently increased 5-HIAA levels in all areas, independently of previous chronic stress. Administration of alpha-MpT drastically reduced NA and increased 5-HIAA levels in all brain regions excepting the frontal cortex. The effect of the drug on serotoninergic function was not altered by previous chronic exposure to IMO. These data suggest that the noradrenergic system appears to exert a tonic inhibitory effect on serotoninergic activity in the brain, with the intensity of the effect depending on the brain area studied. In addition, chronic stress does not appear to alter the functional relationship between noradrenergic and serotoninergic activities, although interactions might exist in more restricted brain areas; this deserves further study.

  7. Secretory patterns of catecholamines in Indo-Pacific bottlenose dolphins.

    PubMed

    Suzuki, Miwa; Nozawa, Aoi; Ueda, Keiichi; Bungo, Takashi; Terao, Hiromi; Asahina, Kiyoshi

    2012-05-15

    Catecholamines (CAs), namely adrenaline (A), noradrenaline (NA), and dopamine (DA), are secreted by the sympathoadrenal system and participate in a diverse array of functions, e.g., heat production, cardiovascular regulation, stress response and so on. However, little is known regarding peripheral CA fluctuations in cetaceans; nevertheless aquatic animals like them have needed to modify their physiological response especially for thermoregulation in water and oxygen economy during diving. To understand CA dynamism in cetaceans, diurnal changes in serum A, NA, and DA concentrations were measured during the winter and summer solstices in four Indo-Pacific bottlenose dolphins (Tursiops aduncus). The average serum NA concentration was much higher than the average A and DA concentrations, and all concentrations were higher than those reported in other cetacean species. No distinct diurnal fluctuations were observed in CA concentrations in either solstice, suggesting inhibition of the decrease in CA concentrations during nocturnal periods by the unique sleep pattern of dolphins. All the serum CA concentrations were negatively correlated with water temperature as body temperatures were, indicating that the sympathoadrenal system might be more active during winter than in summer season, suggesting a role of CA in thermoregulation.

  8. Iodothyronines and iodotyrosines as hypothetical receptors for catecholamines and opiates.

    PubMed

    Clur, A

    1985-02-01

    The signs and symptoms of hyperthyroidism are similar to those of phaeochromocytoma and adrenergic stimulation. These changes have been attributed to increased beta receptor numbers in hyperthyroidism, resulting in adrenergic supersensitivity. Beta blockers are used in treatment of hyperthyroidism and inoperable phaeochromocytomas. Beta receptor numbers increase in direct proportion to the dose of thyroid hormone given. Hypothyroidism decreases the number of alpha and beta receptors with greater reduction in beta receptor numbers. Beta responses predominate in hyperthyroidism and alpha responses in hypothyroidism. Hypothyroid patients show increased sensitivity to opiates while hyperthyroid patients are tolerant to opiates. In the present paper it is proposed that the various iodothyronine amino acids are incorporated into the various catecholamine and opiate receptors, providing the phenyl binding sites in the receptors. T3 and T4 are proposed as part of beta 1 chronotropic and inotropic receptors and those mediating vasodilation. T2 and rT3 are proposed as part of alpha 1 and alpha 2 receptors and dopamine and opiate receptors. T2 is probably incorporated into beta 2 receptors causing bronchodilation. The different structural features of the various amino acids would account in part for the selectivity of various drugs for various receptors.

  9. Irrelevant stimulus processing in ADHD: catecholamine dynamics and attentional networks

    PubMed Central

    Aboitiz, Francisco; Ossandón, Tomás; Zamorano, Francisco; Palma, Bárbara; Carrasco, Ximena

    2014-01-01

    A cardinal symptom of attention deficit and hyperactivity disorder (ADHD) is a general distractibility where children and adults shift their attentional focus to stimuli that are irrelevant to the ongoing behavior. This has been attributed to a deficit in dopaminergic signaling in cortico-striatal networks that regulate goal-directed behavior. Furthermore, recent imaging evidence points to an impairment of large scale, antagonistic brain networks that normally contribute to attentional engagement and disengagement, such as the task-positive networks and the default mode network (DMN). Related networks are the ventral attentional network (VAN) involved in attentional shifting, and the salience network (SN) related to task expectancy. Here we discuss the tonic–phasic dynamics of catecholaminergic signaling in the brain, and attempt to provide a link between this and the activities of the large-scale cortical networks that regulate behavior. More specifically, we propose that a disbalance of tonic catecholamine levels during task performance produces an emphasis of phasic signaling and increased excitability of the VAN, yielding distractibility symptoms. Likewise, immaturity of the SN may relate to abnormal tonic signaling and an incapacity to build up a proper executive system during task performance. We discuss different lines of evidence including pharmacology, brain imaging and electrophysiology, that are consistent with our proposal. Finally, restoring the pharmacodynamics of catecholaminergic signaling seems crucial to alleviate ADHD symptoms; however, the possibility is open to explore cognitive rehabilitation strategies to top-down modulate network dynamics compensating the pharmacological deficits. PMID:24723897

  10. Catecholamine-synthesizing enzymes in adrenals of seasonally acclimatized voles.

    PubMed

    Feist, D D; Feist, C F

    1978-01-01

    Tyrosine hydroxylase (TH) and phenylethanolamine-N-methyltransferase (PNMT) activities were assayed in adrenal glands of the following groups of the Alaskan red-backed vole (Clethrionomys rutilus dawsoni): 1) laboratory reared at 20 degrees C and 2) exposed to 5 degrees C for 1, 3, 7, and 28 days; 3) wild, summer acclimatized; 4) wild, fall acclimatized; and 5) wild, winter acclimatized. TH activity in laboratory-acclimated voles exposed to 5 degrees C was increased by 2 times after 3 days and remained elevated after 28 days. PNMT activity in these same voles was increased after 7 days and also remained elevated after 28 days of cold exposure. In wild-acclimatized voles TH activity and PNMT activity in summer were equivalent to levels in 28-day cold-acclimated laboratory voles. In fall, TH activity was increased to 2.5 times the summer value. It decreased by midwinter, but remained elevated above the summer level. In contrast, PNMT activity appeared unchanged from summer through fall and winter. Pregnant summer voles had markedly increased TH activity. Adrenal norepinephrine and epinephrine did not change significantly with cold acclimation or seasonal acclimatization. Thus, acclimatization of wild voles to fall and winter conditions involved aquisition of a greater capacity to synthesize adrenal catecholamines than that produced by exposing laboratory-reared voles to an extended period of cold.

  11. Prefrontal/accumbal catecholamine system processes high motivational salience

    PubMed Central

    Puglisi-Allegra, Stefano; Ventura, Rossella

    2012-01-01

    Motivational salience regulates the strength of goal seeking, the amount of risk taken, and the energy invested from mild to extreme. Highly motivational experiences promote highly persistent memories. Although this phenomenon is adaptive in normal conditions, experiences with extremely high levels of motivational salience can promote development of memories that can be re-experienced intrusively for long time resulting in maladaptive outcomes. Neural mechanisms mediating motivational salience attribution are, therefore, very important for individual and species survival and for well-being. However, these neural mechanisms could be implicated in attribution of abnormal motivational salience to different stimuli leading to maladaptive compulsive seeking or avoidance. We have offered the first evidence that prefrontal cortical norepinephrine (NE) transmission is a necessary condition for motivational salience attribution to highly salient stimuli, through modulation of dopamine (DA) in the nucleus accumbens (NAc), a brain area involved in all motivated behaviors. Moreover, we have shown that prefrontal-accumbal catecholamine (CA) system determines approach or avoidance responses to both reward- and aversion-related stimuli only when the salience of the unconditioned stimulus (UCS) is high enough to induce sustained CA activation, thus affirming that this system processes motivational salience attribution selectively to highly salient events. PMID:22754514

  12. Altered catecholamine receptor affinity in rabbit aortic intimal hyperplasia

    SciTech Connect

    O'Malley, M.K.; Cotecchia, S.; Hagen, P.O. )

    1991-08-01

    Intimal thickening is a universal response to endothelial denudation and is also thought to be a precursor of atherosclerosis. The authors have demonstrated selective supersensitivity in arterial intimal hyperplasia to norepinephrine and they now report a possible mechanism for this. Binding studies in rabbit aorta with the selective alpha 1-adrenergic radioligand 125I-HEAT demonstrated that there was no change in receptor density (20 {plus minus} 4 fmole/10(6) cells) in intact vascular smooth muscle cells at either 5 or 14 days after denudation. However, competition studies showed a 2.6-fold increase in alpha 1-adrenergic receptor affinity for norepinephrine in intimal hyperplastic tissue (P less than 0.05). This increased affinity for norepinephrine was associated with a greater increase in 32P-labeled phosphatidylinositol (148% intimal thickening versus 76% control) and phosphatidic acid (151% intimal thickening versus 56% control) following norepinephrine stimulation of free floating rings of intimal hyperplastic aorta. These data suggest that the catecholamine supersensitivity in rabbit aortic intimal hyperplasia is receptor mediated and may be linked to the phosphatidylinositol cycle.

  13. Plasma adrenocorticotropin, cortisol and catecholamines response to various exercises.

    PubMed

    Nagata, S; Takeda, F; Kurosawa, M; Mima, K; Hiraga, A; Kai, M; Taya, K

    1999-07-01

    The responses of plasma adrenocorticotropin (ACTH), cortisol, noradrenaline and adrenaline in 5 Thoroughbred horses to an incremental exercise and 2 relative workload exercises, at 105 and 80% maximal oxygen consumption (VO2max), on a treadmill were examined. These hormone concentrations increased (P < 0.05) with each exercise and the maximal plasma concentrations of ACTH, cortisol were observed between 5 and 30 min after the end of the exercise, while maximal catecholamine concentrations occurred just at exhaustion time. The plasma ACTH, noradrenaline and adrenaline responses during exercise were more sensitive to the intensity of exercise than that of cortisol and showed a significant correlation with blood lactate concentrations (r = 0.605, P < 0.001 for ACTH; r = 0.718, P < 0.001 for noradrenaline; r = 0.738, P < 0.001 for adrenaline). The plasma cortisol response appeared to be connected with the duration of exercise (r = 0.71, P < 0.05). The recovery of these hormones was related to the exercise styles. These results suggest that the autonomic nervous system and the pituitary-adrenal axis of the horse are efficiently stimulated by various treadmill exercises, and these hormones may be used in the evaluation of exercise-induced stress.

  14. Stress stimulates production of catecholamines in rat adipocytes.

    PubMed

    Kvetnansky, R; Ukropec, J; Laukova, M; Manz, B; Pacak, K; Vargovic, P

    2012-07-01

    The sympathoadrenal system is the main source of catecholamines (CAs) in adipose tissues and therefore plays the key role in the regulation of adipose tissue metabolism. We recently reported existence of an alternative CA-producing system directly in adipose tissue cells, and here we investigated effect of various stressors-physical (cold) and emotional stress (immobilization) on dynamics of this system. Acute or chronic cold exposure increased intracellular norepinephrine (NE) and epinephrine (EPI) concentration in isolated rat mesenteric adipocytes. Gene expression of CA biosynthetic enzymes did not change in adipocytes but was increased in stromal vascular fraction (SVF) after 28 day cold. Exposure of rats to a single IMO stress caused increases in NE and EPI levels, and also gene expression of CA biosynthetic enzymes in adipocytes. In SVF changes were similar but more pronounced. Animals adapted to a long-term cold exposure (28 days, 4°C) did not show those responses found after a single IMO stress either in adipocytes or SVF. Our data indicate that gene machinery accommodated in adipocytes, which is able to synthesize NE and EPI de novo, is significantly activated by stress. Cold-adapted animals keep their adaptation even after an exposure to a novel stressor. These findings suggest the functionality of CAs produced endogenously in adipocytes. Taken together, the newly discovered CA synthesizing system in adipocytes is activated in stress situations and might significantly contribute to regulation of lipolysis and other metabolic or thermogenetic processes.

  15. Irrelevant stimulus processing in ADHD: catecholamine dynamics and attentional networks.

    PubMed

    Aboitiz, Francisco; Ossandón, Tomás; Zamorano, Francisco; Palma, Bárbara; Carrasco, Ximena

    2014-01-01

    A cardinal symptom of attention deficit and hyperactivity disorder (ADHD) is a general distractibility where children and adults shift their attentional focus to stimuli that are irrelevant to the ongoing behavior. This has been attributed to a deficit in dopaminergic signaling in cortico-striatal networks that regulate goal-directed behavior. Furthermore, recent imaging evidence points to an impairment of large scale, antagonistic brain networks that normally contribute to attentional engagement and disengagement, such as the task-positive networks and the default mode network (DMN). Related networks are the ventral attentional network (VAN) involved in attentional shifting, and the salience network (SN) related to task expectancy. Here we discuss the tonic-phasic dynamics of catecholaminergic signaling in the brain, and attempt to provide a link between this and the activities of the large-scale cortical networks that regulate behavior. More specifically, we propose that a disbalance of tonic catecholamine levels during task performance produces an emphasis of phasic signaling and increased excitability of the VAN, yielding distractibility symptoms. Likewise, immaturity of the SN may relate to abnormal tonic signaling and an incapacity to build up a proper executive system during task performance. We discuss different lines of evidence including pharmacology, brain imaging and electrophysiology, that are consistent with our proposal. Finally, restoring the pharmacodynamics of catecholaminergic signaling seems crucial to alleviate ADHD symptoms; however, the possibility is open to explore cognitive rehabilitation strategies to top-down modulate network dynamics compensating the pharmacological deficits.

  16. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis

    PubMed Central

    Nguyen, Khoa D.; Qiu, Yifu; Cui, Xiaojin; Goh, Y.P. Sharon; Mwangi, Julia; David, Tovo; Mukundan, Lata; Brombacher, Frank; Locksley, Richard M.; Chawla, Ajay

    2011-01-01

    All homeotherms utilize thermogenesis to maintain core body temperature, ensuring that cellular functions and physiologic processes can ensue in cold environments1-3. In the prevailing model, when the hypothalamus senses cold temperatures, it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue (BAT) and white adipose tissue (WAT)4,5. Acting via the β3-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes6, whereas it stimulates the expression of thermogenic genes, such as PPARγ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1), and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes7-9. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report an unexpected requirement for the interleukin 4 (IL4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Cold exposure rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in BAT and lipolysis in WAT. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL4 increased thermogenic gene expression, fatty acid mobilization, and energy expenditure, all in a macrophage-dependent manner. We have thus discovered a surprising role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold. PMID:22101429

  17. Oral administration of D-aspartate, but not L-aspartate, depresses rectal temperature and alters plasma metabolites in chicks.

    PubMed

    Erwan, Edi; Chowdhury, Vishwajit Sur; Nagasawa, Mao; Goda, Ryosei; Otsuka, Tsuyoshi; Yasuo, Shinobu; Furuse, Mitsuhiro

    2014-07-25

    L-Aspartate (L-Asp) and D-aspartate (D-Asp) are physiologically important amino acids in mammals and birds. However, the functions of these amino acids have not yet been fully understood. In this study, we therefore examined the effects of L-Asp and D-Asp in terms of regulating body temperature, plasma metabolites and catecholamines in chicks. Chicks were first orally administered with different doses (0, 3.75, 7.5 and 15 mmol/kg body weight) of L- or D-Asp to monitor the effects of these amino acids on rectal temperature during 120 min of the experimental period. Oral administration of D-Asp, but not of L-Asp, linearly decreased the rectal temperature in chicks. Importantly, orally administered D-Asp led to a significant reduction in body temperature in chicks even under high ambient temperature (HT) conditions. However, centrally administered D-Asp did not significantly influence the body temperature in chicks. As for plasma metabolites and catecholamines, orally administered D-Asp led to decreased triacylglycerol and uric acid concentrations and increased glucose and chlorine concentrations but did not alter plasma catecholamines. These results suggest that oral administration of D-Asp may play a potent role in reducing body temperature under both normal and HT conditions. The alteration of plasma metabolites further indicates that D-Asp may contribute to the regulation of metabolic activity in chicks. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. NEUROTOXICITY PRODUCED BY DIBROMOACETIC ACID IN DRINKING WATER OF RATS.

    EPA Science Inventory

    This manuscript examines the neurotoxic potential of a commonly found disinfection by-product (DBP), dibromoacetic acid (DBA). While the Safe Drinking Water Act requires evaluation of DBPs for noncancer health effects, surprisingly few have been tested for neurotoxicity. Rats e...

  19. 40 CFR 799.9620 - TSCA neurotoxicity screening battery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA neurotoxicity screening battery... REQUIREMENTS Health Effects Test Guidelines § 799.9620 TSCA neurotoxicity screening battery. (a) Scope. This... battery consists of a functional observational battery, motor activity, and neuropathology. The functional...

  20. Multiple mechanisms mediate aluminum kinetics and neurotoxicity

    SciTech Connect

    Provan, S.D.

    1988-01-01

    There is considerable evidence suggesting that calcium (Ca) and membrane Ca-regulating systems may influence the kinetics and neurotoxicity of aluminum (Al). These interactions likely occur at the membrane level under physiological conditions. To more fully examine these mechanisms, the hypothesis that Al would interact with membranes under physiological conditions was tested. The results suggest that Al, under these conditions, could interact with and traverse biological membranes. A biological membrane model was used to test the hypothesis that Al interacts with an intestinal Ca transporting system. To evaluate the effects of a Ca deficient diet on Al absorption, rats were maintained on a Ca-deficient or Ca-replete diet for up to four weeks. A modified in situ preparations was prepared. Rats maintained on the Ca-deficient diet exhibited a more rapid disappearance rate from the gut and greater extent of absorption into the portal blood. To evaluate Al distribution, rats were injected with Al and maintained on the above diets for four weeks. There was generally more Al in the tissues of rats maintained on a Ca-deficient diet with the exception of heart and muscle. More Al accumulated within the hippocampus than the cerebral cortex in those rats fed a Ca-deficient diet and injected with 400 {mu}mol Al/kg. The release of radiolabeled glutamate from transverse, rat hippocampal slices was used as a model of Al neurotoxicity.

  1. Neurotoxicity of Dietary Supplements from Annonaceae Species.

    PubMed

    Höllerhage, Matthias; Rösler, Thomas W; Berjas, Magda; Luo, Rensheng; Tran, Kevin; Richards, Kristy M; Sabaa-Srur, Armando U; Maia, José Guilherme S; Moraes, Maria Rosa de; Godoy, Helena T; Höglinger, Günter U; Smith, Robert E

    2015-01-01

    Dietary supplements containing plant materials of Annonaceae species (Annona muricata L., A. squamosa L., A. mucosa JACQ., A. squamosa × cherimola Mabb.) were extracted by hot, pressurized ethyl acetate and analyzed for their effect in vitro on Lund human mesencephalic neurons. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell death was determined by lactate dehydrogenase levels. Three supplements strongly decreased the cell viability at extract concentrations of 1 µg/mL, of which 1 decreased cell viability at 0.1 µg/µL. Also, strong neuronal toxicities of these supplements were found. Cell death was observed at concentrations of 10 µg/mL. The degree of toxicity was comparable to the ones found in Annonaceous fruit extracts. Two fruit pulps of Annonaceae (A. muricata and A. squamosa) showed a reduction in cell viability at lower concentrations. The fruit pulp extract of A. muricata revealed the strongest neurotoxic effect, with 67% cell death at a concentration of 1 µg/mL. A high reduction in cell viability coupled with pronounced cell death was found at 0.1 µg/mL for an Annonaceous seed extract. These results demonstrate that the intake of dietary supplements containing plant material from Annonaceae may be hazardous to health in terms of neurotoxicity.

  2. Protection against kainate neurotoxicity by pyrrolidine dithiocarbamate.

    PubMed

    Shin, Eun-Joo; Jhoo, Jin Hyeong; Kim, Won-Ki; Jhoo, Wang Kee; Lee, Chaeyoung; Jung, Bae Dong; Kim, Hyoung-Chun

    2004-01-01

    The effect of pyrrolidine dithiocarbamate (PDTC) on kainate (KA)-induced neurotoxicity was examined in Sprague-Dawley rats. At 10 mg/kg, i.p., KA produced seizures accompanied by neuronal loss in the hippocampus and increased levels of malondialdehyde (MDA) and protein carbonyl. Pretreatment with PDTC (100 or 200 mg/kg, p.o., every 12 h x 5) blocked KA-induced neurotoxicities (seizures, increases in MDA and protein carbonyl and neuronal losses) in a dose-dependent manner. These effects were counteracted by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (25 or 50 micro g/kg, i.p.), but not by the A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1 mg/kg, i.p.) or the A(2B) receptor antagonist alloxazine (1.5 or 3.0 mg/kg, i.p.). Our results suggest that the anticonvulsant and neuroprotective effects of PDTC are mediated, at least in part, via adenosine A(1) receptor stimulation.

  3. Investigate the chronic neurotoxic effects of diquat.

    PubMed

    Karuppagounder, Senthilkumar S; Ahuja, Manuj; Buabeid, Manal; Parameshwaran, Koodeswaran; Abdel-Rehman, Engy; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishanan

    2012-05-01

    Chronic exposure to agricultural chemicals (pesticides/herbicides) has been shown to induce neurotoxic effects or results in accumulation of various toxic metabolic by-products. These substances have the relevant ability to cause or increase the risk for neurodegeneration. Diquat is an herbicide that has been extensively used in the United States of America and other parts of the world. Diquat is constantly released into the environment during its use as a contact herbicide. Diquat structurally resembles 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and paraquat. Rotenone, paraquat, maneb and MPTP reproduce features of movement disorders in experimental animal models. Based on the structural similarity to other neurotoxins, chronic exposure of diquat can induce behavioral and neurochemical alterations associated with dopaminergic neurotoxicity. However, in the present study, diquat unlike other neurotoxins (rotenone, 6-hydroxydopamine, MPTP, paraquat and maneb) did not induce dopamine depletion in the mouse striatum. Although, notable exacerbation in motor impairment (swimming score, akinesia and open field) were evident that may be due to the decreased dopamine turnover and mild nigrostriatal neurodegeneration. These data indicate that, despite the apparent structural similarity to other dopaminergic neurotoxins, diquat did not exert severe deleterious effects on dopamine neurons in a manner that is unique to rotenone and MPTP.

  4. Meeting Report: Alternatives for Developmental Neurotoxicity Testing

    PubMed Central

    Lein, Pamela; Locke, Paul; Goldberg, Alan

    2007-01-01

    Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are collaborating in a program called TestSmart DNT, the goals of which are to: (a) develop alternative methodologies for identifying and prioritizing chemicals and exposures that may cause developmental neurotoxicity in humans; (b) develop the policies for incorporating DNT alternatives into regulatory decision making; and (c) identify opportunities for reducing, refining, or replacing the use of animals in DNT. The first TestSmart DNT workshop was an open registration meeting held 13–15 March 2006 in Reston, Virginia. The primary objective was to bring together stakeholders (test developers, test users, regulators, and advocates for children’s health, animal welfare, and environmental health) and individuals representing diverse disciplines (developmental neurobiology, toxicology, policy, and regulatory science) from around the world to share information and concerns relating to the science and policy of DNT. Individual presentations are available at the CAAT TestSmart website. This report provides a synthesis of workgroup discussions and recommendations for future directions and priorities, which include initiating a systematic evaluation of alternative models and technologies, developing a framework for the creation of an open database to catalog DNT data, and devising a strategy for harmonizing the validation process across international jurisdictional borders. PMID:17520065

  5. Meeting report: alternatives for developmental neurotoxicity testing.

    PubMed

    Lein, Pamela; Locke, Paul; Goldberg, Alan

    2007-05-01

    Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are collaborating in a program called TestSmart DNT, the goals of which are to: (a) develop alternative methodologies for identifying and prioritizing chemicals and exposures that may cause developmental neurotoxicity in humans; (b) develop the policies for incorporating DNT alternatives into regulatory decision making; and (c) identify opportunities for reducing, refining, or replacing the use of animals in DNT. The first TestSmart DNT workshop was an open registration meeting held 13-15 March 2006 in Reston, Virginia. The primary objective was to bring together stakeholders (test developers, test users, regulators, and advocates for children's health, animal welfare, and environmental health) and individuals representing diverse disciplines (developmental neurobiology, toxicology, policy, and regulatory science) from around the world to share information and concerns relating to the science and policy of DNT. Individual presentations are available at the CAAT TestSmart website. This report provides a synthesis of workgroup discussions and recommendations for future directions and priorities, which include initiating a systematic evaluation of alternative models and technologies, developing a framework for the creation of an open database to catalog DNT data, and devising a strategy for harmonizing the validation process across international jurisdictional borders.

  6. The Portland Neurotoxicity Scale: Validation of a Brief Self-Report Measure of Antiepileptic-Drug-Related Neurotoxicity

    ERIC Educational Resources Information Center

    Salinsky, Martin C.; Storzbach, Daniel

    2005-01-01

    The Portland Neurotoxicity Scale (PNS) is a brief patient-based survey of neurotoxicity complaints commonly encountered with the use of antiepileptic drugs (AEDs). The authors present data on the validity of this scale, particularly when used in longitudinal studies. Participants included 55 healthy controls, 23 epilepsy patient controls, and 86…

  7. Increased gene expression of catecholamine-synthesizing enzymes in adrenal glands contributes to high circulating catecholamines in pigs with tachycardia-induced cardiomyopathy.

    PubMed

    Tomaszek, A; Kiczak, L; Bania, J; Paslawska, U; Zacharski, M; Janiszewski, A; Noszczyk-Nowak, A; Dziegiel, P; Kuropka, P; Ponikowski, P; Jankowska, E A

    2015-04-01

    High levels of circulating catecholamines have been established as fundamental pathophysiological elements of heart failure (HF). However, it is unclear whether the increased gene expression of catecholamine-synthesis enzymes in the adrenal glands contributes to these hormone abnormalities in large animal HF models. We analyzed the mRNA levels of catecholamine-synthesizing enzymes: tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AAAD), dopamine-β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in adrenal glands of 18 pigs with chronic systolic non-ischaemic HF (tachycardia-induced cardiomyopathy due to right ventricle pacing) and 6 sham-operated controls. Pigs with severe HF demonstrated an increased expression of TH and DBH (but neither AAAD nor PNMT) as compared to animals with milder HF and controls (P<0.05 in all cases). The increased adrenal mRNA expression of TH and DBH was accompanied by a reduced left ventricle ejection fraction (LVEF) (P<0.001) and an elevated plasma B-type natriuretic peptide (BNP) (P<0.01), the other indices reflecting HF severity. There was a positive relationship between the increased adrenal mRNA expression of TH and DBH, and the high levels of circulating adrenaline and noradrenaline (all P<0.05). The association with noradrenaline remained significant also when adjusted for LVEF and plasma BNP, suggesting a significant contribution of adrenals to the circulating pool of catecholamines in subjects with systolic HF.

  8. GABAB receptors modulate catecholamine secretion in chromaffin cells by a mechanism involving cyclic AMP formation.

    PubMed

    Oset-Gasque, M J; Parramón, M; González, M P

    1993-12-01

    1. The function of gamma-aminobutyric acidB (GABAB) receptors in modulation of catecholamine secretion by chromaffin cells and the possible mechanism involved in this action have been examined. 2. The GABAB agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) were found to induce a dose-dependent increase of basal catecholamine secretion. The EC50s were 151 +/- 35 microM and 225 +/- 58 microM for baclofen and 3-APPA, respectively. This stimulatory effect was specific since it could be blocked by 0.5 mM of the specific GABAB antagonist CGP-35348. 3. In contrast, preincubation of chromaffin cells with the GABAB agonists was found to inhibit, in a dose-dependent manner, the catecholamine secretion evoked by 10 microM nicotine and 200 microM muscimol. 4. The effects of GABAB agonists on both basal and evoked catecholamine secretion were found to be accompanied by parallel changes in intracellular calcium concentration ([Ca2+]i). GABAB agonists produced a dose-dependent increase in [Ca2+]i which was partially blocked by CGP 35348, but they produced a strong inhibition of the [Ca2+]i increase induced by nicotine and muscimol. 5. The GABAB agonists also produced a dose-dependent increase in intracellular cyclic AMP levels, there being a direct correlation between both increase in catecholamine secretion and in intracellular cyclic AMP levels. 6. The pretreatment of chromaffin cells with pertussis toxin doubled the catecholamine secretion and increased by four times the intracellular cyclic AMP levels evoked by GABAB agonists. 7. The possible involvement of adenylate cyclase in the mechanism of GABAA receptor modulation of catecholamine secretion is discussed.

  9. Evidence for a Critical Role of Catecholamines for Cardiomyocyte Lineage Commitment in Murine Embryonic Stem Cells

    PubMed Central

    Lehmann, Martin; Nguemo, Filomain; Wagh, Vilas; Pfannkuche, Kurt; Hescheler, Jürgen; Reppel, Michael

    2013-01-01

    Catecholamine release is known to modulate cardiac output by increasing heart rate. Although much is known about catecholamine function and regulation in adults, little is known about the presence and role of catecholamines during heart development. The present study aimed therefore to evaluate the effects of different catecholamines on early heart development in an in vitro setting using embryonic stem (ES) cell-derived cardiomyocytes. Effects of catecholamine depletion induced by reserpine were examined in murine ES cells (line D3, αPIG44) during differentiation. Cardiac differentiation was assessed by immunocytochemistry, qRT-PCR, quantification of beating clusters, flow cytometry and pharmacological approaches. Proliferation was analyzed by EB cross-section measurements, while functionality of cardiomyocytes was studied by extracellular field potential (FP) measurements using microelectrode arrays (MEAs). To further differentiate between substance-specific effects of reserpine and catecholamine action via α- and β-receptors we proved the involvement of adrenergic receptors by application of unspecific α- and β-receptor antagonists. Reserpine treatment led to remarkable down-regulation of cardiac-specific genes, proteins and mesodermal marker genes. In more detail, the average ratio of ∼40% spontaneously beating control clusters was significantly reduced by 100%, 91.1% and 20.0% on days 10, 12, and 14, respectively. Flow cytometry revealed a significant reduction (by 71.6%, n = 11) of eGFP positive CMs after reserpine treatment. By contrast, reserpine did not reduce EB growth while number of neuronal cells in reserpine-treated EBs was significantly increased. MEA measurements of reserpine-treated EBs showed lower FP frequencies and weak responsiveness to adrenergic and muscarinic stimulation. Interestingly we found that developmental inhibition after α- and β-adrenergic blocker application mimicked developmental changes with reserpine. Using several

  10. GABAB receptors modulate catecholamine secretion in chromaffin cells by a mechanism involving cyclic AMP formation.

    PubMed Central

    Oset-Gasque, M. J.; Parramón, M.; González, M. P.

    1993-01-01

    1. The function of gamma-aminobutyric acidB (GABAB) receptors in modulation of catecholamine secretion by chromaffin cells and the possible mechanism involved in this action have been examined. 2. The GABAB agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) were found to induce a dose-dependent increase of basal catecholamine secretion. The EC50s were 151 +/- 35 microM and 225 +/- 58 microM for baclofen and 3-APPA, respectively. This stimulatory effect was specific since it could be blocked by 0.5 mM of the specific GABAB antagonist CGP-35348. 3. In contrast, preincubation of chromaffin cells with the GABAB agonists was found to inhibit, in a dose-dependent manner, the catecholamine secretion evoked by 10 microM nicotine and 200 microM muscimol. 4. The effects of GABAB agonists on both basal and evoked catecholamine secretion were found to be accompanied by parallel changes in intracellular calcium concentration ([Ca2+]i). GABAB agonists produced a dose-dependent increase in [Ca2+]i which was partially blocked by CGP 35348, but they produced a strong inhibition of the [Ca2+]i increase induced by nicotine and muscimol. 5. The GABAB agonists also produced a dose-dependent increase in intracellular cyclic AMP levels, there being a direct correlation between both increase in catecholamine secretion and in intracellular cyclic AMP levels. 6. The pretreatment of chromaffin cells with pertussis toxin doubled the catecholamine secretion and increased by four times the intracellular cyclic AMP levels evoked by GABAB agonists. 7. The possible involvement of adenylate cyclase in the mechanism of GABAA receptor modulation of catecholamine secretion is discussed. PMID:8306105

  11. Individual differences in the motivation to communicate relate to levels of midbrain and striatal catecholamine markers in male European starlings.

    PubMed

    Heimovics, Sarah A; Salvante, Katrina G; Sockman, Keith W; Riters, Lauren V

    2011-11-01

    Individuals display dramatic differences in social communication even within similar social contexts. Across vertebrates dopaminergic projections from the ventral tegmental area (VTA) and midbrain central gray (GCt) strongly influence motivated, reward-directed behaviors. Norepinephrine is also rich in these areas and may alter dopamine neuronal activity. The present study was designed to provide insight into the roles of dopamine and norepinephrine in VTA and GCt and their efferent striatal target, song control region area X, in the regulation of individual differences in the motivation to sing. We used high pressure liquid chromatography with electrochemical detection to measure dopamine, norepinephrine and their metabolites in micropunched samples from VTA, GCt, and area X in male European starlings (Sturnus vulgaris). We categorized males as sexually motivated or non-sexually motivated based on individual differences in song produced in response to a female. Dopamine markers and norepinephrine in VTA and dopamine in area X correlated positively with sexually-motivated song. Norepinephrine in area X correlated negatively with non-sexually-motivated song. Dopamine in GCt correlated negatively with sexually-motivated song, and the metabolite DOPAC correlated positively with non-sexually-motivated song. Results highlight a role for evolutionarily conserved dopaminergic projections from VTA to striatum in the motivation to communicate and highlight novel patterns of catecholamine activity in area X, VTA, and GCt associated with individual differences in sexually-motivated and non-sexually-motivated communication. Correlations between dopamine and norepinephrine markers also suggest that norepinephrine may contribute to individual differences in communication by modifying dopamine neuronal activity in VTA and GCt. Copyright © 2011. Published by Elsevier Inc.

  12. Individual differences in the motivation to communicate relate to levels of midbrain and striatal catecholamine markers in male European starlings

    PubMed Central

    Heimovics, Sarah A; Salvante, Katrina G; Sockman, Keith W; Riters, Lauren V

    2013-01-01

    Individuals display dramatic differences in social communication even within similar social contexts. Across vertebrates dopaminergic projections from the ventral tegmental area (VTA) and midbrain central gray (GCt) strongly influence motivated, reward-directed behaviors. Norepinephrine is also rich in these areas and may alter dopamine neuronal activity. The present study was designed to provide insight into the roles of dopamine and norepinephrine in VTA and GCt and their efferent striatal target, song control region area X, in the regulation of individual differences in the motivation to sing. We used high pressure liquid chromatography with electrochemical detection to measure dopamine, norepinephrine and their metabolites in micropunched samples from VTA, GCt, and area X in male European starlings (Sturnus vulgaris). We categorized males as sexually motivated or non-sexually motivated based on individual differences in song produced in response to a female. Dopamine markers and norepinephrine in VTA and dopamine in area X correlated positively with sexually-motivated song. Norepinephrine in area X correlated negatively with non-sexually-motivated song. Dopamine in GCt correlated negatively with sexually-motivated song, and the metabolite DOPAC correlated positively with non-sexually-motivated song. Results highlight a role for evolutionarily conserved dopaminergic projections from VTA to striatum in the motivation to communicate and highlight novel patterns of catecholamine activity in area X, VTA, and GCt associated with individual differences in sexually-motivated and non-sexually-motivated communication. Correlations between dopamine and norepinephrine markers also suggest that norepinephrine may contribute to individual differences in communication by modifying dopamine neuronal activity in VTA and GCt. PMID:21907203

  13. Acute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma.

    PubMed

    Giavarini, Alessandra; Chedid, Antoine; Bobrie, Guillaume; Plouin, Pierre-François; Hagège, Albert; Amar, Laurence

    2013-10-01

    Phaeochromocytomas and paragangliomas (PPGL) can cause acute catecholamine cardiomyopathy (ACC). We assessed the prevalence of ACC and compared the presentation of cases with and without ACC in a large series of PPGL. Single centre retrospective study. Hypertension Unit, University Hospital, Paris. 140 consecutive patients with PPGL, referred from January 2003 to September 2012. Left ventricular ejection fraction (LVEF), perioperative mortality. Fifteen patients (11%) had suffered an ACC, occurring in 14 cases before the diagnosis of PPGL. Precipitating factors were identified in 11 cases. Twelve patients presented with acute pulmonary oedema, including 10 with cardiogenic shock, requiring life support in eight cases. Seven patients (five with pulmonary oedema) presented with acute chest pain and cardiac dysfunction. Electrocardiographic abnormalities were present in 14 cases: ST segment elevation or pathological Q waves, ST segment depression, and/or diffuse T wave inversion. Six patients displayed classical (apical ballooning) or inverted (basal/mid ventricular stunning) takotsubo-like cardiomyopathy. Coronary arteries were always normal on angiography. In patients with ACC, median LVEF rose from 30% (IQR 23-33%) during ACC to 71% (50-72%) before surgery (n=11, p<0.001). Median LVEF before PPGL surgery was 65% (51-72%) and 65% (60-70%) in patients with and without a history of ACC, respectively (not significant). PPGL may present as ACC in 11% of cases, excluding patients dying from undiagnosed tumours. Left ventricular dysfunction is usually reversible before surgery. PPGL should be suspected in patients with acute heart failure without evidence of valvular or coronary artery disease.

  14. EXTENT AND MAGNITUDE OF CATECHOLAMINE SURGE IN PEDIATRIC BURNED PATIENTS

    PubMed Central

    Kulp, Gabriela A; Herndon, David N.; Lee, Jong O.; Suman, Oscar E.; Jeschke, Marc G

    2009-01-01

    Increased catecholamine (CA) levels after severe burn are associated with stress, inflammation, hypermetabolism and impaired immune function. The CA secretion profiles in burned patients are not well described. Mechanisms, duration and extent of CA surge are unknown. The purpose of this large unicenter study was to evaluate the extent and magnitude of CA surge following severe burn in pediatric patients. Patients admitted between 1996 and 2008 were enrolled in this study. Twenty-four-hour urine collections were performed during acute hospitalization and up to 2 years post burn. Results from the samples collected from 12 normal, healthy volunteers were compared with the data from the burned patients. Relevant demographic and clinical information was obtained from Medical Records. Student’s t-test and one way ANOVA were used to analyze the data where appropriate. Significance was accepted at p<0.05. Four-hundred thirteen patients were enrolled in this study, 17 patients died during acute hospitalization. Burn caused a marked stress and inflammatory response, indicated by massive tachycardia and elevated pro-inflammatory cytokines. In burned patients, CA levels are consistently and significantly modulated after burn when compared to the levels in normal, healthy volunteers. CA levels were significantly higher in males compared to females, correlated with burn size in burns over 40% and were increased in older children. There were differences over time in survivors vs. non-survivors, with CA levels significantly higher in non-survivors at 2 time points. Inflammatory cytokines show a similar profile during the study period. Our study gives clinicians a useful insight into the extent and magnitude of CA elevation to better design treatment strategies. PMID:20407405

  15. Catecholamine regulation of lactate dehydrogenase in rat brain cell culture

    SciTech Connect

    Kumar, S.; McGinnis, J.F.; de Vellis, J.

    1980-03-25

    The mechanism of catecholamine induction of the soluble cytoplasmic enzyme lactate dehydrogenase (EC 1.1.1.27) was studied in the rat glial tumor cell line, C6. Lactate dehydrogenase was partially purified from extracts of (/sup 3/H)leucine-labeled cells by affinity gel chromatography and quantitatively immunoprecipitated with anti-lactate dehydrogenase-5 IgG and with antilactate dehydrogenase-1 IgG. The immunoprecipitates were dissociated and electrophoresed on sodium dodecyl sulfate polyacrylamide gels. Using this methodology, the increased enzyme activity of lactate dehydrogenase in norepinephrine-treated C6 cells was observed to be concomitant with the increased synthesis of enzyme molecules. Despite the continued presence of norepinephrine, the specific increase in the rate of synthesis of lactate dehydrogenase was transient. It was first detected at 4 h, was maximum at 9 h, and returned to basal levels by 24 h. The half-life of lactate dehydrogenase enzyme activity was 36 h during the induction and 40 h during deinduction. The half-life for decay of /sup 3/H-labeled lactate dehydrogenase was 41 h. These observations suggest that the increase in lactate dehydrogenase activity in norepinephrine-treated cells does not involve any change in the rate of degradation. Norepinephrine increased the specific rate of synthesis of both lactate dehydrogenase-5 (a tetramer of four M subunits) and lactate dehydrogenase-1 (a tetramer of four H subunits), although to different extents. Since these subunits are coded for by two separate genes on separate chromosomes, it suggests that the regulatory mechanism involves at least two separate sites of action.

  16. Plasma catecholamines and renin activity in wrestlers following vigorous swimming.

    PubMed

    Vigas, M; Celko, J; Juránková, E; Jezová, D; Kvetnanský, R

    1998-01-01

    Cardiovascular and neuroendocrine responses to exercise in a physically fit and an untrained group of young healthy subjects were compared to study the significance of physical fitness for performance in a discipline for which the athletes were not trained. Ten wrestlers of national rank prepared for an international competition (age 18 years) and 9 untrained healthy males (age 21 years). Exercise consisted of 27-min swimming, freestyle, in water of 29 degrees C, with last 3 min increased to maximal effort. The blood pressure, heart rate and sublingual temperature were measured and blood samples were withdrawn before exercise, immediately after and after a 30 min period of rest. Catecholamines were analyzed by radioenzymatic method and plasma renin activity (PRA) using commercial kits. Systolic blood pressure and heart rate after swimming were increased comparably in the two groups, diastolic pressure was unchanged in the controls and decreased in the wrestlers. Plasma cortisol remained unchanged. Plasma glucose tended to increase in the controls and so decrease in wrestlers, with a significant difference between them after swimming (p < 0.05). However, plasma adrenaline was concomitantly increased in both groups (p < 0.01). Noradrenaline and PRA were increased after swimming in both the control and trained group. The increments of noradrenaline and PRA in wrestlers were significantly reduced compared to the control group (p < 0.01, p < 0.05, respectively). Higher physical fitness in athletes significantly reduced plasma noradrenaline and angiotensin responses to maximal exercise demanding special skill in work performance which had not been included in their training program. Training of wrestlers did not cause an exaggerated plasma adrenaline response to exercise.

  17. DOPAMINE RECEPTOR ACTIVATION REVEALS A NOVEL, KYNURENATE-SENSITIVE COMPONENT OF STRIATAL NMDA NEUROTOXICITY

    PubMed Central

    Poeggeler, Burkhard; Rassoulpour, Arash; Wu, Hui-Qiu; Guidetti, Paolo; Roberts, Rosalinda C.; Schwarcz, Robert

    2007-01-01

    The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, non-physiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in 2-3-fold increases in excitotoxic lesion size. Pre-treatment with kynurenine 3-hydroxylase inhibitors or dopamine receptor antagonists, two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum. PMID:17629627

  18. Mithramycin protects against dopaminergic neurotoxicity in the mouse brain after administration of methamphetamine.

    PubMed

    Hagiwara, Hiroko; Iyo, Masaomi; Hashimoto, Kenji

    2009-12-08

    The present study was undertaken to examine the effects of mithramycin, an inhibitor of transcription factor Specificity protein (Sp)-1, on the behavioral changes and dopaminergic neurotoxicity in the mouse striatum after administration of methamphetamine (METH). Pretreatment with mithramycin (75, 150 or 300 microg/kg) did not alter acute hyperlocomotion in mice after a single administration of METH (3 mg/kg). However, the development of behavioral sensitization in mice after repeated administration of METH (3 mg/kg/day, once daily for 5 days) was significantly blocked by pretreatment with mithramycin (300 microg/kg). Furthermore, pretreatment with mithramycin (300 microg/kg) significantly attenuated the hyperthermia in mice after repeated administration of METH (3 mg/kgx3, 3-h intervals). Moreover, the combination of pretreatment and subsequent administration of mithramycin (75, 150 or 300 microg/kg) significantly attenuated the reductions of dopamine (DA), its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and DA transporter (DAT) in the striatum after repeated administration of METH (3 mg/kgx3, 3-h intervals), and these attenuations were dose dependent. These findings suggest that mithramycin attenuates the development of behavioral sensitization and dopaminergic neurotoxicity in mice after repeated administration of METH. Therefore, mithramycin could have potential for the treatment of METH abusers, particularly since this drug has been approved by the Food and Drug Administration in the United States. In the future, however, another Sp1 inhibitors with fewer side effects might be more appropriate.

  19. Personality traits of aggression-submissiveness and perfectionism associate with ABO blood groups through catecholamine activities.

    PubMed

    Hobgood, Donna K

    2011-08-01

    Personality trait research has shown associations with many genes, prominently those of the catecholamine metabolism such as dopamine beta hydroxylase (DBH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). Because DBH gene is in linkage disequilibrium with ABO gene, there is reason to think that other catecholamine genes using the same substrate as DBH may also have associations with ABO blood groups, and this paper demonstrates how this may be so. Reasons include similarities in hapmap population frequency distributions, similarities in illness risks between ABO blood groups and DBH activities as well as between ABO blood groups and COMT activities and between ABO blood groups and MAOA activities. If ABO blood groups can be demonstrated to associate with all these catecholamine genes, then the catecholamine personality trait research can be applied to ABO blood groups and tested for confirmation. ABO blood typing is widely available and affords ability to test this hypothesis and thus confirm the possible joint association of personality traits of aggression-submissiveness and perfectionism to catecholamine genes and to ABO blood groups. Clinical applications and implications are discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. Preparation of Sticky Escherichia coli through Surface Display of an Adhesive Catecholamine Moiety

    PubMed Central

    Park, Joseph P.; Choi, Min-Jung; Kim, Se Hun

    2014-01-01

    Mussels attach to virtually all types of inorganic and organic surfaces in aqueous environments, and catecholamines composed of 3,4-dihydroxy-l-phenylalanine (DOPA), lysine, and histidine in mussel adhesive proteins play a key role in the robust adhesion. DOPA is an unusual catecholic amino acid, and its side chain is called catechol. In this study, we displayed the adhesive moiety of DOPA-histidine on Escherichia coli surfaces using outer membrane protein W as an anchoring motif for the first time. Localization of catecholamines on the cell surface was confirmed by Western blot and immunofluorescence microscopy. Furthermore, cell-to-cell cohesion (i.e., cellular aggregation) induced by the displayed catecholamine and synthesis of gold nanoparticles on the cell surface support functional display of adhesive catecholamines. The engineered E. coli exhibited significant adhesion onto various material surfaces, including silica and glass microparticles, gold, titanium, silicon, poly(ethylene terephthalate), poly(urethane), and poly(dimethylsiloxane). The uniqueness of this approach utilizing the engineered sticky E. coli is that no chemistry for cell attachment are necessary, and the ability of spontaneous E. coli attachment allows one to immobilize the cells on challenging material surfaces such as synthetic polymers. Therefore, we envision that mussel-inspired catecholamine yielded sticky E. coli that can be used as a new type of engineered microbe for various emerging fields, such as whole living cell attachment on versatile material surfaces, cell-to-cell communication systems, and many others. PMID:24123747

  1. Plasma catecholamine and nephrine responses to brief intermittent maximal intensity exercise.

    PubMed

    Bracken, Richard M; Linnane, Denise M; Brooks, Stephen

    2009-02-01

    Catecholamines (noradrenaline, NA; adrenaline, AD; dopamine, DA) influence the metabolic and cardiovascular responses to exercise. However, changes in catecholamine metabolism during exercise are unclear. Plasma normetanephrine (NMET), metanephrine (MET) and catecholamine responses to a laboratory-based model of games-type exercise were examined. Twelve healthy men completed a resting control trial and a trial consisting of ten 6 s cycle ergometer sprints interspersed with 30 s recovery, in randomised order. Resting and post-sprint venous blood samples were taken. Plasma NA and AD increased after each sprint but DA was unaltered. Plasma nephrines increased significantly from sprint 4 onwards with peak NMET increasing 60% to 0.76 +/- 0.19 nmol l(-1) and MET 230% to 0.37 +/- 0.16 nmol l(-1) from resting values (P < 0.05). The results demonstrate increased catecholamine metabolism via elevated catechol-O-methyl transferase activity during intermittent sprinting. The results may aid regulation of the metabolic and cardiovascular responses to exercise by maintaining tissue adrenoceptor sensitivity to circulating catecholamines.

  2. Intra-adrenal interactions in fish: catecholamine stimulated cortisol release in sea bass (Dicentrarchus labrax L.).

    PubMed

    Rotllant, Josep; Ruane, Neil M; Dinis, Maria T; Canario, Adelino V M; Power, Deborah M

    2006-03-01

    The effect of the catecholamines, adrenaline and noradrenaline, on sea bass (Dicentrarchus labrax) and sea bream (Sparus auratus) interrenal cortisol production was studied in vitro using a dynamic superfusion system technique. Increasing concentrations of catecholamines (10(-6), 10(-8) and 10(-10) M) stimulated cortisol production in a dose-dependent manner, in sea bass only. The increase in cortisol production stimulated by adrenaline (10(-6) M) and noradrenaline (10(-6) M) was inhibited by sotalol (2 x 10(-5) M), but not by prazosin suggesting that catecholamines stimulate cortisol release through the beta-receptor subtype. To evaluate catecholamine-induced signal transduction in head kidney cells, measurements of cAMP production and [H3]myo-inositol incorporation were determined in head kidney cell suspensions. Adrenaline and noradrenaline (10(-6) M) increased cAMP production, but had no effect on total inositol phosphate accumulation. These results indicate that catecholamines released from the chromaffin cells within the interrenal tissue may act as a paracrine factor to stimulate interrenal steroidogenesis in the sea bass.

  3. Osmotic pressures of solutions of ATP and catecholamines relating to storage in chromaffin granules.

    PubMed

    Kopell, W N; Westhead, E W

    1982-05-25

    The chromaffin granule, which is the catecholamine storage organelle of the adrenal medulla, contains at least 0.73 M ions, yet it is isotonic with 0.3 osM solutions. One hypothesis which accounts for this disparity is formation of a complex between major constituents of the granule: the catecholamines, the proteins, and the ATP. In this paper we show by vapor pressure osmometry, which affords a direct measure of colligative properties, that ATP-catecholamine mixtures form highly nonideal solutions. At 37 degrees C, solutions containing 0.6 M epinephrine and 0.15 M ATP show an effective osmotic pressure of only 0.25 osM. The existence of polymeric complexes is implied by the fact that the increase of osmotic pressure with increasing concentrations of ATP and catecholamine falls off substantially at concentrations approaching those in the chromaffin granules. Neither inorganic ions nor calcium chelators cause regain of ideal colligative behavior. Osmotic measurements on model compounds suggest that the primary interaction is between the phosphate and amino groups. There is also evidence that the effects are not wholly due to the formation of discrete complexes; factors of nonideal solution behavior also play a role in lowering the osmotic pressure. These observations show that the stability of the chromaffin granule in situ can be accounted for, perhaps entirely, by spontaneous interactions among nucleotides and catecholamines.

  4. Studies on the role of neurotoxic esterase in organophosphorous compound-induced delayed neurotoxicity

    SciTech Connect

    Carrington, C.D.

    1984-01-01

    Neurotoxic esterase (NTE) is a protein with esterase activity that is proposed to be the site at which organophosphorus compound (OP) induced delayed neurotoxicity (OPIDIN) is initiated. The role of NTE in OPIDIN in unknown. The studies described in this dissertation were designed to further elucidate potential mechanisms underlying the involvement of NTE in OPIDN. The prophylactic effect of phenylmethylsulfonyl fluoride (PMSF) was found to be correlated with the time course of inhibition of NTE by PMSF and two neurotoxic OPs, and is therefore most likely to be due to the prevention of the binding of the OP to the initiation site. A membrane bound protein labelled with /sup 3/H-diisopropyl phosphorofluoridate (DiFP) with an apparent molecular weight of 160 K was the major binding site with a specificity similar to that of NTE. Recovery of NTE activity following in vivo inhibition by DiFP was found to be slower in hen brain when compared to chicks or rats. Differences in recovery in peripheral nerve were not found to be correlated with differences in susceptibility between species or between young and adult animals. The anterograde transport rate for NTE was estimated to be about 300 mm/day. Since exchange between mobile and stationary transport pools appeared to be rapid, it is concluded that the proximodistal delay in NTE recovery is due to a dilution of newly synthesized NTE by inhibited NTE as it is transported down the nerve.

  5. Neurotoxicity of anhydroecgonine methyl ester, a crack cocaine pyrolysis product.

    PubMed

    Garcia, Raphael Caio Tamborelli; Dati, Livia Mendonça Munhoz; Fukuda, Suelen; Torres, Larissa Helena Lobo; Moura, Sidnei; de Carvalho, Nathalia Delazeri; Carrettiero, Daniel Carneiro; Camarini, Rosana; Levada-Pires, Adriana Cristina; Yonamine, Mauricio; Negrini-Neto, Osvaldo; Abdalla, Fernando Maurício Francis; Sandoval, Maria Regina Lopes; Afeche, Solange Castro; Marcourakis, Tania

    2012-07-01

    Smoking crack cocaine involves the inhalation of cocaine and its pyrolysis product, anhydroecgonine methyl ester (AEME). Although there is evidence that cocaine is neurotoxic, the neurotoxicity of AEME has never been evaluated. AEME seems to have cholinergic agonist properties in the cardiovascular system; however, there are no reports on its effects in the central nervous system. The aim of this study was to investigate the neurotoxicity of AEME and its possible cholinergic effects in rat primary hippocampal cell cultures that were exposed to different concentrations of AEME, cocaine, and a cocaine-AEME combination. We also evaluated the involvement of muscarinic cholinergic receptors in the neuronal death induced by these treatments using concomitant incubation of the cells with atropine. Neuronal injury was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The results of the viability assays showed that AEME is a neurotoxic agent that has greater neurotoxic potential than cocaine after 24 and 48 h of exposure. We also showed that incubation for 48 h with a combination of both compounds in equipotent concentrations had an additive neurotoxic effect. Although both substances decreased cell viability in the MTT assay, only cocaine increased LDH release. Caspase-3 activity was increased after 3 and 6 h of incubation with 1mM cocaine and after 6 h of 0.1 and 1.0mM AEME exposure. Atropine prevented the AEME-induced neurotoxicity, which suggests that muscarinic cholinergic receptors are involved in AEME's effects. In addition, binding experiments confirmed that AEME has an affinity for muscarinic cholinergic receptors. Nevertheless, atropine was not able to prevent the neurotoxicity produced by cocaine and the cocaine-AEME combination, suggesting that these treatments activated other neuronal death pathways. Our results suggest a higher risk for neurotoxicity after smoking crack cocaine than after

  6. Why do metabolites circulate?

    PubMed

    Smith, Dennis A; Dalvie, Deepak

    2012-01-01

    The aim of most metabolism and excretion processes is to remove the drug and drug related material from the body; however, in most cases metabolites are present in abundance in circulation. To allow better in vitro/in vivo correlations a greater understanding of why metabolites formed in organs such as the liver are present in the circulation is necessary. Separating metabolites into highly lipid permeable and low lipid permeable allows the role of passive efflux from the liver and active transport to be dissected. Many drugs form glucuronide metabolites that circulate at high total concentrations and attention is drawn to low lipid permeability, efflux from the liver by MRP3, high plasma protein binding and restricted distribution as the explanation for this. The use of metabolite maps is suggested as a way of displaying complex processes in a simple form.

  7. Neurotoxicity testing during long-term studies.

    PubMed

    Ivens, I

    1990-01-01

    Several tests and methods for the investigation of neurotoxicity were performed with female Wistar rats for up to 187 days. The methods were validated by testing 10 rats treated with beta,beta'-iminodipropionitrile (IDPN) and 10 control rats. Cage side observation of the animals revealed signs of altered behavior and motor dysfunction of the IDPN-treated rats. Results of a neuromuscular screen indicated changes in gait, righting reflex, grip strength and performance of the negative geotropism test. Investigation of the animals in activity monitors and on the accelerating rotarod showed changes of several parameters. The motor nerve conduction velocity, measured 6 months after the first treatment, was reduced by 6.7 meters per second in the IDPN group compared to controls. From the results of the tests it can be concluded that the methods chosen can be used during long-term studies but may be most useful for animals not older than 12 months.

  8. [Link between aluminum neurotoxicity and neurodegenerative disorders].

    PubMed

    Kawahara, Masahiro

    2016-07-01

    Aluminum is an old element that has been known for a long time, but some of its properties are only now being discovered. Although environmentally abundant, aluminum is not essential for life; in fact, because of its specific chemical properties, aluminum inhibits more than 200 biologically important functions and exerts various adverse effects in plants, animals, and humans. Aluminum is a widely recognized neurotoxin. It has been suggested that there is a relationship between exposure to aluminum and neurodegenerative diseases, including dialysis encephalopathy, amyotrophic lateral sclerosis and parkinsonism dementia in the Kii Peninsula and Guam, as well as Alzheimer' s disease: however, this claim remains to be verified. In this chapter, we review the detailed characteristics of aluminum neurotoxicity and the link between Alzheimer' s disease and other neurodegenerative diseases, based on recent findings on metal-metal interactions and the functions of metalloproteins in synapses.

  9. Studies of (±)-3,4-Methylenedioxymethamphetamine (MDMA) Metabolism and Disposition in Rats and Mice: Relationship to Neuroprotection and Neurotoxicity Profile

    PubMed Central

    Mueller, Melanie; Maldonado-Adrian, Concepcion; Yuan, Jie; McCann, Una D.

    2013-01-01

    The neurotoxicity of (±)-3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”) is influenced by temperature and varies according to species. The mechanisms underlying these two features of MDMA neurotoxicity are unknown, but differences in MDMA metabolism have recently been implicated in both. The present study was designed to 1) assess the effect of hypothermia on MDMA metabolism, 2) determine whether the neuroprotective effect of hypothermia is related to inhibition of MDMA metabolism, and 3) determine if different neurotoxicity profiles in mice and rats are related to differences in MDMA metabolism and/or disposition in the two species. Rats and mice received single neurotoxic oral doses of MDMA at 25°C and 4°C, and body temperature, pharmacokinetic parameters, and serotonergic and dopaminergic neuronal markers were measured. Hypothermia did not alter MDMA metabolism in rats and only modestly inhibited MDMA metabolism in mice; however, it afforded complete neuroprotection in both species. Rats and mice metabolized MDMA in a similar pattern, with 3,4-methylenedioxyamphetamine being the major metabolite, followed by 4-hydroxy-3-methoxymethamphetamine and 3,4-dihydroxymethamphetamine, respectively. Differences between MDMA pharmacokinetics in rats and mice, including faster elimination in mice, did not account for the different profile of MDMA neurotoxicity in the two species. Taken together, the results of these studies indicate that inhibition of MDMA metabolism is not responsible for the neuroprotective effect of hypothermia in rodents, and that different neurotoxicity profiles in rats and mice are not readily explained by differences in MDMA metabolism or disposition. PMID:23209329

  10. Fumonisin B(1): a neurotoxic mycotoxin.

    PubMed

    Domijan, Ana-Marija

    2012-12-01

    Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium spp. moulds that contaminate crop, predominantly maize, all around the world. More than 15 types of fumonisins have been indentified so far, but FB(1) is the most abundant and toxicologically the most significant one. FB(1) has a wide range of toxic effects, depending on animal species. In horses FB(1) causes equine leukoencephalomalacia (ELEM), in pigs pulmonary oedema and in experimental rodents nephrotoxicity and hepatotoxicity. In humans exposure to FB(1) is linked with higher incidence of primary liver cancer and oesophageal cancer, which are frequent in certain regions of the world (such as Transkei region in South Africa) where maize is staple food. The occurrence of neural tube defect in children in some countries of Central America (such as Mexico and Honduras) is connected with the consumption of FB(1)-contaminated maize-based food. However, possible involvement of FB(1) in the development of human diseases is not clear. Nevertheless, the International Agency for Research on Cancer (IARC) has classified FB(1) as a possible carcinogen to humans (group 2B). FB(1) is a causative agent of ELEM, a brain disorder in equines, indicating that brain is a target organ of FB(1) toxicity. Several studies on experimental animals or on cell cultures of neural origin have established that FB(1) has a neurodegenerative potential, although the mechanism of its neurotoxicity is still vague. The aim of this article is to give an overview of available literature on FB(1) neurotoxicity and involved mechanisms, and to offer a new perspective for future studies.

  11. Endoplasmic Reticulum Stress and Ethanol Neurotoxicity.

    PubMed

    Yang, Fanmuyi; Luo, Jia

    2015-10-14

    Ethanol abuse affects virtually all organ systems and the central nervous system (CNS) is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD) which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER) regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR) which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer's disease (AD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity.

  12. Bortezomib-induced peripheral neurotoxicity: an update.

    PubMed

    Argyriou, Andreas A; Cavaletti, Guido; Bruna, Jordi; Kyritsis, Athanasios P; Kalofonos, Haralabos P

    2014-09-01

    This review paper provides a critical exploration of updates concerning the spectrum of characteristics and treatment options of bortezomib-induced peripheral neuropathy (BIPN). Emphasis is given on pathogenesis issues. Although the mechanism underlying BIPN still remains elusive, it is increasingly acknowledged that the inhibition of proteasome activity in dorsal root ganglia and peripheral nerves, the mitochondrial-mediated disruption of Ca⁺⁺ intracellular homeostasis and the disregulation in nuclear factor κB and brain-derived neurotrophic factor play a significant pathogenic role. Assessment of BIPN is based on comprehensive grading scales, using a combination of "subjective" and "objective" parameters, which turn out to be ambiguously interpreted, thus leading to both under- and misreporting of its true incidence and severity. BIPN is clinically defined as a typical example of a dose-dependent, distally attenuated painful, sensory neuronopathy. Patients pre-treated with neurotoxic regimens and those with pre-existing neuropathy are more likely to develop severe neurotoxicity. To date, there is no effective pharmacological treatment to prevent BIPN, and therefore, interventions remain merely symptomatic to focus on the alleviation of neuropathic pain. Hence, strict adherence to the dose reduction and schedule change algorithm is recommended in order to prevent treatment-emergent BIPN and allow the continuation of treatment. Further studies in animal models and humans, including experimental, clinical, neurophysiological and pharmacogenetic approaches, are needed to allow the identification of the true spectrum of BIPN pathogenesis and characteristics. It is expected that such comprehensive approaches would be the starting point for the development of early preventive and therapeutic interventions against BIPN.

  13. Prospective, longitudinal assessment of developmental neurotoxicity.

    PubMed Central

    Jacobson, J L; Jacobson, S W

    1996-01-01

    Methodological issues in the design of prospective, longitudinal studies of developmental neurotoxicity in humans are reviewed. A comprehensive assessment of potential confounding influences is important in these studies because inadequate assessment of confounders can threaten the validity of causal inferences drawn from the data. Potential confounders typically include demographic background variables, alcohol and smoking during pregnancy, the quality of parental stimulation, the child's age at test, and the examiner. Exposure to other substances is assessed where significant exposure is expected in the target population. In most studies, control variables even weakly related to outcome are included in all multivariate statistical analyses, and a toxic effect is inferred only if the effect of exposure is significant after controlling for the potential confounders. Once a neurotoxic effect has been identified, suspected mediating variables may be added to the analysis to examine underlying processes or mechanisms through which the exposure may impact on developmental outcome. Individual differences in vulnerability may be examined in terms of either an additive compensatory model or a synergistic "risk and resilience" approach. Failure to detect real effects (Type II error) is of particular concern in these studies because public policy considerations make it likely that negative findings will be interpreted to mean that the exposure is safe. Important sources of Type II error include inadequate representation of highly exposed individuals, overcontrol for confounders, and inappropriate correction for multiple comparisons. Given the high cost and complexity of prospective, longitudinal investigations, cross-sectional pilot studies focusing on highly exposed individuals can be valuable for the initial identification of salient domains of impairment. PMID:9182034

  14. Cyclosporine-A induced neurotoxicity after renal transplantation.

    PubMed

    Derici, U; Arinsoy, T; Sindel, S; Tali, T; Leventoglu, A; Sert, S

    2001-06-01

    Cyclosporine-A is a highly potent immunosuppressive agent for solid organ transplantation, but has many side effects including nephrotoxicity, hypertension, gum hyperplasia, hepatotoxicity, and neurotoxicity. Neurotoxicity is a less known toxic effect. The pathogenesis of this effect is unclear. However, it has been postulated that hypomagnesemia, hypocholesterolemia, corticosteroids, and/or neurotoxic substances can induce this syndrome. Also, it has been suggested that the endothelial damage caused by Cyclosporine-A may contribute to neuropeptide-mediated ischemia in the brain and lead to the development of neurological symptoms. In this report, we present a case with reversible neurologic deficits whose symptoms returned to normal after the cessation of cyclosporine-A.

  15. Urinary Metabolite Markers of Precocious Puberty*

    PubMed Central

    Qi, Ying; Li, Pin; Zhang, Yongyu; Cui, Lulu; Guo, Zi; Xie, Guoxiang; Su, Mingming; Li, Xin; Zheng, Xiaojiao; Qiu, Yunping; Liu, Yumin; Zhao, Aihua; Jia, Weiping; Jia, Wei

    2012-01-01

    The incidence of precocious puberty (PP, the appearance of signs of pubertal development at an abnormally early age), is rapidly rising, concurrent with changes of diet, lifestyles, and social environment. The current diagnostic methods are based on a hormone (gonadotropin-releasing hormone) stimulation test, which is costly, time-consuming, and uncomfortable for patients. The lack of molecular biomarkers to support simple laboratory tests, such as a blood or urine test, has been a long standing bottleneck in the clinical diagnosis and evaluation of PP. Here we report a metabolomic study using an ultra performance liquid chromatography-quadrupole time of flight mass spectrometry and gas chromatography-time of flight mass spectrometry. Urine metabolites from 163 individuals were profiled, and the metabolic alterations were analyzed after treatment of central precocious puberty (CPP) with triptorelin depot. A panel of biomarkers selected from >70 differentially expressed urinary metabolites by receiver operating characteristic and logistic regression analysis provided excellent predictive power with high sensitivity and specificity for PP. The altered metabolic profile of the PP patients was characterized by three major perturbed metabolic pathways: catecholamine, serotonin metabolism, and tricarboxylic acid cycle, presumably resulting from activation of the sympathetic nervous system and the hypothalamic-pituitary-gonadal axis. Treatment with triptorelin depot was able to normalize these three altered pathways. Additionally, significant changes in the urine levels of 4-hydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, indoleacetic acid, 5-hydroxytryptophan, and 5-hydroxykynurenamine in the CPP group suggest that the development of CPP condition may involve an alteration in symbiotic gut microbial composition. PMID:22027199

  16. The mixture of "ecstasy" and its metabolites is toxic to human SH-SY5Y differentiated cells at in vivo relevant concentrations.

    PubMed

    Barbosa, Daniel José; Capela, João Paulo; Silva, Renata; Vilas-Boas, Vânia; Ferreira, Luísa Maria; Branco, Paula Sério; Fernandes, Eduarda; Bastos, Maria de Lourdes; Carvalho, Félix

    2014-02-01

    The neurotoxicity of "ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) is thought to involve hepatic metabolism, though its real contribution is not completely understood. Most in vitro neurotoxicity studies concern isolated exposures of MDMA or its metabolites, at high concentrations, not considering their mixture, as expected in vivo. Therefore, our postulate is that combined deleterious effects of MDMA and its metabolites, at low micromolar concentrations that may be attained into the brain, may elicit neurotoxicity. Using human SH-SY5Y differentiated cells as dopaminergic neuronal model, we studied the neurotoxicity of MDMA and its MDMA metabolites α-methyldopamine and N-methyl-α-methyldopamine and their correspondent glutathione and N-acetylcysteine monoconjugates, under isolated exposure and as a mixture, at normothermic or hyperthermic conditions. The results showed that the mixture of MDMA and its metabolites was toxic to SH-SY5Y differentiated cells, an effect potentiated by hyperthermia and prevented by N-acetylcysteine. As a mixture, MDMA and its metabolites presented a different toxicity profile, compared to each compound alone, even at equimolar concentrations. Caspase 3 activation, increased reactive oxygen species production, and intracellular Ca(2+) raises were implicated in the toxic effect. The mixture increased intracellular glutathione levels by increasing its de novo synthesis. In conclusion, this study demonstrated, for the first time, that the mixture of MDMA and its metabolites, at low micromolar concentrations, which represents a more realistic approach of the in vivo scenario, elicited toxicity to human SH-SY5Y differentiated cells, thus constituting a new insight into the context of MDMA-related neurotoxicity.

  17. Lesson of the month 2: Catecholamine-induced cardiomyopathy - pitfalls in diagnosis and medical management.

    PubMed

    Mamoojee, Yaasir; Arham, Munawar; Elsaify, Wael; Nag, Sath

    2016-04-01

    Cardiomyopathy as the initial presentation of phaeochromocytoma (PCA) is uncommon. Diagnostic work-up and perioperative management may be challenging within this context. We report three cases of PCA presenting with cardiomyopathy to illustrate the pitfalls in diagnosis and management. None of the patients had typical adrenergic symptoms and all three were established on beta-blockers prior to diagnosis. Their fractionated plasma catecholamine levels were elevated and the diagnosis of PCA was confirmed with various imaging modalities and post adrenalectomy. Interpretation of fractionated catecholamine levels in the context of established cardiomyopathy is difficult as cardiac failure of any aetiology generates an adrenergic response. Hence screening all patients with idiopathic cardiomyopathy is likely to generate a high false-positive rate. However, a high index of suspicion should prompt further diagnostic work-up in patients with idiopathic cardiomyopathy for occult PCAs. Peer-reviewed guidelines are required to guide the investigation and management of suspected catecholamine-induced cardiomyopathy.

  18. Effects of uptake inhibitors on responses of sheep coronary arteries to catecholamines and sympathetic nerve stimulation.

    PubMed Central

    Brine, F.; Cornish, E. J.; Miller, R. C.

    1979-01-01

    1. Transmural stimulation of intrinsic sympathetic nerves and exogenous catecholamines produce beta 1-adrenoceptor mediated relaxant responses in strips of contracted sheep coronary artery. 2. The neuronal uptake inhibitors, metaraminol, cocaine and desipramine and the extraneuronal uptake inhibitor, cortisol, failed to potentiate responses to noradrenaline or sympathetic stimulation; responses to isoprenaline were enhanced by cortisol. 3. Oxytetracycline, which inhibits binding to connective tissue fibres, did not affect responses to noradrenaline or nerve stimulation. 4. 17 beta-Oestradiol, caffeine and U0521 proved to be unsuitable compounds for studying catecholamine inactivation since they non-selectively potentiated responses to noradrenaline and isoprenaline. 5. It is concluded that catecholamine inactivation processes do not modify transmitter function in sheep coronary arteries. PMID:519107

  19. [Extra-adrenal pheochromocytoma with the manifestation of catecholamines cardiomyopathy: a case report].

    PubMed

    Kuramoto, Tomomi; Nishizawa, Satoshi; Fujii, Reona; Nanpou, Yoshihito; Matsumura, Nagahide; Inagaki, Takeshi; Kohjimoto, Yasuo; Hara, Isao

    2010-11-01

    A 22-year old female had an episode of acute heart and respiratory failure requiring mechanical ventilation ducing a trip overseas. Echocardiography demonstrated akinesis of the apical area (left ventricle ejectionfraction(LVEF) =15%). Since computed tomography (CT) with coronary angiography to rule out acute coronary syndrome showed no abnormalities, she was diagnosed with morphological stress cardiomyopathy due to akinesis of the apical area. After returning to Japan, she was admitted to our hospital for further examination. She had an increased level of catecholamines in 24-hour urine. ¹³¹Imetaiodobenzyguanidine scintigraphy, CT scan and fluorodexyglucose positron emission tomography revealed a retroperitoneal mass. From these results, a diagnosis of extra-adrenal pheochromocytoma with catecholamine-induced cardiomyopathy was made. Histological diagnosis of the laparoscopically resected tumor was pheochromocytoma. After the operation, the level of catecholamines in 24-hour urine was normalized.

  20. Immunohistochemical localization of epinephrine, norepinephrine, catecholamine-synthesizing enzymes, and chromogranin in neuroendocrine cells and tumors.

    PubMed

    Lloyd, R V; Sisson, J C; Shapiro, B; Verhofstad, A A

    1986-10-01

    The immunohistochemical localization of epinephrine (E), norepinephrine (NE), and chromogranin was analyzed in normal and neoplastic neuroendocrine cells. The immunohistochemical detection of tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) was used to distinguish between uptake and biosynthesis of catecholamines. E, NE, chromogranin, TH, DBH, and PNMT were found in the normal human adrenal medulla and in pheochromocytomas. Although many neuroendocrine tissues outside of the adrenal gland contained immunoreactive NE, only a small percentage of these tissues contained DBH. E was found in a few neuroendocrine tissues outside of the adrenal, including cardiac paragangliomas, and the enzyme PNMT was localized in some of these neoplasms. There was very close agreement between the localization of chromogranin and of catecholamines in normal and neoplastic neuroendocrine tissues. These results indicate that the presence of catecholamines and chromogranin in neuroendocrine cells and tumors within the adrenal medulla and in many other sites may be closely related.

  1. Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels.

    PubMed

    Duce, J A; Ayton, S; Miller, A A; Tsatsanis, A; Lam, L Q; Leone, L; Corbin, J E; Butzkueven, H; Kilpatrick, T J; Rogers, J T; Barnham, K J; Finkelstein, D I; Bush, A I

    2013-02-01

    The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.

  2. Effects of Labor Contractions on Catecholamine Release and Breathing Frequency in Newborn Rats

    PubMed Central

    Ronca, April E.; Abel, Regina A.; Ronan, Patrick J.; Renner, Kenneth J.; Alberts, Jeffrey R.

    2009-01-01

    Plasma catecholamines in newborn rats (0–2 hr old) were analyzed following vaginal birth, cesarean section with simulated labor contractions, or cesarean section without labor contractions. Upon delivery, pups were exposed to key elements of the rat’s natural birth process, that is, umbilical cord occlusion, tactile stimulation, and cooling. Only pups exposed to actual or simulated labor showed an immediate rise in norepinephrine and epinephrine. Initial postpartum respiratory frequencies were higher in vaginal than in cesarean delivered pups and, in all groups, inversely correlated with catecholamine titers, suggesting respiratory distress or transient tachypnea at lower catecholamine levels. These findings establish a rat model for analyzing effects of labor on neonatal adaptive response during the transition from prenatal to postnatal life. PMID:17201476

  3. Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder

    PubMed Central

    Birner, Armin; Platzer, Martina; Bengesser, Susanne Astrid; Dalkner, Nina; Fellendorf, Frederike T.; Queissner, Robert; Pilz, Rene; Rauch, Philipp; Maget, Alexander; Hamm, Carlo; Herzog-Eberhard, Simone; Mangge, Harald; Fuchs, Dietmar; Moll, Natalie; Zelzer, Sieglinde; Schütze, Gregor; Schwarz, Markus; Reininghaus, Bernd; Kapfhammer, Hans-Peter; Reininghaus, Eva Z.

    2017-01-01

    Introduction Bipolar disorder (BD) is a chronic psychiatric disease which can take most different and unpredictable courses. It is accompanied by unspecific brainstructural changes and cognitive decline. The neurobiological underpinnings of these processes are still unclear. Emerging evidence suggests that tryptophan catabolites (TRYCATs), which involve all metabolites of tryptophan towards the kynurenine (KYN) branch, are involved in the etiology as well as in the course of BD. They are proposed to be mediators of immune-inflammation and neurodegeneration. In this study we measured the levels of KYN and its main catabolites consisting of the neurotoxic hydroxykynurenine (3-HK), the more neuroprotective kynurenic acid (KYNA) and anthranilic acid (AA) and evaluated the ratios between end-products and substrates as proxies for the specific enzymatic activity (3-HK/KYN, KYNA/KYN, AA/KYN) as well as 3-HK/KYNA as a proxy for neurotoxic vs. neuroprotective end-product relation in individuals with BD compared to healthy controls (HC). Methods We took peripheral TRYCAT blood levels of 143 euthymic to mild depressive BD patients and 101 HC. For statistical analyses MANCOVA’s controlled for age, sex, body mass index, cardiovascular disease and smoking were performed. Results The levels of KYNA (F = 5,579; p <.05) were reduced in BD compared to HC. The enzymatic activity of the kynurenine-3-monooxygenase (KMO) reflected by the 3-HK/KYN ratio was increased in BD individuals compared to HC (F = 5,394; p <.05). Additionally the ratio of 3-HK/KYNA was increased in individuals with BD compared to healthy controls (F = 11,357; p <.01). Discussion In conclusion our findings subserve the concept of KYN -pathway alterations in the pathophysiology of BD. We present evidence of increased breakdown towards the neurotoxic branch in KYN metabolism even in a euthymic to mild depressive state in BD. From literature we know that depression and mania are accompanied by inflammatory states

  4. Gintonin facilitates catecholamine secretion from the perfused adrenal medulla

    PubMed Central

    Na, Seung-Yeol; Kim, Ki-Hwan; Choi, Mi-Sung; Ha, Kang-Su

    2016-01-01

    The present study was designed to investigate the characteristics of gintonin, one of components isolated from Korean Ginseng on secretion of catecholamines (CA) from the isolated perfused model of rat adrenal gland and to clarify its mechanism of action. Gintonin (1 to 30 µg/ml), perfused into an adrenal vein, markedly increased the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. The gintonin-evoked CA secretion was greatly inhibited in the presence of chlorisondamine (1 µM, an autonomic ganglionic bloker), pirenzepine (2 µM, a muscarinic M1 receptor antagonist), Ki14625 (10 µM, an LPA1/3 receptor antagonist), amiloride (1 mM, an inhibitor of Na+/Ca2+ exchanger), a nicardipine (1 µM, a voltage-dependent Ca2+ channel blocker), TMB-8 (1 µM, an intracellular Ca2+ antagonist), and perfusion of Ca2+-free Krebs solution with 5mM EGTA (a Ca2+chelater), while was not affected by sodium nitroprusside (100 µM, a nitrosovasodialtor). Interestingly, LPA (0.3~3 µM, an LPA receptor agonist) also dose-dependently enhanced the CA secretion from the adrenal medulla, but this facilitatory effect of LPA was greatly inhibited in the presence of Ki 14625 (10 µM). Moreover, acetylcholine (AC)-evoked CA secretion was greatly potentiated during the perfusion of gintonin (3 µg/ml). Taken together, these results demonstrate the first evidence that gintonin increases the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. This facilitatory effect of gintonin seems to be associated with activation of LPA- and cholinergic-receptors, which are relevant to the cytoplasmic Ca2+ increase by stimulation of the Ca2+ influx as well as by the inhibition of Ca2+ uptake into the cytoplasmic Ca2+ stores, without the increased nitric oxide (NO). Based on these results, it is thought that gintonin, one of ginseng components, can elevate the CA secretion from adrenal medulla by regulating the Ca2+ mobilization for exocytosis, suggesting

  5. Effect of locally released catecholamines on lipolysis and injury of the hypoxic isolated rabbit heart.

    PubMed

    Karwatowska-Kryńska, E; Beresewicz, A

    1983-08-01

    The ability of endogenous myocardial catecholamines to stimulate lipolysis of endogenous triglycerides and the role of this process in the development of myocardial injury were studied in isolated, Langendorff-perfused rabbit heart preparations exposed to 3 h of hypoxic perfusion followed by 30 min of aerobic perfusion. Untreated hearts responded not only to hypoxia but also to reoxygenation with surges of noradrenaline outflow lasting 10 and 5 min, respectively. During hypoxia but not during reoxygenation a parallel surge of glycerol outflow was observed. Nicotinic acid (10(-5) M) prevented glycerol outflow during hypoxia but did not influence the outflow of noradrenaline during either hypoxia or reoxygenation. Neither noradrenaline nor glycerol were detected in the effluent from the hearts depleted of endogenous catecholamines by reserpine pretreatment. Those hearts also showed a smaller lactate dehydrogenase release during hypoxia (49% reduction) and no increase in lactate dehydrogenase release during reoxygenation. Similar reduction of lactate dehydrogenase release during hypoxia (52% reduction) was observed in the hearts treated with nicotinic acid. This drug, however, did not prevent the reoxygenation-induced lactate dehydrogenase release. The effects of reserpinization and nicotinic acid treatment on lactate dehydrogenase release were not additive. It is concluded that hypoxia is a stimulus for lipolysis in the isolated rabbit heart and most probably this process is catecholamine dependent. At least part of the deleterious effect of endogenous catecholamines on hypoxic myocardium might be attributed to catecholamine-stimulated lipolysis of endogenous triglycerides. The latter, however, does not seem to contribute to deleterious effects of endogenous catecholamines during reoxygenation.

  6. Synthesis and Neurotoxicity Profile of 2,4,5-Trihydroxymethamphetamine and its 6-(N-Acetylcystein-S-yl) Conjugate

    PubMed Central

    Neudörffer, Anne; Mueller, Melanie; Martinez, Claire-Marie; Mechan, Annis; McCann, Una; Ricaurte, George A.; Largeron, Martine

    2011-01-01

    The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, “ecstasy”) or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), plays a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in brains of these animals was not related to the unstable nature of the THMA molecule, because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA, or oxidized cyclic forms (e.g. the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo. PMID:21557581

  7. Developmental Neurotoxicology: History and Outline of Developmental Neurotoxicity Study Guidelines.

    EPA Science Inventory

    The present work provides a brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics. Historically, DNT was initially recognized as a “functional” teratoge...

  8. Neurotoxicity of Biologically Targeted Agents in Pediatric Cancer Trials

    PubMed Central

    Wells, Elizabeth M.; Rao, Amulya A. Nageswara; Scafidi, Joseph; Packer, Roger J.

    2013-01-01

    Biologically targeted agents offer the promise of delivering specific anticancer effects while limiting damage to healthy tissue, including the central and peripheral nervous systems. During the past 5-10 years, these agents were examined in preclinical and adult clinical trials, and are used with increasing frequency in children with cancer. This review evaluates current knowledge about neurotoxicity from biologically targeted anticancer agents, particularly those in pediatric clinical trials. For each drug, neurotoxicity data are reviewed in adult (particularly studies of brain tumors) and pediatric studies when available. Overall, these agents are well tolerated, with few serious neurotoxic effects. Data from younger patients are limited, and more neurotoxicity may occur in the pediatric population because these agents target pathways that control not only tumorigenesis but also neural maturation. Further investigation is needed into long-term neurologic effects, particularly in children. PMID:22490765

  9. Recommendations for Developing Alternative Test Methods for Developmental Neurotoxicity

    EPA Science Inventory

    There is great interest in developing alternative methods for developmental neurotoxicity testing (DNT) that are cost-efficient, use fewer animals and are based on current scientific knowledge of the developing nervous system. Alternative methods will require demonstration of the...

  10. ONTOGENY OF PROTEINS FOR USE AS BIOMARKERS OF DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    The developing nervous system can be uniquely susceptible to adverse effects following exposure to environmental chemicals, and several advisory panels (e.g. ILSI, NRC, NAS) have highlighted the need for rapid and sensitive developmental neurotoxicity testing methods. Measurement...

  11. Recommendations for Developing Alternative Test Methods for Developmental Neurotoxicity

    EPA Science Inventory

    There is great interest in developing alternative methods for developmental neurotoxicity testing (DNT) that are cost-efficient, use fewer animals and are based on current scientific knowledge of the developing nervous system. Alternative methods will require demonstration of the...

  12. Developmental Neurotoxicology: History and Outline of Developmental Neurotoxicity Study Guidelines.

    EPA Science Inventory

    The present work provides a brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics. Historically, DNT was initially recognized as a “functional” teratoge...

  13. TESTING FOR DEVELOPMENTAL NEUROTOXICITY: CURRENT APPROACHES AND FUTURE NEEDS.

    EPA Science Inventory

    There are many adverse effects on the nervous system following exposure to environmental chemicals during development. In a number of cases (e.g., lead, methyl mercury) the developing nervous system is a highly susceptible. Developmental Neurotoxicity Testing (DNT) guidelines...

  14. TESTING FOR DEVELOPMENTAL NEUROTOXICITY: CURRENT APPROACHES AND FUTURE NEEDS.

    EPA Science Inventory

    There are many adverse effects on the nervous system following exposure to environmental chemicals during development. In a number of cases (e.g., lead, methyl mercury) the developing nervous system is a highly susceptible. Developmental Neurotoxicity Testing (DNT) guidelines...

  15. INTEGRATING EPIDEMIOLOGY AND TOXICOLOGY IN NEUROTOXICITY RISK ASSESSMENT.

    EPA Science Inventory

    Neurotoxicity risk assessments depend on the best available scientific information, including data from animal toxicity, human experimental studies and human epidemiology studies. There are several factors to consider when evaluating the comparability of data from studies. Reg...

  16. INTEGRATING EPIDEMIOLOGY AND TOXICOLOGY IN NEUROTOXICITY RISK ASSESSMENT.

    EPA Science Inventory

    Neurotoxicity risk assessments depend on the best available scientific information, including data from animal toxicity, human experimental studies and human epidemiology studies. There are several factors to consider when evaluating the comparability of data from studies. Reg...

  17. Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine.

    PubMed

    Cass, Wayne A; Smith, Michael P; Peters, Laura E

    2006-08-01

    Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in brain dopamine (DA) and serotonin (5-HT) content. Calcitriol, the active metabolite of vitamin D, has potent effects on brain cells, both in vitro and in vivo, including the ability to upregulate trophic factors and protect against various lesions. The present experiments were designed to examine the ability of calcitriol to protect against METH-induced reductions in striatal and nucleus accumbens levels of DA and 5-HT. Male Fischer-344 rats were administered vehicle or calcitriol (1 microg/kg, s.c.) once a day for eight consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline four times in 1 day at 2-h intervals. Seven days later the striata and accumbens were harvested from the animals for high-performance liquid chromatography (HPLC) analysis of monoamines and metabolites. In animals treated with vehicle and METH, there were significant reductions in DA, 5-HT, and their metabolites in both the striatum and accumbens. In animals treated with calcitriol and METH, the magnitude of the METH-induced reductions in DA, 5-HT, and metabolites was substantially and significantly attenuated. The calcitriol treatments did not reduce the hyperthermia associated with multiple injections of METH, indicating that the neuroprotective effects of calcitriol are not due to the prevention of increases in body temperature. These results suggest that calcitriol can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of METH.

  18. Dual effects of nobiletin, a citrus polymethoxy flavone, on catecholamine secretion in cultured bovine adrenal medullary cells.

    PubMed

    Zhang, Han; Toyohira, Yumiko; Ueno, Susumu; Shinohara, Yuko; Itoh, Hideaki; Furuno, Yumi; Yamakuni, Tohru; Tsutsui, Masato; Takahashi, Kojiro; Yanagihara, Nobuyuki

    2010-08-01

    Nobiletin, a compound of polymethoxy flavones found in citrus fruits, possesses a wide range of pharmacological activities. Here we report the effects of nobiletin on catecholamine secretion in cultured bovine adrenal medullary cells. Nobiletin (1.0-100 microM) concentration-dependently stimulated catecholamine secretion and (45)Ca(2+) influx. Its stimulatory effect of nobiletin on catecholamine secretion was abolished by deprivation of extracellular Ca(2+) and partially inhibited by specific inhibitors of voltage-dependent Ca(2+) channels and Na(+)/Ca(2+) exchangers. On the other hand, nobiletin suppressed catecholamine secretion and (22)Na(+) and (45)Ca(2+) influx induced by acetylcholine, an agonist of nicotinic acetylcholine receptors, in a concentration-dependent manner. It also inhibited catecholamine secretion, (22)Na(+) influx and/or (45)Ca(2+) influx induced by veratridine, an activator of voltage-dependent Na(+) channels, and 56 mM K(+), an activator of voltage-dependent Ca(2+) channels. In Xenopus oocytes expressing alpha3beta4 neuronal acetylcholine receptors, nobiletin directly inhibited the current evoked by acetylcholine in a concentration-dependent manner similar to that observed in catecholamine secretion. The present findings suggest that nobiletin, by itself, stimulates catecholamine secretion via activation of voltage-dependent Ca(2+) channels or Na(+)/Ca(2+) exchangers, whereas it inhibits catecholamine secretion induced by acetylcholine through the suppression of Na(+) influx and Ca(2+) influx in cultured bovine adrenal medullary cells.

  19. Involvement of multiple distinct Bordetella receptor proteins in the utilization of iron liberated from transferrin by host catecholamine stress hormones

    PubMed Central

    Armstrong, Sandra K.; Brickman, Timothy J.; Suhadolc, Ryan J.

    2012-01-01

    Summary Bordetella bronchiseptica is a pathogen that can acquire iron using its native alcaligin siderophore system, but can also use the catechol xenosiderophore enterobactin via the BfeA outer membrane receptor. Transcription of bfeA is positively controlled by a regulator that requires induction by enterobactin. Catecholamine hormones also induce bfeA transcription and B. bronchiseptica can use the catecholamine norepinephrine for growth on transferrin. In this study, B. bronchiseptica was shown to use catecholamines to obtain iron from both transferrin and lactoferrin in the absence of siderophore. In the presence of siderophore, norepinephrine augmented transferrin utilization by B. bronchiseptica, as well as siderophore function in vitro. Genetic analysis identified BfrA, BfrD and BfrE as TonB dependent outer membrane catecholamine receptors. The BfeA enterobactin receptor was found to not be involved directly in catecholamine utilization; however, the BfrA, BfrD and BfrE catecholamine receptors could serve as receptors for enterobactin and its degradation product 2,3-dihydroxybenzoic acid. Thus, there is a functional link between enterobactin-dependent and catecholamine-dependent transferrin utilization. This investigation characterizes a new B. bronchiseptica mechanism for iron uptake from transferrin that uses host stress hormones that not only deliver iron directly to catecholamine receptors, but also potentiate siderophore activity by acting as iron shuttles. PMID:22458330

  20. Effect of. beta. -endorphin on catecholamine levels in rat hypothalamus and cerebral cortex

    SciTech Connect

    Slavnov, V.N.; Valueva, G.V.; Markov, V.V.; Luchitskii, E.V.

    1986-10-01

    The authors studied the effect of beta-endorphin on catecholamine concentrations in the hypothalmus and cerebral cortex in rats, as a contribution to the explanation of the mechanism of action of this peptide on certain pituitary trophic functions. Concentrations of dopamine, noradrenalin, and adrenalin were determined by a radioenzymatic method. A Mark 3 scintillation system was used for radiometric investigation of the samples. The results of these experiments indicate that beta-endorphin has a marked effect on brain catecholamine levels mainly in the hypothalamus.

  1. [A case of adrenal pheochromocytoma with normotention and normal levels of urinary excretion of catecholamines].

    PubMed

    Motomura, K; Okano, J; Sasaki, I; Ogihara, T; Ishii, H; Tanaka, A; Ibayashi, H; Abe, Y; Kuramoto, H; Yanase, T

    1994-09-01

    A 62-year-old man was admitted to our hospital for further examination of right adrenal mass accidentally pointed out by ultrasonogram. He had no symptoms and no physiological abnormalities. Endcrinological examinations revealed normal adrenocortical function, excluding the possibility of functioning adrenocortical adenoma. Pheochromocytoma seemed to be also unlikely since 24-hr urinary excretion of catecholamines were within normal limits. The tumor was surgically removed and histopathologically diagnosed as pheochromocytoma. This case of adrenal incidentaloma is unique in that little sign of pheochromocytoma was presented before operation. The reasons were discussed especially in respect of tissue contents of catecholamines and opioid peptide in comparison with other cases with pheochromocytoma we had experienced.

  2. Catecholamines and myocardial contractile function during hypodynamia and with an altered thyroid hormone balance

    NASA Technical Reports Server (NTRS)

    Pruss, G. M.; Kuznetsov, V. I.; Zhilinskaya, A. A.

    1980-01-01

    The dynamics of catecholamine content and myocardial contractile function during hypodynamia were studied in 109 white rats whose motor activity was severely restricted for up to 30 days. During the first five days myocardial catecholamine content, contractile function, and physical load tolerance decreased. Small doses of thyroidin counteracted this tendency. After 15 days, noradrenalin content and other indices approached normal levels and, after 30 days, were the same as control levels, although cardiac functional reserve was decreased. Thyroidin administration after 15 days had no noticeable effect. A detailed table shows changes in 17 indices of myocardial contractile function during hypodynamia.

  3. Changes in plasma catecholamines levels as preclinical biomarkers in experimental models of Parkinson's disease.

    PubMed

    Kim, A R; Ugryumov, M V

    2015-01-01

    The goal of this study was to investigate the changes in the concentrations of blood plasma catecholamines as possible biomarkers of Parkinson's disease (PD) in the mouse experimental model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A significant decrease was detected in the levels of dopamine and L-DOPA in the PD preclinical stage model as a result of the catecholamines systemic metabolism disfunction. In the PD early clinical stage models, the level of L-DOPA and dihydroxyphenylacetic acid decreased, which is consistent with the results of blood tests in untreated patients.

  4. Modulation of the Interaction of Enteric Bacteria with Intestinal Mucosa by Stress-Related Catecholamines.

    PubMed

    Stevens, Mark P

    2016-01-01

    Stress associated with parturition, transport or mixing has long been correlated with enhanced faecal excretion of diarrhoeal zoonotic pathogens in animals such as Salmonella enterica and Escherichia coli. It may also predispose humans to infection and/or be associated with more severe outcomes. One possible explanation for this phenomenon is the ability of enteric bacterial pathogens to sense and respond to host stress-related catecholamines. This article reviews evidence of the ability of catecholamine hormones to modulate interactions between Gram-negative diarrhoeal pathogens and intestinal mucosa, as well as the molecular mechanisms that may be at work.

  5. Histochemical evidence for catecholamines as neurotransmitters in the statocyst of Octopus vulgaris.

    PubMed

    Budelmann, B U; Bonn, U

    1982-01-01

    Formaldehyde-induced fluorescence (Falck-Hillarp technique) provided histochemical evidence for the presence of catecholamines in the sensory epithelia (macula and crista) of the Octopus statocyst. A specific bright green fluorescence occurred in the neuronal plexus beneath the receptor cell layers of the epithelia and in the appropriate nerves. The histochemical findings are discussed with reference to the well-known neuronal and synaptic organization of the epithelia and to relevant results in cephalopods as well as in other molluscs. All data support the hypothesis that in the receptor systems of the Octopus statocyst catecholamines (probably dopamine and/or noradrenaline) act as neurotransmitters in the efferent fibre system.

  6. Shrinking and development of lipid droplets in adipocytes during catecholamine-induced lipolysis.

    PubMed

    Nagayama, Masafumi; Shimizu, Kyoko; Taira, Toshio; Uchida, Tsutomu; Gohara, Kazutoshi

    2010-01-04

    Time-lapse observation of adipocytes during catecholamine-induced lipolysis clearly shows that shrinking of existing lipid droplets (LDs) occurs in some adipocytes and that small LDs are newly developed in almost all cells. Immunofluorescence imaging reveals that activation and localization of hormone-sensitive lipase (HSL) on the surface of LDs, which are required for conferring maximal lipolysis, are necessary for the shrinking of the LDs. However, not all adipocytes in which phosphorylated HSL is localized on LDs exhibit shrinking of LDs. The simultaneous shrinking and development of LDs yield apparent fragmentation and dispersion of LDs in adipocytes stimulated with catecholamine.

  7. In vitro techniques for the assessment of neurotoxicity.

    PubMed Central

    Harry, G J; Billingsley, M; Bruinink, A; Campbell, I L; Classen, W; Dorman, D C; Galli, C; Ray, D; Smith, R A; Tilson, H A

    1998-01-01

    Risk assessment is a process often divided into the following steps: a) hazard identification, b) dose-response assessment, c) exposure assessment, and d) risk characterization. Regulatory toxicity studies usually are aimed at providing data for the first two steps. Human case reports, environmental research, and in vitro studies may also be used to identify or to further characterize a toxic hazard. In this report the strengths and limitations of in vitro techniques are discussed in light of their usefulness to identify neurotoxic hazards, as well as for the subsequent dose-response assessment. Because of the complexity of the nervous system, multiple functions of individual cells, and our limited knowledge of biochemical processes involved in neurotoxicity, it is not known how well any in vitro system would recapitulate the in vivo system. Thus, it would be difficult to design an in vitro test battery to replace in vivo test systems. In vitro systems are well suited to the study of biological processes in a more isolated context and have been most successfully used to elucidate mechanisms of toxicity, identify target cells of neurotoxicity, and delineate the development and intricate cellular changes induced by neurotoxicants. Both biochemical and morphological end points can be used, but many of the end points used can be altered by pharmacological actions as well as toxicity. Therefore, for many of these end points it is difficult or impossible to set a criterion that allows one to differentiate between a pharmacological and a neurotoxic effect. For the process of risk assessment such a discrimination is central. Therefore, end points used to determine potential neurotoxicity of a compound have to be carefully selected and evaluated with respect to their potential to discriminate between an adverse neurotoxic effect and a pharmacologic effect. It is obvious that for in vitro neurotoxicity studies the primary end points that can be used are those affected

  8. (1)H NMR-Based Metabolomics and Neurotoxicity Study of Cerebrum and Cerebellum in Rats Treated with Cinnabar, a Traditional Chinese Medicine.

    PubMed

    Wei, Lai; Xue, Rong; Zhang, Panpan; Wu, Yijie; Li, Xiaojing; Pei, Fengkui

    2015-08-01

    Cinnabar, an important traditional Chinese mineral medicine, has been widely used as a Chinese patent medicine ingredient for sedative therapy. Nevertheless, the neurotoxic effects of cinnabar have also been noted. In this study, (1)H NMR-based metabolomics, combined with multivariate pattern recognition, were applied to investigate the neurotoxic effects of cinnabar after intragastrical administration (dosed at 2 and 5 g/kg body weight) on male Wistar rats. The metabolite variations induced by cinnabar were characterized by increased levels of glutamate, glutamine, myo-inositol, and choline, as well as decreased levels of GABA, taurine, NAA, and NAAG in tissue extracts of the cerebellum and cerebrum. These findings suggested that cinnabar induced glutamate excitotoxicity, neuronal cell loss, osmotic state changes, membrane fluidity disruption, and oxidative injury in the brain. We also show here that there is a dose- and time-dependent neurotoxicity of cinnabar, and that cerebellum was more sensitive to cinnabar induction than cerebrum. This work illustrates the utility and reliability of (1)H NMR-based metabolomics approach for examining the potential neurotoxic effects of cinnabar and other traditional Chinese medicines.

  9. LITHIUM NEUROTOXICITY AT ‘THERAPEUTIC’ LEVELS A CASE REPORT

    PubMed Central

    Sampath, G.; Kumar, Y. Vikram; Narayanan, H. S.; Rama Rao, B. S. Sridhara

    1980-01-01

    SUMMARY A case of a young manic patient who developed severe neurotoxicity when on lithium alone has been presented. Investigations did not reveal presence of any infection, electrolyte imbalance or rise in lithium level. The possibility of lithium producing neurotoxicity at therapeutic levels for as yet unknown reasons is pointed out. It is suggested that this element of risk be considered when starting lithium for therapy or prophylaxis of affective disorders. PMID:22058487

  10. Effects of early pregnancy and acute 17 beta-estradiol administration on porcine uterine secretion, cyclic nucleotides, and catecholamines.

    PubMed

    Young, K H; Bazer, F W; Simpkins, J W; Roberts, R M

    1987-01-01

    This study investigated acute effects of 17 beta-estradiol (E) on ions, cyclic nucleotides, and catecholamines and their association with temporal changes in uterine secretory products in pregnant, cyclic, and nonpregnant gilts. Uterine flushings (UTF) and endometrium (ENDOM) from one uterine horn of nonpregnant and pregnant gilts (n = 9) were collected on days 10, 12, and 14 (n = 3). Protein, plasma inhibitor (P less than 0.05), Na+, and K+ (P less than 0.01) increased linearly in UTF of pregnant gilts. Ca2+ changed biphasically, with higher concentrations (P less than 0.01) in pregnant gilts on day 12. Endometrial cAMP and cGMP (P less than 0.05) increased between days 12 and 14 of pregnancy. The UTF norepinephrine (NE) concentrations increased (P less than 0.01) in cyclic gilts between days 12 and 14, while endometrial NE increased between days 10 and 12 and then decreased on day 14. The UTF of pregnant gilts had higher (P less than 0.05) concentrations of dopamine (DA), which peaked on day 12 and then decreased (P less than 0.01) by day 14. DA in UTF of nonpregnant gilts decreased between days 10 and 12 and remained low on day 14. A catecholamine metabolite, 3,4-dihydroxyphenylglycol, in ENDOM (P less than 0.05) and UTF (P less than 0.01) decreased linearly between days 10 and 14. The turnover rate of endometrial catecholamines was 2.4-fold higher (P less than 0.05) during early pregnancy compared with that in cyclic gilts. Effects of acute administration of exogenous E (0.5 mg) were also studied. The UTF and ENDOM were from day 11 nonpregnant gilts 0, 30, 60, and 360 min (n = 3) post-E or post-saline-ethanol (C) injection (n = 9). Potassium, plasma inhibitor (P less than 0.01), and cGMP (P less than 0.05) increased rapidly (30 min) after E injection. The K+ level changed biphasically, with increased concentrations again at 360 min. Plasmin inhibitor returned to levels similar to controls by 60 min, whereas cGMP remained elevated until 360 min postinjection

  11. Neurotoxicity in Snakebite—The Limits of Our Knowledge

    PubMed Central

    Ranawaka, Udaya K.; Lalloo, David G.; de Silva, H. Janaka

    2013-01-01

    Snakebite is classified by the WHO as a neglected tropical disease. Envenoming is a significant public health problem in tropical and subtropical regions. Neurotoxicity is a key feature of some envenomings, and there are many unanswered questions regarding this manifestation. Acute neuromuscular weakness with respiratory involvement is the most clinically important neurotoxic effect. Data is limited on the many other acute neurotoxic manifestations, and especially delayed neurotoxicity. Symptom evolution and recovery, patterns of weakness, respiratory involvement, and response to antivenom and acetyl cholinesterase inhibitors are variable, and seem to depend on the snake species, type of neurotoxicity, and geographical variations. Recent data have challenged the traditional concepts of neurotoxicity in snake envenoming, and highlight the rich diversity of snake neurotoxins. A uniform system of classification of the pattern of neuromuscular weakness and models for predicting type of toxicity and development of respiratory weakness are still lacking, and would greatly aid clinical decision making and future research. This review attempts to update the reader on the current state of knowledge regarding this important issue. PMID:24130909

  12. Tissue Plasminogen Activator Neurotoxicity is Neutralized by Recombinant ADAMTS 13

    PubMed Central

    Fan, Mengchen; Xu, Haochen; Wang, Lixiang; Luo, Haiyu; Zhu, Ximin; Cai, Ping; Wei, Lixiang; Lu, Lu; Cao, Yongliang; Ye, Rong; Fan, Wenying; Zhao, Bing-Qiao

    2016-01-01

    Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke, but its neurotoxicity is a significant problem. Here we tested the hypothesis that recombinant ADAMTS 13 (rADAMTS 13) would reduce tPA neurotoxicity in a mouse model of stroke. We show that treatment with rADAMTS 13 in combination with tPA significantly reduced infarct volume compared with mice treated with tPA alone 48 hours after stroke. The combination treatment significantly improved neurological deficits compared with mice treated with tPA or vehicle alone. These neuroprotective effects were associated with significant reductions in fibrin deposits in ischemic vessels and less severe cell death in ischemic brain. The effect of rADAMTS13 on tPA neurotoxicity was mimicked by the N-methyl-D-aspartate (NMDA) receptor antagonist M-801, and was abolished by injection of NMDA. Moreover, rADAMTS 13 prevents the neurotoxicity effect of tPA, by blocking its interaction with the NMDA receptor NR2B and the attendant phosphorylation of NR2B and activation of ERK1/2. Finally, the NR2B-specific NMDA receptor antagonist ifenprodil abolished tPA neurotoxicity and rADAMTS 13 treatment had no further beneficial effect. Our data suggest that the combination of rADAMTS 13 and tPA may provide a novel treatment of ischemic stroke by diminishing the neurotoxic effects of exogenous tPA. PMID:27181025

  13. Potential developmental neurotoxicity of pesticides used in Europe.

    PubMed

    Bjørling-Poulsen, Marina; Andersen, Helle Raun; Grandjean, Philippe

    2008-10-22

    Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe--including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides--can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development.

  14. The neurotoxicity of amphetamines during the adolescent period.

    PubMed

    Teixeira-Gomes, Armanda; Costa, Vera Marisa; Feio-Azevedo, Rita; Bastos, Maria de Lourdes; Carvalho, Félix; Capela, João Paulo

    2015-04-01

    Amphetamine-type psychostimulants (ATS), such as amphetamine (AMPH), 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) are psychoactive substances widely abused, due to their powerful central nervous system (CNS) stimulation ability. Young people particularly use ATS as recreational drugs. Moreover, AMPH is used clinically, particularly for attention deficit hyperactivity disorder, and has the ability to cause structural and functional brain alterations. ATS are known to interact with monoamine transporter sites and easily diffuse across cellular membranes, attaining high levels in several tissues, particularly the brain. Strong evidence suggests that ATS induce neurotoxic effects, raising concerns about the consequences of drug abuse. Considering that many teenagers and young adults commonly use ATS, our main aim was to review the neurotoxic effects of amphetamines, namely AMPH, MDMA, and METH, in the adolescence period of experimental animals. Reports agree that adolescent animals are less susceptible than adult animals to the neurotoxic effects of amphetamines. The susceptibility to the neurotoxic effects of ATS seems roughly located in the early adolescent period of animals. Many authors report that the age of exposure to ATS is crucial for the neurotoxic outcome, showing that the stage of brain maturity has a strong importance. Moreover, recent studies have been undertaken in young adults and/or consumers during adolescence that clearly indicate brain or behavioural damage, arguing for long-term neurotoxic effects in humans. There is an urgent need for more studies during the adolescence period, in order to unveil the mechanisms and the brain dysfunctions promoted by ATS.

  15. A 21st Century Update on Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing was proposed in “A 21st Century Update on Neurotoxicity Risk Assessment “ (NRC, 2007), stating that traditional toxicity testing was too slow and expensive to develop information on the potential toxicity of the large number of untested chemicals already used in commerce. In addition, new technologies have compounded the problem as new materials, such as engineered nanomaterials, are introduced at a rate exceeding traditional testing capacity. There is currently much effort to develop higher throughput neurotoxicity testing capabilities, especially for developmental neurotoxicity, but there is no general consensus regarding how alternative testing data should be interpreted for neurotoxicity risk assessment. The dependence of critical functions, such as learning, memory or sensory perception, on the operation of integrated neural systems makes the interpretation of data from simple test assays particularly difficult. The concept of Adverse Outcome Pathways (AOP), in which molecular initiating events (MIE) trigger a sequence of steps leading to an adverse outcome, may provide a conceptual framework in which simple alternative testing data indicative of MIEs can be used to predict neur

  16. A 21st Century Update on Neurotoxicity Risk Assessment ...

    EPA Pesticide Factsheets

    In 1998, EPA published Guidelines for Neurotoxicity Risk Assessment as the basis for interpreting neurotoxicity results. At that time, the focus was on traditional toxicity testing and human clinical /epidemiological data. More recently, a change in approach to toxicity testing was proposed in “A 21st Century Update on Neurotoxicity Risk Assessment “ (NRC, 2007), stating that traditional toxicity testing was too slow and expensive to develop information on the potential toxicity of the large number of untested chemicals already used in commerce. In addition, new technologies have compounded the problem as new materials, such as engineered nanomaterials, are introduced at a rate exceeding traditional testing capacity. There is currently much effort to develop higher throughput neurotoxicity testing capabilities, especially for developmental neurotoxicity, but there is no general consensus regarding how alternative testing data should be interpreted for neurotoxicity risk assessment. The dependence of critical functions, such as learning, memory or sensory perception, on the operation of integrated neural systems makes the interpretation of data from simple test assays particularly difficult. The concept of Adverse Outcome Pathways (AOP), in which molecular initiating events (MIE) trigger a sequence of steps leading to an adverse outcome, may provide a conceptual framework in which simple alternative testing data indicative of MIEs can be used to predict neur

  17. Potential developmental neurotoxicity of pesticides used in Europe

    PubMed Central

    Bjørling-Poulsen, Marina; Andersen, Helle Raun; Grandjean, Philippe

    2008-01-01

    Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development. PMID:18945337

  18. Estrogenic protection against gp120 neurotoxicity: role of microglia.

    PubMed

    Zemlyak, Ilona; Brooke, Sheila; Sapolsky, Robert

    2005-06-07

    HIV infection of the nervous system can cause neurotoxicity, and the glycoprotein gp120 of HIV seems to play a key role in this. gp120 is neurotoxic through a multi-cellular pathway, stimulating microglia to release excitotoxins, cytokines and reactive oxygen species, which then damage neurons. We have previously shown that estrogen decreases the neurotoxicity of gp120 in mixed neuronal/glial cultures. In this study, we determine whether estrogen a) decreases the collective neurotoxicity of the factors released by gp120-treated microglia, and/or b) enhances the ability of neurons to survive such factors. To do so, we established microglial cultures, mixed neuronal/glial hippocampal cultures, and neuron-enriched cultures, independently manipulating gp120 and estrogen exposure in each type of culture, and inducing neurotoxicity in neuron-containing cultures by introducing conditioned media from gp120-treated microglial cultures. We observe that estrogen can exert some small protective effects at the level of bolstering neuronal resistance, but that the bulk of its protective effects arise at the level of decreasing the neurotoxicity of factors released by microglia.

  19. Pro-oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes

    PubMed Central

    Barbosa, Daniel José; Capela, João Paulo; Oliveira, Jorge MA; Silva, Renata; Ferreira, Luísa Maria; Siopa, Filipa; Branco, Paula Sério; Fernandes, Eduarda; Duarte, José Alberto; de Lourdes Bastos, Maria; Carvalho, Félix

    2012-01-01

    BACKGROUND AND PURPOSE 3,4-Methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) is a worldwide major drug of abuse known to elicit neurotoxic effects. The mechanisms underlying the neurotoxic effects of MDMA are not clear at present, but the metabolism of dopamine and 5-HT by monoamine oxidase (MAO), as well as the hepatic biotransformation of MDMA into pro-oxidant reactive metabolites is thought to contribute to its adverse effects. EXPERIMENTAL APPROACH Using mouse brain synaptosomes, we evaluated the pro-oxidant effects of MDMA and its metabolites, α-methyldopamine (α-MeDA), N-methyl-α-methyldopamine (N-Me-α-MeDA) and 5-(glutathion-S-yl)-α-methyldopamine [5-(GSH)-α-MeDA], as well as those of 5-HT, dopamine, l-DOPA and 3,4-dihydroxyphenylacetic acid (DOPAC). KEY RESULTS 5-HT, dopamine, l-DOPA, DOPAC and MDMA metabolites α-MeDA, N-Me-α-MeDA and 5-(GSH)-α-MeDA, concentration- and time-dependently increased H2O2 production, which was significantly reduced by the antioxidants N-acetyl-l-cysteine (NAC), ascorbic acid and melatonin. From experiments with MAO inhibitors, it was observed that H2O2 generation induced by 5-HT was totally dependent on MAO-related metabolism, while for dopamine, it was a minor pathway. The MDMA metabolites, dopamine, l-DOPA and DOPAC concentration-dependently increased quinoproteins formation and, like 5-HT, altered the synaptosomal glutathione status. Finally, none of the compounds modified the number of polarized mitochondria in the synaptosomal preparations, and the compounds’ pro-oxidant effects were unaffected by prior mitochondrial depolarization, excluding a significant role for mitochondrial-dependent mechanisms of toxicity in this experimental model. CONCLUSIONS AND IMPLICATIONS MDMA metabolites along with high levels of monoamine neurotransmitters can be major effectors of neurotoxicity induced by Ecstasy. PMID:21506960

  20. Enhanced metabolite generation

    DOEpatents

    Chidambaram, Devicharan [Middle Island, NY

    2012-03-27

    The present invention relates to the enhanced production of metabolites by a process whereby a carbon source is oxidized with a fermentative microbe in a compartment having a portal. An electron acceptor is added to the compartment to assist the microbe in the removal of excess electrons. The electron acceptor accepts electrons from the microbe after oxidation of the carbon source. Other transfers of electrons can take place to enhance the production of the metabolite, such as acids, biofuels or brewed beverages.

  1. Anatomical and pharmacological characterization of catecholamine transients in the medial prefrontal cortex evoked by ventral tegmental area stimulation

    PubMed Central

    Shnitko, Tatiana A.; Robinson, Donita L.

    2014-01-01

    Voltammetric measurements of catecholamines in the medial prefrontal cortex (mPFC) are infrequent because of lack of chemical selectivity between dopamine and norepinephrine and their overlapping anatomical inputs. Here, we examined the contribution of norepinephrine to the catecholamine release in the mPFC evoked by electrical stimulation of the ventral tegmental area (VTA). Initially, electrical stimulation was delivered in the midbrain at incremental depths of −5 to −9.4mm from bregma while catecholamine release was monitored in the mPFC. Although catecholamine release was observed at dorsal stimulation sites that may correspond to the dorsal noradrenergic bundle (DNB, containing noradrenergic axonal projections to the mPFC), maximal release was evoked by stimulation of the VTA (the source of dopaminergic input to the mPFC). Next, VTA-evoked catecholamine release was monitored in the mPFC before and after knife incision of the DNB, and no significant changes in the evoked catecholamine signals were found These data indicated that DNB fibers did not contribute to the VTA-evoked catecholamine release observed in the mPFC. Finally, while the D2-receptor antagonist raclopride significantly altered VTA-evoked catecholamine release, the α2-adrenergic receptor antagonist idazoxan did not. Specifically, raclopride reduced catecholamine release in the mPFC, opposite to that observed in the striatum, indicating differential autoreceptor regulation of mesocortical and mesostriatal neurons. Together, these findings suggest that the catecholamine release in the mPFC arising from VTA stimulation was predominately dopaminergic rather than noradrenergic. PMID:24285555

  2. Mechanism of neurotoxic action of beta,beta'-iminodipropionitrile (IDPN): N-hydroxylation enhances neurotoxic potency.

    PubMed

    Morandi, A; Gambetti, P; Arora, P K; Sayre, L M

    1987-12-22

    The molecular mechanism(s) whereby beta, beta'-iminodipropionitrile (IDPN) induces an excitatory behavioral syndrome and a distinct alteration of the axonal cytoskeleton in experimental animals is not known. We demonstrate here that upon intraperitoneal administration to rats, the N-hydroxy analog of IDPN (HOIDPN) induces a parallel spectrum of both neurotoxic effects of IDPN and is approximately 8 times more potent than IDPN in this regard. This is consistent with the involvement of a flavin monooxygenase-mediated N-oxygenation pathway in the toxic activation of IDPN.

  3. Cadmium neurotoxicity to a freshwater planarian.

    PubMed

    Wu, Jui-Pin; Lee, Hui-Ling; Li, Mei-Hui

    2014-11-01

    Although freshwater planarians are evolutionarily primitive, they are some of the simplest bilateral animals possessing integrated neural networks similar to those in vertebrates. We attempted to develop planarian Dugesia japonica as a model for investigating the neurotoxicity of environmental pollutants such as cadmium (Cd). This study was therefore designed to study the effects of Cd on the locomotor activity, neurobehavior, and neurological enzymes of D. japonica. After planarians were exposed to Cd at high concentrations, altered neurobehavior was observed that exhibited concentration-dependent patterns. Morphological alterations in Cd-treated planarians included irregular shape, body elongation, screw-like hyperkinesia, and bridge-like position. To study the direct effects of Cd on neurological enzymes, tissue homogenates of planarians were incubated in vitro with Cd before their activity was measured. Results showed that acetylcholinesterase (AChE), adenosine triphosphatase (ATPase), and monoamine oxidase A (MAO-A) activities were inhibited in a concentration-dependent manner. MAO-B activity was significantly induced by Cd at low concentrations and inhibited at high concentrations. Changes in the in vivo activity of AChE and ATPase were also found after planarians were treated with Cd at a sublethal concentration (5.56 μM). These observations indicate that neurotransmission systems in planarians are disturbed after Cd exposure.

  4. Neurotoxicity of traffic-related air pollution.

    PubMed

    Costa, Lucio G; Cole, Toby B; Coburn, Jacki; Chang, Yu-Chi; Dao, Khoi; Roqué, Pamela J

    2017-03-01

    The central nervous system is emerging as an important target for adverse health effects of air pollution, where it may contribute to neurodevelopmental and neurodegenerative disorders. Air pollution comprises several components, including particulate matter (PM) and ultrafine particulate matter (UFPM), gases, organic compounds, and metals. An important source of ambient PM and UFPM is represented by traffic-related air pollution, primarily diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution, and to traffic-related air pollution or DE in particular, may lead to neurotoxicity. In particular, air pollution is emerging as a possible etiological factor in neurodevelopmental (e.g. autism spectrum disorders) and neurodegenerative (e.g. Alzheimer's disease) disorders. The most prominent effects caused by air pollution in both humans and animals are oxidative stress and neuro-inflammation. Studies in mice acutely exposed to DE (250-300μg/m(3) for 6h) have shown microglia activation, increased lipid peroxidation, and neuro-inflammation in various brain regions, particularly the hippocampus and the olfactory bulb. An impairment of adult neurogenesis was also found. In most cases, the effects of DE were more pronounced in male mice, possibly because of lower antioxidant abilities due to lower expression of paraoxonase 2.

  5. Oxidative and nitrosative stress in ammonia neurotoxicity.

    PubMed

    Skowrońska, Marta; Albrecht, Jan

    2013-04-01

    Increased ammonia accumulation in the brain due to liver dysfunction is a major contributor to the pathogenesis of hepatic encephalopathy (HE). Fatal outcome of rapidly progressing (acute) HE is mainly related to cytotoxic brain edema associated with astrocytic swelling. An increase of brain ammonia in experimental animals or treatment of cultured astrocytes with ammonia generates reactive oxygen and nitrogen species in the target tissues, leading to oxidative/nitrosative stress (ONS). In cultured astrocytes, ammonia-induced ONS is invariably associated with the increase of the astrocytic cell volume. Interrelated mechanisms underlying this response include increased nitric oxide (NO) synthesis which is partly coupled to the activation of NMDA receptors and increased generation of reactive oxygen species by NADPH oxidase. ONS and astrocytic swelling are further augmented by excessive synthesis of glutamine (Gln) which impairs mitochondrial function following its accumulation in there and degradation back to ammonia ("the Trojan horse" hypothesis). Ammonia also induces ONS in other cell types of the CNS: neurons, microglia and the brain capillary endothelial cells (BCEC). ONS in microglia contributes to the central inflammatory response, while its metabolic and pathophysiological consequences in the BCEC evolve to the vasogenic brain edema associated with HE. Ammonia-induced ONS results in the oxidation of mRNA and nitration/nitrosylation of proteins which impact intracellular metabolism and potentiate the neurotoxic effects. Simultaneously, ammonia facilitates the antioxidant response of the brain, by activating astrocytic transport and export of glutathione, in this way increasing the availability of precursors of neuronal glutathione synthesis.

  6. Role of prion protein aggregation in neurotoxicity.

    PubMed

    Corsaro, Alessandro; Thellung, Stefano; Villa, Valentina; Nizzari, Mario; Florio, Tullio

    2012-01-01

    In several neurodegenerative diseases, such as Parkinson, Alzheimer's, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP), the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126) and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death.

  7. Developmental neurotoxicity test guidelines: problems and perspectives.

    PubMed

    Tohyama, Chiharu

    2016-01-01

    Epidemiologic evidence has demonstrated associations between early life exposure to industrial chemicals and the occurrence of disease states, including cognitive and behavioral abnormalities, in children. The developing brain in the fetal and infantile periods is extremely vulnerable to chemicals because the blood-brain barrier is not completely formed during these periods. The Organisation for Economic Co-operation and Development (OECD) developmental neurotoxicity (DNT) test guideline, TG426, updated in 2007, comprises in vivo behavioral observational tests and other tests intended to assess DNT induced by exposure to industrial chemicals. These chemicals may enter the market without having been subjected to DNT testing, as DNT test data is not mandated by law at the time of chemical registration. In addition, proprietary rights have led to problems concerning the non-disclosure of industrial chemical toxicity test data, including DNT test data. To overcome the disadvantages of high-cost and low time efficiency of in vivo DNT tests, in vitro or in silico tests are the proposed alternatives, but it is unlikely that the results of such tests would reflect changes in higher brain functions. Accordingly, the current DNT test guidelines need to be revised to avoid overlooking or neglecting the occurrence of DNT induced by exposure to low doses of chemicals. This review also proposes the introduction of novel in vivo DNT testing methods in light of a cost-performance analysis.

  8. Gemifloxacin-associated neurotoxicity presenting as encephalopathy.

    PubMed

    Barrett, Matthew J; Login, Ivan S

    2009-04-01

    To report a case of acute encephalopathy associated with ingestion of gemifloxacin, a fluoroquinolone. A 67-year-old woman presented to the emergency department with an acute alteration in mental status. Twenty-four hours earlier she had taken one 320-mg tablet of her husband's gemifloxacin prescription to treat symptoms of a mild upper respiratory infection. During her initial evaluation at our institution, the woman was dysphasic, unable to follow commands, and agitated, suggesting encephalopathy. A thorough diagnostic investigation did not reveal any structural, metabolic, or infectious etiology. Her mental status returned to normal within 2 days without any definitive treatment. Fluoroquinolone-associated neurotoxicity may manifest as encephalopathy, seizures, confusion, or toxic psychosis. To date, none of these adverse effects, specifically encephalopathy, has been reported with gemifloxacin. An objective causality assessment revealed that encephalopathy was probably associated with gemifloxacin use. Seizures, either convulsive or nonconvulsive, may have contributed to our patient's presentation, but she denied seizures prior to this event and did not suffer a seizure in the 18 months following her discharge. However, her second electroencephalograph revealed an underlying predisposition to seizures, which gemifloxacin may have unmasked. This report illustrates that severe central nervous system adverse effects associated with some fluoroquinolones may also occur with gemifloxacin. Gemifloxacin and other fluoroquinolones should be considered in the etiologic evaluation of patients with acute encephalopathy.

  9. Neurotoxic Alkaloids: Saxitoxin and Its Analogs

    PubMed Central

    Wiese, Maria; D’Agostino, Paul M.; Mihali, Troco K.; Moffitt, Michelle C.; Neilan, Brett A.

    2010-01-01

    Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria (prokaryotes), which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs—each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids. PMID:20714432

  10. Role of Prion Protein Aggregation in Neurotoxicity

    PubMed Central

    Corsaro, Alessandro; Thellung, Stefano; Villa, Valentina; Nizzari, Mario; Florio, Tullio

    2012-01-01

    In several neurodegenerative diseases, such as Parkinson, Alzheimer’s, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP), the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126) and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death. PMID:22942726

  11. Alternative Test Methods for Developmental Neurotoxicity: A ...

    EPA Pesticide Factsheets

    Exposure to environmental contaminants is well documented to adversely impact the development of the nervous system. However, the time, animal and resource intensive EPA and OECD testing guideline methods for developmental neurotoxicity (DNT) are not a viable solution to characterizing potential chemical hazards for the thousands of untested chemicals currently in commerce. Thus, research efforts over the past decade have endeavored to develop cost-effective alternative DNT testing methods. These efforts have begun to generate data that can inform regulatory decisions. Yet there are major challenges to both the acceptance and use of this data. Major scientific challenges for DNT include development of new methods and models that are “fit for purpose”, development of a decision-use framework, and regulatory acceptance of the methods. It is critical to understand that use of data from these methods will be driven mainly by the regulatory problems being addressed. Some problems may be addressed with limited datasets, while others may require data for large numbers of chemicals, or require the development and use of new biological and computational models. For example mechanistic information derived from in vitro DNT assays can be used to inform weight of evidence (WoE) or integrated approaches to testing and assessment (IATA) approaches for chemical-specific assessments. Alternatively, in vitro data can be used to prioritize (for further testing) the thousands

  12. The Janus faces of 3-hydroxykynurenine: dual redox modulatory activity and lack of neurotoxicity in the rat striatum.

    PubMed

    Colín-González, Ana Laura; Maya-López, Marisol; Pedraza-Chaverrí, José; Ali, Syed F; Chavarría, Anahí; Santamaría, Abel

    2014-11-17

    3-Hydroxykynurenine (3-HK), an intermediate metabolite of the kynurenine pathway, has been largely hypothesized as a neurotoxic molecule contributing to neurodegeneration in several experimental and clinical conditions. Interestingly, the balance in literature points to a dual role of this molecule in the CNS: in vitro studies describe neurotoxic and/or antioxidant properties, whereas in vivo studies suggest a role of this metabolite as a weak neurotoxin. This work was designed to investigate, under different experimental conditions, whether or not 3-HK is toxic to cells, and if the redox activity exerted by this molecule modulates its actions in the rat striatum. In order to evaluate these effects, 3-HK was administered in vitro to isolated striatal slices, and in vivo to the striatum of rats. In striatal slices, 3-HK exerted a concentration- and time-dependent effect on lipid peroxidation, inducing both pro-oxidant actions at low (5-20) micromolar concentrations, and antioxidant activity at a higher concentration (100µM). Interestingly, while 3-HK was unable to induce mitochondrial dysfunction in slices, at the same range of concentrations it prevented the deleterious effects exerted by the neurotoxin and related metabolite quinolinic acid (QUIN), the mitochondrial toxin 3-nitropropionic acid, and the pro-oxidant compound iron sulfate. These protective actions were related to the stimulation of glutathione S-transferase (GST) and superoxide dismutase (SOD) activities. In addition, 3-HK stimulated the protein content of the transcription factor and antioxidant regulator Nrf2, and some of its related proteins. Accordingly, 3-HK, but not QUIN, exhibited reductive properties at high concentrations. The striatal tissue of animals infused with 3-HK exhibited moderate levels of lipid and protein oxidation at short times post-lesion (h), but these endpoints were substantially decreased at longer times (days). These effects were correlated with an early increase in

  13. Development of Sensitive and Direct Methods for Measuring Plasma Aldosterone and Catecholamine Concentrations

    NASA Technical Reports Server (NTRS)

    Haber, E.

    1972-01-01

    Radioimmunoassays for renin activity, angiotensin 1, and angiotensin 2 in the study of vasomotor regulation give new insight into the role of the renin system in maintaining postural homeostatsis. Similar laboratory procedures for specific assays of aldosterone and catecholamines achieve accurate determinations in small human blood samples.

  14. Fully automated high-performance liquid chromatographic assay for the analysis of free catecholamines in urine.

    PubMed

    Said, R; Robinet, D; Barbier, C; Sartre, J; Huguet, C

    1990-08-24

    A totally automated and reliable high-performance liquid chromatographic method is described for the routine determination of free catecholamines (norepinephrine, epinephrine and dopamine) in urine. The catecholamines were isolated from urine samples using small alumina columns. A standard automated method for pH adjustment of urine before the extraction step has been developed. The extraction was performed on an ASPEC (Automatic Sample Preparation with Extraction Columns, Gilson). The eluate was collected in a separate tube and then automatically injected into the chromatographic column. The catecholamines were separated by reversed-phase ion-pair liquid chromatography and quantified by fluorescence detection. No manual intervention was required during the extraction and separation procedure. One sample may be run every 15 min, ca. 96 samples in 24 h. Analytical recoveries for all three catecholamines are 63-87%, and the detection limits are 0.01, 0.01, and 0.03 microM for norepinephrine, epinephrine and dopamine, respectively, which is highly satisfactory for urine. Day-to-day coefficients of variation were less than 10%.

  15. Protective Effects of D-Penicillamine on Catecholamine-Induced Myocardial Injury

    PubMed Central

    Říha, Michal; Hašková, Pavlína; Martin, Jan; Filipský, Tomáš; Váňová, Kateřina; Vávrová, Jaroslava; Holečková, Magdalena; Homola, Pavel; Vítek, Libor; Palicka, Vladimír; Šimůnek, Tomáš; Mladěnka, Přemysl

    2016-01-01

    Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury both in vitro and in vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additional in vitro experiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application. PMID:26788248

  16. Concepts of Scientific Integrative Medicine Applied to the Physiology and Pathophysiology of Catecholamine Systems

    PubMed Central

    Goldstein, David S.

    2016-01-01

    This review presents concepts of scientific integrative medicine and relates them to the physiology of catecholamine systems and to the pathophysiology of catecholamine-related disorders. The applications to catecholamine systems exemplify how scientific integrative medicine links systems biology with integrative physiology. Concepts of scientific integrative medicine include (i) negative feedback regulation, maintaining stability of the body’s monitored variables; (ii) homeostats, which compare information about monitored variables with algorithms for responding; (iii) multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; (iv) effector sharing, accounting for interactions among homeostats and phenomena such as hyperglycemia attending gastrointestinal bleeding and hyponatremia attending congestive heart failure; (v) stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; (vi) distress, using a noncircular definition that does not presume pathology; (vii) allostasis, corresponding to adaptive plasticity of feedback-regulated systems; and (viii) allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models one can predict mathematically the effects of stress and allostatic load on the transition from wellness to symptomatic disease. The review describes acute and chronic clinical disorders involving catecholamine systems—especially Parkinson disease—and how these concepts relate to pathophysiology, early detection, and treatment and prevention strategies in the post-genome era. PMID:24265239

  17. The Control of Responsiveness in ADHD by Catecholamines: Evidence for Dopaminergic, Noradrenergic and Interactive Roles

    ERIC Educational Resources Information Center

    Oades, Robert D.; Sadile, Adolfo G.; Sagvolden, Terje; Viggiano, Davide; Zuddas, Alessandro; Devoto, Paola; Aase, Heidi; Johansen, Espen B.; Ruocco, Lucia A.; Russell, Vivienne A.

    2005-01-01

    We explore the neurobiological bases of attention deficit hyperactivity disorder (ADHD) from the viewpoint of the neurochemistry and psychopharmacology of the catecholamine-based behavioural systems. The contributions of dopamine (DA) and noradrenaline (NA) neurotransmission to the motor and cognitive symptoms of ADHD (e.g. hyperactivity, variable…

  18. Facial swelling secondary to inhaled bronchodilator abuse: catecholamine-induced sialadenosis.

    PubMed

    Loria, R C; Wedner, H J

    1989-04-01

    A patient with asthma presented with a history of recurrent episodes of facial swelling. The swelling occurred in the preauricular area and extended to the angle of the jaw. The patient attributed these episodes to a "food allergy" as they occurred during or immediately following meals. The only medication the patient was using was inhaled epinephrine (Primatene MistR), two puffs, ten to twenty times a day. Subsequent evaluation revealed that the patient had sarcoidosis. Differential diagnosis of the facial swelling included food-related angioedema, sarcoid parotitis, or catecholamine-induced sialadenosis, which is a rare complication associated with excessive catecholamine administration. A gallium-67 citrate scan demonstrated abnormal pulmonary and hilar uptake of the radiotracer, but not lacrimal or parotid gland uptake, strongly arguing against sarcoidosis as the cause of the facial swelling. Episodes of swelling completely abated when the patient stopped using the epinephrine inhalers. At 5 months of follow-up she has had two recurrent episodes of facial swelling, each time associated with the use of inhaled epinephrine. Thus this patient's facial swelling most likely represents catecholamine-induced sialadenosis. This adverse drug reaction, associated with excessive use of inhaled catecholamines must be kept in mind in patients who abuse inhaled beta-adrenergic agonists and report parotid swelling.

  19. Adrenal Medullary Grafts Restore Olfactory Deficits and Catecholamine Levels of 6-OHDA Amygdala Lesioned Animals

    PubMed Central

    Fernández-Ruiz, Juan; Guzmán, Rubén; Martínez, María Dolores; Miranda, María Isabel; Bermúdez-Rattoni, Federico; Drucker-Colín, René

    1993-01-01

    Aside from motor and cognitive deficits, Parkinson patients also manifest a little-studied olfactory deficit. Since in Parkinson's disease there is a dopamine depletion of the amygdala due to mesocorticolimbic system degeneration, we decided to test olfactory and taste performance of 6-OHDA amygdala lesioned rats, as well as the possible restoration of either function with adrenal medullary transplants. Two 6-OHDA lesioned groups and one control group were tested in the potentiation of odor by taste aversion paradigm. On taste aversion none of the groups showed any impairment. In contrast, the 6-OHDA lesioned rats showed a marked impairment in olfactory aversion. At this point, one of the lesioned groups received a bilateral adrenal medullary graft within the lesioned area. After two months, all groups were submitted again to the behavioral paradigm. Taste remained unaffected, but the lesioned only group did not recover either olfactory aversion or normal catecholamine levels. The grafted group, on the other hand, restored olfactory aversion and catecholamine levels. It can be concluded from this study that catecholamine depletion of the amygdala is sufficient to produce a selective olfactory deficit, not accompanied by taste impairments, and that such a deficit can be reversed by adrenal medullary transplants, which in turn restore catecholamine levels. PMID:7948179

  20. POTENTIAL MECHANISMS RESPONSIBLE FOR CHLOROTRIAZINE-INDUCED ALTERATIONS IN CATECHOLAMINES IN PHEOCHROMOCYTOMA (PC12) CELLS

    EPA Science Inventory

    ABSTRACT

    Potential Mechanisms Responsible for Chlorotriazine-induced Changes in Catecholamine Metabolism in Pheochromocytoma (PC12) Cells*
    PARIKSHIT C. DAS1, WILLIAM K. McELROY2 , AND RALPH L. COOPER2+
    1Curriculum in Toxicology, University of North Carolina, Chape...

  1. DIFFERENTIAL MODULATION OF CATECHOLAMINES BY CHLOROTRIAZINE HERBICIDES IN PHEOCHROMOCYTOMA (PC12) CELLS IN VITRO

    EPA Science Inventory

    Differential modulation of catecholamines by chlorotriazine herbicides in pheochromocytoma (PC12) cells in vitro.

    Das PC, McElroy WK, Cooper RL.

    Curriculum in Toxicology, University of North Carolina, Chapel Hill 27599, USA.

    Epidemiological, wildlife, and lab...

  2. Ecological and sociodemographic effects on urinary catecholamine excretion in adult Samoans.

    PubMed

    Bergey, Meredith R; Steele, Matthew S; Bereiter, David A; Viali, Satupaitea; McGarvey, Stephen T

    2011-03-01

    Ecological and sociodemographic correlates of stress may contribute to cardiovascular disease risk in modernizing Samoans. The effects of peri-urban vs rural residence, education, occupation, caffeine intake and cigarette consumption on urinary catecholamine excretion were studied in Samoan adults. Five hundred and seven participants, aged 29-69 years, were randomly selected from nine villages throughout Samoa. Sociodemographic and lifestyle factors were assessed by questionnaire. Epinephrine and norepinephrine excretion rates were measured by high performance liquid chromatography with electrochemical detection in overnight urine samples. Age ( ≤ 40 vs >40 years) and gender-specific regression models were estimated to detect associations with BMI-adjusted catecholamine excretion. Norepinephrine was significantly higher in peri-urban young men and older women. Epinephrine was significantly higher in peri-urban older men. Adjustment for caffeine attenuated the relationship between residence and norepinephrine in young women. General residential exposure to modernization in urban villages is a significant correlate of increased overnight catecholamine excretion rates and is consistent with past studies. Caffeine consumption in younger women plays a complex role in stress-related catecholamine excretion. Further studies of individual level attitudinal and behavioural factors in Samoans are needed to understand psychosocial stress, physiologic arousal and health.

  3. Ecological and sociodemographic effects on urinary catecholamine excretion in adult Samoans

    PubMed Central

    Bergey, Meredith R.; Steele, Matthew S.; Bereiter, David A.; Viali, Satupaitea; McGarvey, Stephen T.

    2013-01-01

    Background Ecological and sociodemographic correlates of stress may contribute to cardiovascular disease risk in modernizing Samoans. Aim The effects of peri-urban vs rural residence, education, occupation, caffeine intake and cigarette consumption on urinary catecholamine excretion were studied in Samoan adults. Subjects and methods Five hundred and seven participants, aged 29–69 years, were randomly selected from nine villages throughout Samoa. Sociodemographic and lifestyle factors were assessed by questionnaire. Epinephrine and norepinephrine excretion rates were measured by high performance liquid chromatography with electrochemical detection in overnight urine samples. Age (≤40 vs >40 years) and gender-specific regression models were estimated to detect associations with BMI-adjusted catecholamine excretion. Results Norepinephrine was significantly higher in peri-urban young men and older women. Epinephrine was significantly higher in peri-urban older men. Adjustment for caffeine attenuated the relationship between residence and norepinephrine in young women. Conclusion General residential exposure to modernization in urban villages is a significant correlate of increased overnight catecholamine excretion rates and is consistent with past studies. Caffeine consumption in younger women plays a complex role in stress-related catecholamine excretion. Further studies of individual level attitudinal and behavioural factors in Samoans are needed to understand psychosocial stress, physiologic arousal and health. PMID:20836724

  4. Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters.

    PubMed

    Toneff, Thomas; Funkelstein, Lydiane; Mosier, Charles; Abagyan, Armen; Ziegler, Michael; Hook, Vivian

    2013-08-01

    Beta-amyloid (Aβ) peptides are secreted from neurons, resulting in extracellular accumulation of Aβ and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Aβ undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Aβ(1-40) and Aβ(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Aβ peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Aβ with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Aβ was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, β- and γ-secretases, that are necessary for production of Aβ. Thus, Aβ can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Aβ(1-40) and Aβ(1-42) with the galanin neurotransmitter. These findings illustrate that Aβ peptides are present in neurotransmitter-containing DCSV, and undergo co-secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions.

  5. Potentiometric and NMR complexation studies of phenylboronic acid PBA and its aminophosphonate analog with selected catecholamines

    NASA Astrophysics Data System (ADS)

    Ptak, Tomasz; Młynarz, Piotr; Dobosz, Agnieszka; Rydzewska, Agata; Prokopowicz, Monika

    2013-05-01

    Boronic acids are a class of intensively explored compounds, which according to their specific properties have been intensively explored in last decades. Among them phenylboronic acids and their derivatives are most frequently examined as receptors for diverse carbohydrates. In turn, there is a large gap in basic research concerning complexation of catecholamines by these compounds. Therefore, we decided to undertake studies on interaction of chosen catecholamines, namely: noradrenaline (norephinephrine), dopamine, L-DOPA, DOPA-P (phosphonic analog of L-DOPA) and catechol, with simple phenyl boronic acid PBA by means of potentiometry and NMR spectroscopy. For comparison, the binding properties of recently synthesized phenylboronic receptor 1 bearing aminophosphonate function in meta-position were investigated and showed promising ability to bind catecholamines. The protonation and stability constants of PBA and receptor 1 complexes were examined by potentiometry. The obtained results demonstrated that PBA binds the catecholamines with the following affinity order: noradrenaline ⩾ dopamine ≈ L-DOPA > catechol > DOPA-P, while its modified analog 1 reveals slightly different preferences: dopamine > noradrenaline > catechol > L-DOPA > DOPA-P.

  6. DIFFERENTIAL MODULATION OF CATECHOLAMINES BY CHLOROTRIAZINE HERBICIDES IN PHEOCHROMOCYTOMA (PC12) CELLS IN VITRO

    EPA Science Inventory

    Differential modulation of catecholamines by chlorotriazine herbicides in pheochromocytoma (PC12) cells in vitro.

    Das PC, McElroy WK, Cooper RL.

    Curriculum in Toxicology, University of North Carolina, Chapel Hill 27599, USA.

    Epidemiological, wildlife, and lab...

  7. POTENTIAL MECHANISMS RESPONSIBLE FOR CHLOROTRIAZINE-INDUCED ALTERATIONS IN CATECHOLAMINES IN PHEOCHROMOCYTOMA (PC12) CELLS

    EPA Science Inventory

    ABSTRACT

    Potential Mechanisms Responsible for Chlorotriazine-induced Changes in Catecholamine Metabolism in Pheochromocytoma (PC12) Cells*
    PARIKSHIT C. DAS1, WILLIAM K. McELROY2 , AND RALPH L. COOPER2+
    1Curriculum in Toxicology, University of North Carolina, Chape...

  8. Fight or flight, forbearance and fortitude: the spectrum of actions of the catecholamines and their cousins.

    PubMed

    Arun, C P

    2004-06-01

    Catecholamines are recognized to play an important part in the fight-or-flight response to impending stress. Catecholamine and other phase-reactant levels are raised in the first 24 h following acute stress, but the bigger picture of their action on the organism is unavailable. In this article, we examine their actions in light of the theory of phase transitions borrowed from the numerate sciences. Phase transitions involve changes in the state of matter or an organism with a common example of what is termed a first-order phase transition (sudden change) being provided by the popular expression "the straw that broke the camel's back." We propose that the response to catecholamines follows a triphasic response: a Phase I response is the fight-or-flight response to impending stress that protects the animal. With mild to intermediate stress, the Phase II or forbearance response allows it to tolerate the physiological upset. With severe stress, however, severe vital organ vasoconstriction leads to a quick death. The present theory has value in understanding the clinical picture in acute stress. Phase II or Forbearance Phase corresponds to Classes I, II, and III of hemorrhagic shock, and Phase III or Fortitude Phase to Class IV. Thus, a Phase III or fortitude response is to the animal what apoptosis is to the individual cell and has social implications. The present framework provides a fresh perspective on the action of the catecholamines and their cousins.

  9. Using size exclusion chromatography to monitor the synthesis of melanins from catecholamines.

    PubMed

    Vercruysse, Koen P; Clark, Astiney M; Bello, Paola A F; Alhumaidi, Majidah

    2017-09-01

    We have employed size exclusion chromatography (SEC) to the study of the auto- and Cu(2+)-mediated oxidation of the catecholamines, dopamine, epinephrine and norepinephrine, into melanins. We observed that, due to non-size exclusion-mediated effects, the catecholamines and some of the low molecular mass intermediates generated during the oxidation reactions, could be resolved from each other and from the high molecular mass pigment generated. Thus, SEC allowed us to monitor the disappearance of the catecholamine starting compounds, the appearance and subsequent disappearance of the low molecular mass chromophores generated in the initial phase of the reactions and the appearance of the high molecular mass melanins. In the process of this research, we observed that many, mostly anionic polysaccharides (PS), enhanced both the auto- and Cu(2+)-mediated oxidation of all three catecholamines. SEC analyses of reaction mixtures involving PS suggested that very high molecular mass aggregates between PS and melanins can be generated. In addition, SEC analysis allowed us to verify the efficiency of the dialysis purification process employed to obtain pure and dried melanin materials for cell-biological studies. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Catecholamine responses to virtual combat: implications for post-traumatic stress and dimensions of functioning

    PubMed Central

    Highland, Krista B.; Costanzo, Michelle E.; Jovanovic, Tanja; Norrholm, Seth D.; Ndiongue, Rochelle B.; Reinhardt, Brian J.; Rothbaum, Barbara; Rizzo, Albert A.; Roy, Michael J.

    2015-01-01

    Posttraumatic stress disorder (PTSD) symptoms can result in functional impairment among service members (SMs), even in those without a clinical diagnosis. The variability in outcomes may be related to underlying catecholamine mechanisms. Individuals with PTSD tend to have elevated basal catecholamine levels, though less is known regarding catecholamine responses to trauma-related stimuli. We assessed whether catecholamine responses to a virtual combat environment impact the relationship between PTSD symptom clusters and elements of functioning. Eighty-seven clinically healthy SMs, within 2 months after deployment to Iraq or Afghanistan, completed self-report measures, viewed virtual-reality (VR) combat sequences, and had sequential blood draws. Norepinephrine responses to VR combat exposure moderated the relationship between avoidance symptoms and scales of functioning including physical functioning, physical-role functioning, and vitality. Among those with high levels of avoidance, norepinephrine change was inversely associated with functional status, whereas a positive correlation was observed for those with low levels of avoidance. Our findings represent a novel use of a virtual environment to display combat-related stimuli to returning SMs to elucidate mind-body connections inherent in their responses. The insight gained improves our understanding of post-deployment symptoms and quality of life in SMs and may facilitate enhancements in treatment. Further research is needed to validate these findings in other populations and to define the implications for treatment effectiveness. PMID:25852586

  11. The Control of Responsiveness in ADHD by Catecholamines: Evidence for Dopaminergic, Noradrenergic and Interactive Roles

    ERIC Educational Resources Information Center

    Oades, Robert D.; Sadile, Adolfo G.; Sagvolden, Terje; Viggiano, Davide; Zuddas, Alessandro; Devoto, Paola; Aase, Heidi; Johansen, Espen B.; Ruocco, Lucia A.; Russell, Vivienne A.

    2005-01-01

    We explore the neurobiological bases of attention deficit hyperactivity disorder (ADHD) from the viewpoint of the neurochemistry and psychopharmacology of the catecholamine-based behavioural systems. The contributions of dopamine (DA) and noradrenaline (NA) neurotransmission to the motor and cognitive symptoms of ADHD (e.g. hyperactivity, variable…

  12. Effects of adrenal medulla grafts on plasma catecholamines and rotational behavior.

    PubMed

    Takashima, H; Poltorak, M; Becker, J B; Freed, W J

    1992-10-01

    The mechanisms by which adrenal medulla grafts influence the function of host brains in animal models of Parkinson's disease are unclear. To explore this issue, fragments of adrenal medulla or sciatic nerve were transplanted into the lateral ventricle of bilaterally adrenalectomized (ADX) or sham-ADX rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. Additional control group received sham-transplantation surgery. Behavioral effects of these procedures were tested following administration of apomorphine, amphetamine, or nicotine. Plasma catecholamines were measured before and after transplantation surgery. In both ADX and sham-ADX rats, adrenal medulla grafts produced greater decreases in apomorphine-induced rotational behavior than did sciatic nerve grafts or sham-transplanted groups. Decreases in rotation were smaller in ADX than in sham-ADX animals, regardless of graft treatment. Plasma catecholamines increased after transplantation surgery in each of the sham-ADX groups, regardless of graft type. Increases in plasma dopamine concentrations were associated with decreases in rotational behavior. Five months after transplantation, grafted chromaffin cells demonstrated catecholamine fluorescence, tyrosine hydroxylase (TH) and chromogranin A immunoreactivities, and expression of TH mRNA. It is concluded that adrenal medulla grafts produce decreases in apomorphine-induced rotation through a combination of two independent effects. One is a specific effect of adrenal medulla grafts. The second is a nonspecific effect that requires an intact adrenal gland and may be related to increases in plasma catecholamine concentrations.

  13. Protective Effects of D-Penicillamine on Catecholamine-Induced Myocardial Injury.

    PubMed

    Říha, Michal; Hašková, Pavlína; Martin, Jan; Filipský, Tomáš; Váňová, Kateřina; Vávrová, Jaroslava; Holečková, Magdalena; Homola, Pavel; Vítek, Libor; Palicka, Vladimír; Šimůnek, Tomáš; Mladěnka, Přemysl

    2016-01-01

    Iron and copper release participates in the myocardial injury under ischemic conditions and hence protection might be achieved by iron chelators. Data on copper chelation are, however, sparse. The effect of the clinically used copper chelator D-penicillamine in the catecholamine model of acute myocardial injury was tested in cardiomyoblast cell line H9c2 and in Wistar Han rats. D-Penicillamine had a protective effect against catecholamine-induced injury both in vitro and in vivo. It protected H9c2 cells against the catecholamine-induced viability loss in a dose-dependent manner. In animals, both intravenous D-penicillamine doses of 11 (low) and 44 mg/kg (high) decreased the mortality caused by s.c. isoprenaline (100 mg/kg) from 36% to 14% and 22%, respectively. However, whereas the low D-penicillamine dose decreased the release of cardiac troponin T (specific marker of myocardial injury), the high dose resulted in an increase. Interestingly, the high dose led to a marked elevation in plasma vitamin C. This might be related to potentiation of oxidative stress, as suggested by additional in vitro experiments with D-penicillamine (iron reduction and the Fenton reaction). In conclusion, D-penicillamine has protective potential against catecholamine-induced cardiotoxicity; however the optimal dose selection seems to be crucial for further application.

  14. Development of Sensitive and Direct Methods for Measuring Plasma Aldosterone and Catecholamine Concentrations

    NASA Technical Reports Server (NTRS)

    Haber, E.

    1972-01-01

    Radioimmunoassays for renin activity, angiotensin 1, and angiotensin 2 in the study of vasomotor regulation give new insight into the role of the renin system in maintaining postural homeostatsis. Similar laboratory procedures for specific assays of aldosterone and catecholamines achieve accurate determinations in small human blood samples.

  15. Concepts of scientific integrative medicine applied to the physiology and pathophysiology of catecholamine systems.

    PubMed

    Goldstein, David S

    2013-10-01

    This review presents concepts of scientific integrative medicine and relates them to the physiology of catecholamine systems and to the pathophysiology of catecholamine-related disorders. The applications to catecholamine systems exemplify how scientific integrative medicine links systems biology with integrative physiology. Concepts of scientific integrative medicine include (i) negative feedback regulation, maintaining stability of the body's monitored variables; (ii) homeostats, which compare information about monitored variables with algorithms for responding; (iii) multiple effectors, enabling compensatory activation of alternative effectors and primitive specificity of stress response patterns; (iv) effector sharing, accounting for interactions among homeostats and phenomena such as hyperglycemia attending gastrointestinal bleeding and hyponatremia attending congestive heart failure; (v) stress, applying a definition as a state rather than as an environmental stimulus or stereotyped response; (vi) distress, using a noncircular definition that does not presume pathology; (vii) allostasis, corresponding to adaptive plasticity of feedback-regulated systems; and (viii) allostatic load, explaining chronic degenerative diseases in terms of effects of cumulative wear and tear. From computer models one can predict mathematically the effects of stress and allostatic load on the transition from wellness to symptomatic disease. The review describes acute and chronic clinical disorders involving catecholamine systems-especially Parkinson disease-and how these concepts relate to pathophysiology, early detection, and treatment and prevention strategies in the post-genome era.

  16. Role of catecholamines in maternal-fetal stress transfer in sheep.

    PubMed

    Rakers, Florian; Bischoff, Sabine; Schiffner, Rene; Haase, Michelle; Rupprecht, Sven; Kiehntopf, Michael; Kühn-Velten, W Nikolaus; Schubert, Harald; Witte, Otto W; Nijland, Mark J; Nathanielsz, Peter W; Schwab, Matthias

    2015-11-01

    We sought to evaluate whether in addition to cortisol, catecholamines also transfer psychosocial stress indirectly to the fetus by decreasing uterine blood flow (UBF) and increasing fetal anaerobic metabolism and stress hormones. Seven pregnant sheep chronically instrumented with uterine ultrasound flow probes and catheters at 0.77 gestation underwent 2 hours of psychosocial stress by isolation. We used adrenergic blockade with labetalol to examine whether decreased UBF is catecholamine mediated and to determine to what extent stress transfer from mother to fetus is catecholamine dependent. Stress induced transient increases in maternal cortisol and norepinephrine (NE). Maximum fetal plasma cortisol concentrations were 8.1 ± 2.1% of those in the mother suggesting its maternal origin. In parallel to the maternal NE increase, UBF decreased by maximum 22% for 30 minutes (P < .05). Fetal NE remained elevated for >2 hours accompanied by a prolonged blood pressure increase (P < .05). Fetuses developed a delayed and prolonged shift toward anaerobic metabolism in the presence of an unaltered oxygen supply. Adrenergic blockade prevented the stress-induced UBF decrease and, consequently, the fetal NE and blood pressure increase and the shift toward anaerobic metabolism. We conclude that catecholamine-induced decrease of UBF is a mechanism of maternal-fetal stress transfer. It may explain the influence of maternal stress on fetal development and on programming of adverse health outcomes in later life especially during early pregnancy when fetal glucocorticoid receptor expression is limited. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. A microfluidic platform for chemical stimulation and real time analysis of catecholamine secretion from neuroendocrine cells.

    PubMed

    Ges, Igor A; Brindley, Rebecca L; Currie, Kevin P M; Baudenbacher, Franz J

    2013-12-07

    Release of neurotransmitters and hormones by calcium-regulated exocytosis is a fundamental cellular process that is disrupted in a variety of psychiatric, neurological, and endocrine disorders. As such, there is significant interest in targeting neurosecretion for drug and therapeutic development, efforts that will be aided by novel analytical tools and devices that provide mechanistic insight coupled with increased experimental throughput. Here, we report a simple, inexpensive, reusable, microfluidic device designed to analyze catecholamine secretion from small populations of adrenal chromaffin cells in real time, an important neuroendocrine component of the sympathetic nervous system and versatile neurosecretory model. The device is fabricated by replica molding of polydimethylsiloxane (PDMS) using patterned photoresist on silicon wafer as the master. Microfluidic inlet channels lead to an array of U-shaped "cell traps", each capable of immobilizing single or small groups of chromaffin cells. The bottom of the device is a glass slide with patterned thin film platinum electrodes used for electrochemical detection of catecholamines in real time. We demonstrate reliable loading of the device with small populations of chromaffin cells, and perfusion/repetitive stimulation with physiologically relevant secretagogues (carbachol, PACAP, KCl) using the microfluidic network. Evoked catecholamine secretion was reproducible over multiple rounds of stimulation, and graded as expected to different concentrations of secretagogue or removal of extracellular calcium. Overall, we show this microfluidic device can be used to implement complex stimulation paradigms and analyze the amount and kinetics of catecholamine secretion from small populations of neuroendocrine cells in real time.

  18. MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains

    PubMed Central

    Alam, Gelareh; Miller, Diane B.; O’Callaghan, James P.; Lu, Lu; Williams, Robert W.; Jones, Byron C.

    2016-01-01

    Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5 mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases. PMID:27182044

  19. Electrostimulation of catecholamine release in the eel: modulation by antagonists and autocrine agonists.

    PubMed

    Abele, B; Hathaway, C B; Nibbio, B; Epple, A

    1998-03-01

    The innervated chromaffin cells of the eel (Anguilla rostrata) release norepinephrine (NE) and epinephrine (E), while a component of the macrovascular wall releases dopamine (DA). The release of the three catecholamines is governed by complex controls which include adrenergic, nicotinergic, muscarinergic, and opioid mechanisms. To gain insight into the interactions between neural and autocrine factors in stimulated catecholamine release, we investigated the effect of adrenergic (phentolamine and propranolol) and muscarinergic (atropine) receptor antagonists, and of autocrine opioids (met-enkephalin, codeine, and morphine) on electrostimulated catecholamine secretion in situ. The hind brain (close to the root of nerve IX) of anesthetized eels was stimulated at four different time points, and segments of the posterior cardinal vein or the caudal vein were perfused with a saline solution, with or without test substances. Electrostimulation (30 s) four times within a total study duration of 14 min increased the release of DA, NE, and E into the perfusate of the cardinal vein. The vessel contains the innervated adrenomedullary equivalent. In the noninnervated caudal vein electrical stimulation had no impact on total DA release, while there was a slight decrease of NE release and a slight increase of E release. In the cardinal vein, both the alpha-adrenergic receptor antagonist phentolamine and the beta-adrenergic receptor antagonist propranolol strongly reduced the effect of electrostimulation on catecholamine release. Met-enkephalin reduced the release of all three catecholamines to a similar degree; its impact on NE release was especially strong. Codeine reduced the catecholamine release moderately, while morphine had no effect. Atropine reduced the release of all three catecholamines in a pattern similar to that of met-enkephalin. The findings on the posterior cardinal vein indicate that neurally stimulated NE and E release (1) involves autocrine/paracrine adrenergic

  20. [Correlation between urinary catecholamines dosage and apnea-hypopnea index in a hypertension population: pilot study].

    PubMed

    Lopez-Sublet, M; Le Jeune, S; Giroux-Leprieur, B; Agnoletti, D; Dhote, R; Mourad, J J

    2014-06-01

    Sleep disorders like obstructive sleep apnea in adults are associated with increased sympathetic activity, which induced high blood pressure and could be associated with resistant hypertension. Some studies have demonstrated that high urinary catecholamine levels in obstructive sleep apnea patients may be decreased with continuous positive airway pressure therapy. However, very few studies have demonstrated a correlation between apnea-hypopnea index and urinary catecholamine levels in hypertension patients. In this pilot study, 20 hypertensive patients referred for hypertension work-up including night-time polygraphy and 24h urinary catecholamine dosage were included. Mean age was 51±11 years (30-76), 68% were males. Diagnosis of obstructive sleep apnea was confirmed in 13 patients at the end of the work-up. Mean apnea-hypopnea index was 14±9 (2-32). The only urinary catecholamine parameter significantly increased in patients with obstructive sleep apnea was 24h urinary normetanephrine (1931±1285 vs 869±293nmol/24h; P<0.05). However, this difference was not significant when this parameter was adjusted to 24h urinary creatinine. We observed a significant positive correlation between AHI and 24h urinary normetanephine (r=0.486; P=0.035). This pilot study confirms an isolated elevation of 24h urinary normetanephrine in hypertensive patients with obstructive sleep apnea and shows a significant correlation between sleep disorders expressed by apnea-hypopnea index and urinary catecholamines excretion. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  1. Alteration of catecholamine phenotype in transgenic mice influences expression of adrenergic receptor subtypes.

    PubMed

    Kobayashi, K; Ota, A; Togari, A; Morita, S; Mizuguchi, T; Sawada, H; Yamada, K; Nagatsu, I; Matsumoto, S; Fujita, K

    1995-08-01

    Agonist-induced regulation of adrenergic receptors (ARs) has an important role in controlling physiological functions in response to changes in catecholamine stimulation. We previously generated transgenic mice expressing phenylethanolamine N-methyltransferase (PNMT) under the control of a human dopamine beta-hydroxylase gene promoter to switch catecholamine specificity from the norepinephrine phenotype to the epinephrine phenotype. In the present study, we first examined changes in catecholamine metabolism in peripheral tissues innervated by sympathetic neurons of the transgenic mice. In the transgenic target tissues, a high-level expression of PNMT led to a dramatic increase in the epinephrine levels, whereas the norepinephrine levels were decreased to 48.6-87.9% of the nontransgenic control levels. Analysis of plasma catecholamines in adrenalectomized mice showed large amounts of epinephrine derived from sympathetic neurons in the transgenic mice. Subsequently, we performed radioligand binding assays with (-)-[125I]iodocyanopindolol to determine changes in binding sites of beta-AR subtypes. In transgenic mice, the number of beta 2-AR binding sites was 56.4-74.9% of their nontransgenic values in the lung, spleen, submaxillary gland, and kidney, whereas the beta 1-AR binding sites were regulated in a different fashion among these tissues. Moreover, northern blot analysis of total RNA from the lung tissues showed that down-regulation of beta 2 binding sites was accompanied by a significant decrease in steady-state levels of the receptor mRNA. These results strongly suggest that alteration of catecholamine specificity in the transgenic sympathetic neurons leads to regulated expression of the beta-AR subtypes in their target tissues.

  2. Distribution of catecholamine and indoleamine neurons in the brain of the common marmoset (Callithrix jacchus).

    PubMed Central

    Schofield, S P; Dixson, A F

    1982-01-01

    The distribution of monoamine neurons in the brains of ten common marmosets (Callithrix jacchus) was examined by means of the Falck-Hillarp formaldehyde histofluorescence technique. Large populations of catecholamine and indoleamine neurons were found throughout the brain stem. Catecholamine cell bodies corresponded essentially to th noradrenaline and dopamine groups defined as A1-A7 and A8-A14, respectively. In contrast to Old World primate species, however, the noradrenaline cell populations (particularly the pontine coeruleal A6 group) were less numerous. Ascending catecholamine fibre pathways were not observed within the medulla or pons, although numerous axons were found near the mesodiencephalic border. These were fine and smooth in appearance in contrast to those of other species and this finding may represent a significant morphological difference. The catecholamine terminal innervation of the diencephalon was modest in the marmoset and was less dense than in other primates. In contrast, limbic areas and the striatum contained very large numbers of terminals. Indoleamine cell bodies, equivalent to the serotonin groups defined as B1-B9, were also observed. The most rostral cell populations (B7-9) were large. In addition, pontine and medullary indoleamine neurons extended laterally through the tegmentum as noted in other primates, such that they often adjacent to catecholamine neurons. A prominent bundle of indoleamine axons was observed in the mesencephalon and corresponded to a fibre pathway seen in rodents and other primates. No terminal varicosities were noted. Images Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 PMID:6804424

  3. Catecholamines as outcome markers in isolated traumatic brain injury: the COMA-TBI study.

    PubMed

    Rizoli, Sandro B; Jaja, Blessing N R; Di Battista, Alex P; Rhind, Shawn G; Neto, Antonio Capone; da Costa, Leodante; Inaba, Kenji; da Luz, Luis Teodoro; Nascimento, Bartolomeu; Perez, Adic; Baker, Andrew J; de Oliveira Manoel, Airton Leonardo

    2017-02-23

    Elevated catecholamine levels might be associated with unfavorable outcome after traumatic brain injury (TBI). We investigated the association between catecholamine levels in the first 24 h post-trauma and functional outcome in patients with isolated moderate-to-severe TBI. A cohort of 174 patients who sustained isolated blunt TBI was prospectively enrolled from three Level-1 Trauma Centers. Epinephrine (Epi) and norepinephrine (NE) concentrations were measured at admission (baseline), 6, 12 and 24 h post-injury. Outcome was assessed at 6 months by the extended Glasgow Outcome Scale (GOSE) score. Fractional polynomial plots and logistic regression models (fixed and random effects) were used to study the association between catecholamine levels and outcome. Effect size was reported as the odds ratio (OR) associated with one logarithmic change in catecholamine level. At 6 months, 109 patients (62.6%) had an unfavorable outcome (GOSE 5-8 vs. 1-4), including 51 deaths (29.3%). Higher admission levels of Epi were associated with a higher risk of unfavorable outcome (OR, 2.04, 95% CI: 1.31-3.18, p = 0.002) and mortality (OR, 2.86, 95% CI: 1.62-5.01, p = 0.001). Higher admission levels of NE were associated with higher risk of unfavorable outcome (OR, 1.59, 95% CI: 1.07-2.35, p = 0.022) but not mortality (OR, 1.45, 95% CI: 0.98-2.17, p = 0.07). There was no relationship between the changes in Epi levels over time and mortality or unfavorable outcome. Changes in NE levels with time were statistically associated with a higher risk of mortality, but the changes had no relation to unfavorable outcome. Elevated circulating catecholamines, especially Epi levels on hospital admission, are independently associated with functional outcome and mortality after isolated moderate-to-severe TBI.

  4. Heart rate and catecholamine contribution to QT interval shortening on exercise.

    PubMed

    Davey, P; Bateman, J

    1999-08-01

    QT interval shortens with exercise. Some of this shortening is due to an increase in heart rate, and some is due to other effects of exercise, probably mostly neuroendocrine effects. Data from subjects with cardiac transplants have suggested that non-heart rate-related changes in QT interval on exercise are due to the effects of circulating catecholamines. We sought to determine whether changes in plasma catecholamine levels with exercise are an important contributor to non-heart rate-related QT interval shortening. Subjects with DDD pacemakers were recruited. Subjects had QT intervals measured at rest, during a low fixed level exercise test designed to increase heart rate to about 110 beats/min, and, after resting, during pacing at a heart rate of 110 beats/min. Catecholamine levels were measured at each stage of the study. QT interval at rest was 420 +/- 12 ms, during pacing 366 +/- 16 ms, and on exercise 325 +/- 14 ms. This then gave the proportion of QT interval shortening due to heart rate as 68.6 +/- 9.3% of total QT shortening, with the range between 35 and 95.6%. There was no proportionality between the degree of QT interval shortening on exercise that was not due to increases in heart rate and changes in plasma catecholamine levels. Two-thirds of exercise-induced QT interval shortening are due to an increase in heart rate, and one-third to other effects. Changes in plasma catecholamine levels on exercise were not closely related to changes in the QT interval on exercise.

  5. Neural response to catecholamine depletion in remitted bulimia nervosa: Relation to depression and relapse.

    PubMed

    Mueller, Stefanie Verena; Mihov, Yoan; Federspiel, Andrea; Wiest, Roland; Hasler, Gregor

    2017-07-01

    Bulimia nervosa has been associated with a dysregulated catecholamine system. Nevertheless, the influence of this dysregulation on bulimic symptoms, on neural activity, and on the course of the illness is not clear yet. An instructive paradigm for directly investigating the relationship between catecholaminergic functioning and bulimia nervosa has involved the behavioral and neural responses to experimental catecholamine depletion. The purpose of this study was to examine the neural substrate of catecholaminergic dysfunction in bulimia nervosa and its relationship to relapse. In a randomized, double-blind and crossover study design, catecholamine depletion was achieved by using the oral administration of alpha-methyl-paratyrosine (AMPT) over 24 h in 18 remitted bulimic (rBN) and 22 healthy (HC) female participants. Cerebral blood flow (CBF) was measured using a pseudo continuous arterial spin labeling (pCASL) sequence. In a follow-up telephone interview, bulimic relapse was assessed. Following AMPT, rBN participants revealed an increased vigor reduction and CBF decreases in the pallidum and posterior midcingulate cortex (pMCC) relative to HC participants showing no CBF changes in these regions. These results indicated that the pallidum and the pMCC are the functional neural correlates of the dysregulated catecholamine system in bulimia nervosa. Bulimic relapse was associated with increased depressive symptoms and CBF reduction in the hippocampus/parahippocampal gyrus following catecholamine depletion. AMPT-induced increased CBF in this region predicted staying in remission. These findings demonstrated the importance of depressive symptoms and the stress system in the course of bulimia nervosa. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Nonhydrolytic sol-gel approach to facile creation of surface-bonded zirconia organic-inorganic hybrid coatings for sample preparation. Ι. Capillary microextraction of catecholamine neurotransmitters.

    PubMed

    Alhendal, Abdullah; Mengis, Stephanie; Matthews, Jacob; Malik, Abdul

    2016-10-14

    Nonhydrolytic sol-gel (NHSG) route was used for the creation of novel zirconia-polypropylene oxide (ZrO2-PPO) sol-gel hybrid sorbents in the form of surface coatings for the extraction and preconcentration of catecholamine neurotransmitters and molecules structurally related to their deaminated metabolites. In comparison to other sorbents made of inorganic transition metal oxides, the presented hybrid organic-inorganic sorbents facilitated reversible sorption properties that allowed for efficient desorption of the extracted analytes by LC-MS compatible mobile phases. The presented sol-gel hybrid sorbents effectively overcame the major drawbacks of traditional silica- or polymer-based sorbents by providing superior pH stability (pH range: 0-14), and a variety of intermolecular interactions. Nonaqueous sol-gel treatment of PPO with ZrCl4 was employed for the derivatization of the terminal hydroxyl groups on PPO, providing zirconium trichloride-containing end groups characterized by enhanced sol-gel reactivity. NHSG ZrO2-PPO sorbent provided excellent microextraction performance for catecholamines, low detection limits (5.6-9.6pM), high run-to-run reproducibility (RSD 0.6-5.1%), high desorption efficiency (95.0-99.5%) and high enrichment factors (∼1480-2650) for dopamine and epinephrine, respectively, extracted from synthetic urine samples. The presented sol-gel sorbents provided effective alternative to conventional extraction media providing unique physicochemical characteristics and excellent extraction capability. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. 2,2',3,3',6,6'-Hexachlorobiphenyl (PCB 136) is Enantioselectively Oxidized to Hydroxylated Metabolites by Rat Liver Microsomes

    PubMed Central

    Wu, Xianai; Pramanik, Ananya; Duffel, Michael W.; Hrycay, Eugene G.; Bandiera, Stelvio M.; Lehmler, Hans-Joachim; Kania-Korwel, Izabela

    2011-01-01

    Developmental exposure to multiple-ortho substituted polychlorinated biphenyls (PCBs) causes adverse neurodevelopmental outcomes in laboratory animals and humans by mechanisms involving the sensitization of Ryanodine receptors (RyRs). In the case of PCB 136, the sensitization of RyR is enantiospecific, with only (-)-PCB 136 being active. However, the role of enantioselective metabolism in the developmental neurotoxicity of PCB 136 is poorly understood. The present study employed hepatic microsomes from phenobarbital (PB-), dexamethasone (DEX-) and corn oil (VEH-)treated male Sprague-Dawley rats to investigate the hypothesis that PCB 136 atropisomers are enantioselectively metabolized by P450 enzymes to potentially neurotoxic, hydroxylated PCB 136 metabolites. The results demonstrated the time- and isoform-dependent formation of three metabolites, with 5-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol) being the major metabolite. The formation of 5-OH-PCB 136 increased with the activity of P450 2B enzymes in the microsomal preparation, which is consistent with PCB 136 metabolism by rat P450 2B1. The minor metabolite 4-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-4-ol) was produced by a currently unidentified P450 enzymes. An enantiomeric enrichment of (-)-PCB 136 was observed in microsomal incubations due to the preferential metabolism of (+)-PCB 136 to the corresponding 5-OH-PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol) atropisomer. 4-OH-PCB 136 displayed an enrichment of the atropisomer formed from (-)-PCB 136; however, the enrichment of this metabolite atropisomer didn't affect the enantiomeric enrichment of the parent PCB because 4-OH-PCB 136 is only a minor metabolite. Although the formation of 5- and 4-OH-PCB 136 atropisomers increased with time, the enantioselective formation of the OH-PCB metabolites resulted in constant enantiomeric enrichment, especially at later incubation times. These observations not only demonstrate that the chiral signatures of

  8. GABAA and GABAB receptors are functionally active in the regulation of catecholamine secretion by bovine chromaffin cells.

    PubMed

    Castro, E; Oset-Gasque, M J; González, M P

    1989-07-01

    GABA stimulates the basal catecholamine release from adrenal bovine chromaffin cells in a calcium-dependent manner. This release represents about 70% of that obtained by similar doses of nicotine under similar experimental conditions. This effect is mediated by GABAA receptor sites present in chromaffin cells, since it was mimicked by muscimol and reversed by bicuculline. In addition, GABA, through its GABAA receptors, increases the catecholamine release evoked by submaximal doses of nicotine, but it has no effect on nicotine-evoked secretion of catecholamines when nicotine was given at maximal doses. These results seem to indicate that both nicotine and GABA release catecholamines from the same intracellular pool. In contrast, baclofen, a GABAB receptor agonist, depressed both basal and nicotine-evoked catecholamine release; this result indicates that in addition to GABAA control of catecholamine secretion by chromaffin cells, there is a GABAB control of this function. These results support the existence of a dual regulation of catecholamine secretion by both the GABAA and GABAB receptors in a similar way as that proposed for muscarinic and nicotinic cholinergic receptors.

  9. Editor's Highlight: Congener-Specific Disposition of Chiral Polychlorinated Biphenyls in Lactating Mice and Their Offspring: Implications for PCB Developmental Neurotoxicity.

    PubMed

    Kania-Korwel, Izabela; Lukasiewicz, Tracy; Barnhart, Christopher D; Stamou, Marianna; Chung, Haeun; Kelly, Kevin M; Bandiera, Stelvio; Lein, Pamela J; Lehmler, Hans-Joachim

    2017-07-01

    Chiral polychlorinated biphenyl (PCB) congeners have been implicated by laboratory and epidemiological studies in PCB developmental neurotoxicity. These congeners are metabolized by cytochrome P450 (P450) enzymes to potentially neurotoxic hydroxylated metabolites (OH-PCBs). The present study explores the enantioselective disposition and toxicity of 2 environmentally relevant, neurotoxic PCB congeners and their OH-PCB metabolites in lactating mice and their offspring following dietary exposure of the dam. Female C57BL/6N mice (8-weeks old) were fed daily, beginning 2 weeks prior to conception and continuing throughout gestation and lactation, with 3.1 µmol/kg bw/d of racemic 2,2',3,5',6-pentachlorobiphenyl (PCB 95) or 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in peanut butter; controls received vehicle (peanut oil) in peanut butter. PCB 95 levels were higher than PCB 136 levels in both dams and pups, consistent with the more rapid metabolism of PCB 136 compared with PCB 95. In pups and dams, both congeners were enriched for the enantiomer eluting second on enantioselective gas chromatography columns. OH-PCB profiles in lactating mice and their offspring were complex and varied according to congener, tissue and age. Developmental exposure to PCB 95 versus PCB 136 differentially affected the expression of P450 enzymes as well as neural plasticity (arc and ppp1r9b) and thyroid hormone-responsive genes (nrgn and mbp). The results suggest that the enantioselective metabolism of PCBs to OH-PCBs may influence neurotoxic outcomes following developmental exposures, a hypothesis that warrants further investigation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. The sigma receptor ligand (+/-)-BMY 14802 prevents methamphetamine-induced dopaminergic neurotoxicity via interactions at dopamine receptors.

    PubMed

    Terleckyj, I; Sonsalla, P K

    1994-04-01

    The possibility that compounds which interact with the putative sigma receptor might influence the dopaminergic neuropathology produced by the administration of methamphetamine (METH) to mice was investigated. (+/-)-BMY 14802 [alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride] attenuated METH-induced dopaminergic neuropathology whereas several other sigma-acting compounds such as R-(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride, 1,3-di-o-tolyl-guanidine, rimcazole, clorgyline or (-)-butaclamol did not alter neurotoxicity produced by this central nervous system stimulant. (-)-BMY 14802, which has a lower affinity for the sigma site than (+)-BMY 14802, was more potent than (+)-BMY 14802 in antagonizing METH-induced neuropathology. In addition, the ketone metabolite (BMY 14786; alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanone hydrochloride), which is a major metabolite formed from (-)-BMY 14802, also attenuated the METH-induced effects. (+/-)-BMY 14802 pretreatment of mice prevented the reduction in D1 and D2 dopamine receptor number produced by the systemic administration of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and demonstrates that (+/-)-BMY 14802 and/or its metabolites interact with the dopamine receptor subtypes. Taken together, these findings suggest that the protective effect of (+/-)-BMY 14802 against METH-induced neuropathology is mediated, at least in part, through dopamine receptor antagonism. Furthermore, the failure of other sigma-acting compounds to alter METH-induced neurotoxicity indicates that the putative sigma receptor is unlikely to be an important mediator in this type of neuropathology.

  11. Is ZMP the toxic metabolite in Lesch-Nyhan disease?

    PubMed

    López, José M

    2008-11-01

    The genetic deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), located on the X chromosome, causes a severe neurological disorder in man, known as Lesch-Nyhan disease (LND). The enzyme HPRT is part of the savage pathway of purine biosynthesis and catalyzes the conversion of hypoxanthine and guanine to their respective nucleotides, IMP and GMP. HPRT deficiency is associated with a relatively selective dysfunction of brain dopamine systems. Several metabolites that accumulate in the patients (phosphoribosylpyrophosphate (PRPP), hypoxanthine, guanine, xanthine, and Z-nucleotides) have been proposed as toxic agents in LND. Some authors have pointed that Z-riboside, derived from the accumulation of ZMP, could be the toxic metabolite in LND. However, the available experimental data support a better hypothesis. I suggest that ZMP (and not Z-riboside) is the key toxic metabolite in LND. ZMP is an inhibitor of the bifunctional enzyme adenylosuccinate lyase, and a deficiency of this enzyme causes psychomotor and mental retardation in humans. Moreover, it has been reported that ZMP inhibits mitochondrial oxidative phosphorylation and induces apoptosis in certain cell types. ZMP is also an activator of the AMP-activated protein kinase (AMPK), a homeostatic regulator of energy levels in the cell. The AMPK has been implicated in the regulation of cell viability, catecholamine biosynthesis and cell structure. I propose that accumulation of ZMP will induce a pleiotropic effect in the brain by (1) a direct inhibition of mitochondrial respiration and the bifunctional enzyme adenylosuccinate lyase, and (2) a sustained activation of the AMPK which in turns would reduce cell viability, decrease dopamine synthesis, and alters cell morphology. In addition, a mechanism to explain the accumulation of ZMP in LND is presented. The knowledge of the toxic metabolite, and the way it acts, would help to design a better therapy.

  12. Metabolite profiling in Arabidopsis.

    PubMed

    Fiehn, Oliver

    2006-01-01

    Metabolite profiling is the multiparallel relative quantification of a mixture of compounds or compound classes using chromatography and universal detection technologies (GC-MS, LC-MS). In this respect it is an extension of classical single-target methods from which it can be distinguished by its broader view on profiling major biochemical events. This broader scope of analysis outweighs the disadvantages by making compromises in method development and the reduced accuracy for specific metabolites. This chapter exemplifies the strategies in metabolite profiling of polar compounds by gas chromatography-mass spectrometry (GC-MS). It gives experimental details on the basic steps: harvest, homogenization, extraction, fractionation, concentration, derivatization, data acquisition, raw data processing and result data tranformation.

  13. Transportable hyperpolarized metabolites

    NASA Astrophysics Data System (ADS)

    Ji, Xiao; Bornet, Aurélien; Vuichoud, Basile; Milani, Jonas; Gajan, David; Rossini, Aaron J.; Emsley, Lyndon; Bodenhausen, Geoffrey; Jannin, Sami

    2017-01-01

    Nuclear spin hyperpolarization of 13C-labelled metabolites by dissolution dynamic nuclear polarization can enhance the NMR signals of metabolites by several orders of magnitude, which has enabled in vivo metabolic imaging by MRI. However, because of the short lifetime of the hyperpolarized magnetization (typically <1 min), the polarization process must be carried out close to the point of use. Here we introduce a concept that markedly extends hyperpolarization lifetimes and enables the transportation of hyperpolarized metabolites. The hyperpolarized sample can thus be removed from the polarizer and stored or transported for use at remote MRI or NMR sites. We show that hyperpolarization in alanine and glycine survives 16 h storage and transport, maintaining overall polarization enhancements of up to three orders of magnitude.

  14. Transportable hyperpolarized metabolites

    PubMed Central

    Ji, Xiao; Bornet, Aurélien; Vuichoud, Basile; Milani, Jonas; Gajan, David; Rossini, Aaron J.; Emsley, Lyndon; Bodenhausen, Geoffrey; Jannin, Sami

    2017-01-01

    Nuclear spin hyperpolarization of 13C-labelled metabolites by dissolution dynamic nuclear polarization can enhance the NMR signals of metabolites by several orders of magnitude, which has enabled in vivo metabolic imaging by MRI. However, because of the short lifetime of the hyperpolarized magnetization (typically <1 min), the polarization process must be carried out close to the point of use. Here we introduce a concept that markedly extends hyperpolarization lifetimes and enables the transportation of hyperpolarized metabolites. The hyperpolarized sample can thus be removed from the polarizer and stored or transported for use at remote MRI or NMR sites. We show that hyperpolarization in alanine and glycine survives 16 h storage and transport, maintaining overall polarization enhancements of up to three orders of magnitude. PMID:28072398

  15. Ethoxyquin provides neuroprotection against cisplatin-induced neurotoxicity

    PubMed Central

    Zhu, Jing; Carozzi, Valentina Alda; Reed, Nicole; Mi, Ruifa; Marmiroli, Paola; Cavaletti, Guido; Hoke, Ahmet

    2016-01-01

    Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin’s ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols. PMID:27350330

  16. Development of in vivo drug-induced neurotoxicity models.

    PubMed

    Sharma, Hari S; Menon, Preeti; Lafuente, José Vicente; Muresanu, Dafin F; Tian, Z Ryan; Patnaik, Ranjana; Sharma, Aruna

    2014-12-01

    Neurotoxicity caused by diverse psychostimulant drugs, for example, methamphetamine, 3,4-methylenedioxy-methamphetamine, cocaine or morphine is a cause of concern to human populations especially the young generation across the world. These recreational drugs affect brain function severely leading to addiction and brain pathology. Use of psychostimulants may induce breakdown of the blood-brain barrier to serum proteins resulting in adverse brain microenvironment, edema cell injury or eventually neuronal death. Thus, there is an urgent need to find out detailed mechanisms of psychostimulants-induced neurotoxicity in vivo models for suitable therapeutic strategies to induce neuroprotection and also to help de-addiction in clinical situations. In this review, psychostimulants drugs-induced neurotoxicity is discussed in view of recent literature and the financial burden it may pose on our society due to rehabilitation and de-addiction. Furthermore, experimental evidences of drug-induced neuroprotection are also discussed. Use of in vivo models of neurotoxicity caused by psychostimulants is discussed based on author's own research and to find suitable drugs that could induce neuroprotection including nanodelivery. Furthermore, novel therapeutic agents for de-addiction and reducing neurotoxicity following psychostimulants administration are presented.

  17. Is Neurotoxicity of Metallic Nanoparticles the Cascades of Oxidative Stress?

    NASA Astrophysics Data System (ADS)

    Song, Bin; Zhang, YanLi; Liu, Jia; Feng, XiaoLi; Zhou, Ting; Shao, LongQuan

    2016-06-01

    With the rapid development of nanotechnology, metallic (metal or metal oxide) nanoparticles (NPs) are widely used in many fields such as cosmetics, the food and building industries, and bio-medical instruments. Widespread applications of metallic NP-based products increase the health risk associated with human exposures. Studies revealed that the brain, a critical organ that consumes substantial amounts of oxygen, is a primary target of metallic NPs once they are absorbed into the body. Oxidative stress (OS), apoptosis, and the inflammatory response are believed to be the main mechanisms underlying the neurotoxicity of metallic NPs. Other studies have disclosed that antioxidant pretreatment or co-treatment can reverse the neurotoxicity of metallic NPs by decreasing the level of reactive oxygen species, up-regulating the activities of antioxidant enzymes, decreasing the proportion of apoptotic cells, and suppressing the inflammatory response. These findings suggest that the neurotoxicity of metallic NPs might involve a cascade of events following NP-induced OS. However, additional research is needed to determine whether NP-induced OS plays a central role in the neurotoxicity of metallic NPs, to develop a comprehensive understanding of the correlations among neurotoxic mechanisms and to improve the bio-safety of metallic NP-based products.

  18. Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine-induced behavioral sensitization.

    PubMed

    Itzhak, Y; Martin, J L; Black, M D; Ali, S F

    1998-06-01

    Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH-induced locomotor sensitization was investigated. The administration of METH (5 mg kg(-1) x 3) or MPTP (20 mg kg(-1) x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg(-1) METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg(-1)) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH

  19. [Catecholamines and their metabolic enzymes in the rat myocardium after a flight on the Kosmos-936 biosatellite].

    PubMed

    Kwetncanski, R; Tigranian, R A; Torda, T

    1982-01-01

    In the myocardium of the weightless and centrifuged rats flown for 18.5 days onboard the biosatellite Cosmos-936 the catecholamine concentration and activity of enzymes involved in their synthesis and degradation--dopamine-beta-hydroxylase, monoamine oxidase and catechol-O-methyl transferase--were measured. The catecholamine concentration in the myocardium of both flight groups significantly increased, and the enzyme activity did not change. These results suggest that an exposure to space flight increases the catecholamine concentration and exerts no effect on their synthesis and degradation in the rat myocardium.

  20. Tianeptine influence on plasmatic catecholamine levels and anxiety index in rats under variable chronic stress after early maternal separation.

    PubMed

    Trujillo, Verónica; Masseroni, María Lujan; Levin, Gloria; Suárez, Marta Magdalena

    2009-01-01

    The aim of this work was to determine the effect of chronic treatment with 5 mg/kg of tianeptine in male adult Wistar rats separated from the mother as neonates and submitted to variable chronic stress, plasma catecholamines, and anxiety. The plus maze test was performed in order to calculate the anxiety index and catecholamine levels were determined by high-pressure liquid chromatography. Both stress and maternal separation elevated catecholamine levels without affecting anxiety. In the maternally separated stress group, tianeptine decreased epinephrine. Anxiety was reduced in the maternally separated unstressed tianeptine group. Also, all groups showed a tendency to lower anxiety index.

  1. Urinary catecholamines in essential hypertension: results of 24-hour urine catecholamine analyses from patients in the Medical Research Council trial for mild hypertension and from matched controls.

    PubMed

    Brown, M J; Causon, R C; Barnes, V F; Brennan, P; Barnes, G; Greenberg, G

    1985-10-01

    Four consecutive 24-h urine samples were collected from 134 male and 134 female placebo-treated patients in the Medical Research Council Trial for Mild Hypertension. Similar samples were collected from age and sex-matched normotensive controls. On the fourth day noradrenaline excretion was 22.05 +/- 1.01 nmol/mmol creatinine in the hypertensives compared with 22.22 +/- 1.16 nmol/mmol creatinine in the controls. Adrenaline excretion on the same day was 6.13 +/- 0.33 nmol/mmol creatinine in the hypertensive subjects compared with 6.32 +/- 0.38 nmol/mmol creatinine in the controls. There was no significant difference for either catecholamine between the two groups. However, in the control group there was a highly significant correlation between excretion of adrenaline and systolic blood pressure (r = 0.218, p = 0.0004) and between noradrenaline excretion and systolic blood pressure (r = 0.200, p = 0.001). Catecholamine excretion and blood pressure were not significantly correlated in the hypertensive patients. There were no significant correlations in either group between catecholamine excretion and heart rate, caffeine intake, nicotine consumption or the Bortner self-assessment score of personality type. This study has found no evidence of elevated sympathoadrenal activity in mild hypertensives. The correlations in the control group may reflect the role of sympathoadrenal activity in acute fluctuations in blood pressure or may suggest that the level of blood pressure within the 'normal' range depends in part on the level of sympathoadrenal activity.

  2. A screening approach using zebrafish for the detection and characterization of developmental neurotoxicity.

    EPA Science Inventory

    Thousands of chemicals have little or no data to support developmental neurotoxicity risk assessments. Current developmental neurotoxicity guideline studies mandating mammalian model systems are expensive and time consuming. Therefore a rapid, cost-effective method to assess de...

  3. Predicting developmental neurotoxicity in rodents from larval zebrafish - - and vice versa

    EPA Science Inventory

    The complexity of standard mammalian developmental neurotoxicity tests limits evaluation of large numbers of chemicals. Less complex, more rapid assays using larval zebrafish are gaining popularity for evaluating the developmental neurotoxicity of chemicals; there remains, howeve...

  4. A screening approach using zebrafish for the detection and characterization of developmental neurotoxicity.

    EPA Science Inventory

    Thousands of chemicals have little or no data to support developmental neurotoxicity risk assessments. Current developmental neurotoxicity guideline studies mandating mammalian model systems are expensive and time consuming. Therefore a rapid, cost-effective method to assess de...

  5. Predicting developmental neurotoxicity in rodents from larval zebrafish - - and vice versa

    EPA Science Inventory

    The complexity of standard mammalian developmental neurotoxicity tests limits evaluation of large numbers of chemicals. Less complex, more rapid assays using larval zebrafish are gaining popularity for evaluating the developmental neurotoxicity of chemicals; there remains, howeve...

  6. Non-fibrillar amyloid-{beta} peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

    SciTech Connect

    Niidome, Tetsuhiro; Goto, Yasuaki; Kato, Masaru; Wang, Pi-Lin; Goh, Saori; Tanaka, Naoki; Akaike, Akinori; Kihara, Takeshi; Sugimoto, Hachiro

    2009-09-04

    Amyloid-{beta} peptide (A{beta}) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A{beta} has important physiological roles in addition to its pathological roles. We recently demonstrated that A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A{beta}42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A{beta}42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A{beta}42 on glutamate-induced neurotoxicity. Non-fibrillar A{beta}42, but not fibrillar A{beta}42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar A{beta}42 decreased both neurotoxicity and increases in the intracellular Ca{sup 2+} concentration induced by N-methyl-D-aspartate (NMDA), but not by {alpha}-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

  7. Attenuation of Oxidative Damage by Boerhaavia diffusa L. Against Different Neurotoxic Agents in Rat Brain Homogenate.

    PubMed

    Ayyappan, Prathapan; Palayyan, Salin Raj; Kozhiparambil Gopalan, Raghu

    2016-01-01

    Due to a high rate of oxidative metabolic activity in the brain, intense production of reactive oxygen metabolite occurs, and the subsequent generation of free radicals is implicated in the pathogenesis of traumatic brain injury, epilepsy, and ischemia as well as chronic neurodegenerative diseases. In the present study, protective effects of polyphenol rich ethanolic extract of Boerhaavia diffusa (BDE), a neuroprotective edible medicinal plant against oxidative stress induced by different neurotoxic agents, were evaluated. BDE was tested against quinolinic acid (QA), 3-nitropropionic acid (NPA), sodium nitroprusside (SNP), and Fe (II)/EDTA complex induced oxidative stress in rat brain homogenates. QA, NPA, SNP, and Fe (II)/EDTA treatment caused an increased level of thiobarbituric acid reactive substances (TBARS) in brain homogenates along with a decline in the activities of antioxidant enzymes. BDE treatment significantly decreased the production of TBARS (p < .05) and increased the activities of antioxidant enzymes like catalase and superoxide dismutase along with increased concentration of non-enzymatic antioxidant, reduced glutathione (GSH). Similarly, BDE caused a significant decrease in the lipid peroxidation (LPO) in the cerebral cortex. Inhibitory potential of BDE against deoxyribose degradation (IC50 value 38.91 ± 0.12 μg/ml) shows that BDE can protect hydroxyl radical induced DNA damage in the tissues. Therefore, B. diffusa had high antioxidant potential that could inhibit the oxidative stress induced by different neurotoxic agents in brain. Since many of the neurological disorders are associated with free radical injury, these data may imply that B. diffusa, functioning as an antioxidant agent, may be beneficial for reducing various neurodegenerative complications.

  8. Vanadium Exposure Induces Olfactory Dysfunction in an Animal Model of Metal Neurotoxicity

    PubMed Central

    Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

    2014-01-01

    Epidemiological evidence indicates chronic environmental exposure to transition metals may play a role in chronic neurodegenerative conditions such as Parkinson’s disease (PD). Chronic inhalation exposure to welding fumes containing metal mixtures may be associated with development of PD. A significant amount of vanadium is present in welding fumes, as vanadium pentoxide (V2O5), and incorporation of vanadium in the production of high strength steel has become more common. Despite the increased vanadium use in recent years, the neurotoxicological effects of this metal are not well characterized. Recently, we demonstrated that V2O5 induces dopaminergic neurotoxicity via protein kinase C delta (PKCδ)-dependent oxidative signaling mechanisms in dopaminergic neuronal cells. Since anosmia (inability to perceive odors) and non-motor deficits are considered to be early symptoms of neurological diseases, in the present study, we examined the effect of V2O5 on the olfactory bulb in animal models. To mimic the inhalation exposure, we intranasally administered C57 black mice a low-dose of 182 µg of V2O5 three times a week for one month, and behavioral, neurochemical and biochemical studies were performed. Our results revealed a significant decrease in olfactory bulb weights, tyrosine hydroxylase (TH) levels, levels of dopamine (DA) and its metabolite, 3, 4-dihydroxyphenylacetic acid (DOPAC) and increases in astroglia of the glomerular layer of the olfactory bulb in the treatment groups relative to vehicle controls. Neurochemical changes were accompanied by impaired olfaction and locomotion. These findings suggest that nasal exposure to V2O5 adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments. These results expand our understanding of vanadium neurotoxicity in environmentally-linked neurological conditions. PMID:24362016

  9. Acute neurotoxic effects of mancozeb and maneb in mesencephalic neuronal cultures are associated with mitochondrial dysfunction.

    PubMed

    Domico, Lisa M; Zeevalk, Gail D; Bernard, Laura P; Cooper, Keith R

    2006-09-01

    Recent studies suggest that exposure to agrochemicals may contribute to the development of idiopathic Parkinson's disease. Maneb (MB), a widely used Mn-containing ethylene-bis-dithiocarbamate (EBDC) fungicide, has been implicated in selective dopaminergic neurotoxicity. In this study, we examine the potential neurotoxicity of mancozeb (MZ), a widely used EBDC fungicide that is structurally similar to MB, but contains both Zn and Mn. Primary mesencephalic cells isolated from Sprague-Dawley embryonic day 15 rat embryos were exposed in vitro to either MZ or MB to compare their cytotoxic potential. Exposure to 10-120 microM MZ or MB for 24h resulted in a dose-dependent toxicity in both the dopamine (DA) and GABA mesencephalic populations as assessed by a functional assay for high affinity transporter activity. Consistent with this, cell viability as well as tyrosine hydroxylase-positive neurons decreased with increasing doses of MZ or MB. Toxic potencies for MZ and MB were similar and no difference in sensitivity between the DA and GABA populations was observed with the fungicides. Exposure to ethylene thiourea, the major metabolite of either MZ or MB, was not toxic, implicating the parent compound in toxicity. Both the organic and Mn metal components of the fungicides were found to contribute to toxicity. Non-toxic exposures to the fungicides decreased ATP levels in a dose-dependent manner suggesting impairment of energy metabolism. In whole mitochondrial preparations isolated from adult rat brains, MZ and MB inhibited NADH-linked state 3 respiration. Mild to moderate mitochondrial uncoupling was also observed in response to the fungicides. In conclusion, our findings indicate that acute exposure to high doses of MZ and MB produce equipotent toxic effects in both DA and GABA neurons that may be associated with perturbations in mitochondrial respiration.

  10. Vanadium exposure induces olfactory dysfunction in an animal model of metal neurotoxicity.

    PubMed

    Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G

    2014-07-01

    Epidemiological evidence indicates chronic environmental exposure to transition metals may play a role in chronic neurodegenerative conditions such as Parkinson's disease (PD). Chronic inhalation exposure to welding fumes containing metal mixtures may be associated with development of PD. A significant amount of vanadium is present in welding fumes, as vanadium pentoxide (V2O5), and incorporation of vanadium in the production of high strength steel has become more common. Despite the increased vanadium use in recent years, the neurotoxicological effects of this metal are not well characterized. Recently, we demonstrated that V2O5 induces dopaminergic neurotoxicity via protein kinase C delta (PKCδ)-dependent oxidative signaling mechanisms in dopaminergic neuronal cells. Since anosmia (inability to perceive odors) and non-motor deficits are considered to be early symptoms of neurological diseases, in the present study, we examined the effect of V2O5 on the olfactory bulb in animal models. To mimic the inhalation exposure, we intranasally administered C57 black mice a low-dose of 182μg of V2O5 three times a week for one month, and behavioral, neurochemical and biochemical studies were performed. Our results revealed a significant decrease in olfactory bulb weights, tyrosine hydroxylase (TH) levels, levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and increases in astroglia of the glomerular layer of the olfactory bulb in the treatment groups relative to vehicle controls. Neurochemical changes were accompanied by impaired olfaction and locomotion. These findings suggest that nasal exposure to V2O5 adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments. These results expand our understanding of vanadium neurotoxicity in environmentally-linked neurological conditions.

  11. The protective effect of Physalis peruviana L. against cadmium-induced neurotoxicity in rats.

    PubMed

    Abdel Moneim, Ahmed E; Bauomy, Amira A; Diab, Marwa M S; Shata, Mohamed Tarek M; Al-Olayan, Ebtesam M; El-Khadragy, Manal F

    2014-09-01

    The present study was carried out to investigate the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced neurotoxicity in rats. Adult male Wistar rats were randomly divided into four groups. Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg bwt of cadmium chloride for 5 days. Group 3 was treated with 200 mg/kg bwt of methanolic extract of Physalis (MEPh). Group 4 was pretreated with MEPh 1 h before cadmium for 5 days. Cadmium treatment induced marked disturbances in neurochemical parameters as indicating by significant (p < 0.05) reduction in dopamine (DA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in cerebellum, hippocampus, and cerebral cortex and enhanced significantly (p < 0.05) the levels of lipid peroxidation and nitric oxide in the brain. Cadmium treatment also decreased the amount of nonenzymatic and enzymatic antioxidants significantly (p < 0.05). Pretreatment with MEPh resulted in significant (p < 0.05) decreases in lipid peroxidation and nitric oxide levels and restored the amount of glutathione successfully. Although, preadministration of MEPh also brought the activities of cellular antioxidant enzymes, namely superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase significantly (p < 0.05) to the control levels, as well as the levels of Ca(2+), Cl(-), DA, 5-HT, and serotonin metabolite, 5-HIAA. These data indicated that Physalis has a beneficial effect in ameliorating the cadmium-induced oxidative neurotoxicity in the brain of rats.

  12. Manganese-induced Neurotoxicity: From C. elegans to Humans

    PubMed Central

    Chen, Pan; Chakraborty, Sudipta; Peres, Tanara V.; Bowman, Aaron B.; Aschner, Michael

    2014-01-01

    Manganese (Mn) is one of the most abundant metals on the earth. It is required for normal cellular activities, but overexposure leads to toxicity. Neurons are more susceptible to Mn-induced toxicity than other cells, and accumulation of Mn in the brain results in Manganism that presents with Parkinson's disease (PD)-like symptoms. In the last decade, a number of Mn transporters have been identified, which improves our understanding of Mn transport in and out of cells. However, the mechanism of Mn-induced neurotoxicity is only partially uncovered, with further research needed to explore the whole picture of Mn-induced toxicity. In this review, we will address recent progress in Mn-induced neurotoxicity from C. elegans to humans, and explore future directions that will help understand the mechanisms of its neurotoxicity. PMID:25893090

  13. Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity.

    PubMed

    Manucha, Walter

    Multiple mechanisms underlying glutamate-induced neurotoxicity have recently been discussed. Likewise, a clear deregulation of the mitochondrial respiratory mechanism has been described in patients with neurodegeneration, oxidative stress, and inflammation. This article highlights nitric oxide, an atypical neurotransmitter synthesized and released on demand by the post-synaptic neurons, and has many important implications for nerve cell survival and differentiation. Consequently, synaptogenesis, synapse elimination, and neurotransmitter release, are nitric oxide-modulated. Interesting, an emergent role of nitric oxide pathways has been discussed as regards neurotoxicity from glutamate-induced apoptosis. These findings suggest that nitric oxide pathways modulation could prevent oxidative damage to neurons through apoptosis inhibition. This review aims to highlight the emergent aspects of nitric oxide-mediated signaling in the brain, and how they can be related to neurotoxicity, as well as the development of neurodegenerative diseases development.

  14. Secondary metabolites from Ganoderma.

    PubMed

    Baby, Sabulal; Johnson, Anil John; Govindan, Balaji

    2015-06-01

    Ganoderma is a genus of medicinal mushrooms. This review deals with secondary metabolites isolated from Ganoderma and their biological significance. Phytochemical studies over the last 40years led to th