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1.
Sci Rep ; 11(1): 16276, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381165

RESUMO

Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. Traumatic stress during adolescence increases the risk of IBS in adults. The aim of this study was to characterize the juvenile social defeat stress (SDS)-associated IBS model in mice. Juvenile mice were exposed to an aggressor mouse for 10 min once daily for 10 consecutive days. Behavioral tests, visceral sensitivity, immune responses, and fecal bacteria in the colon were evaluated in 5 weeks after SDS exposure. Social avoidance, anxiety- and depression-like behavior, and visceral hypersensitivity were observed. Juvenile SDS exposure significantly increased the number of 5-HT-containing cells and calcitonin gene-related peptide-positive neurons in the colon. The gut microbiota was largely similar between the control and juvenile SDS groups. The alterations in fecal pellet output, bead expulsion time, plasma corticosterone concentration, and colonic 5-HT content in response to restraint stress were exacerbated in the juvenile SDS group compared with the control group. The combination of juvenile SDS and restraint stress increased the noradrenaline metabolite 3-Methoxy-4-hydroxyphenylglycol (MHPG) content and MHPG/noradrenaline ratio in the amygdala when compared with restraint stress in control mice. These results suggest that juvenile SDS exposure results in later onset of IBS-like symptoms.


Assuntos
Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/psicologia , Derrota Social , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Dor Abdominal , Fatores Etários , Animais , Ansiedade , Aprendizagem da Esquiva , Comportamento Animal , Colo/metabolismo , Modelos Animais de Doenças , Síndrome do Intestino Irritável/metabolismo , Masculino , Metoxi-Hidroxifenilglicol/metabolismo , Camundongos , Norepinefrina/metabolismo , Serotonina/metabolismo , Comportamento Social , Estresse Psicológico/etiologia , Estresse Psicológico/metabolismo
2.
J Alzheimers Dis ; 80(2): 521-526, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33554915

RESUMO

The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-ß is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer's disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer's disease-related processes.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Transtornos da Memória/psicologia , Norepinefrina/metabolismo , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Aprendizagem , Locus Cerúleo/metabolismo , Masculino , Transtornos da Memória/patologia , Metoxi-Hidroxifenilglicol/metabolismo , Pessoa de Meia-Idade , Testes Neuropsicológicos , Norepinefrina/líquido cefalorraquidiano , Valor Preditivo dos Testes , Proteínas tau/genética , Proteínas tau/metabolismo
3.
Bioanalysis ; 11(10): 971-986, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31218903

RESUMO

Aim: To evaluate suitability of the LC-MS/MS method to quantify 3,4-dihydroxyphenylglycol (DHPG) that is used as a biomarker for monoamine oxidase (MAO) inhibition. Methods: DHPG was extracted using alumina basic cartridges and quantified on a triple quadrupole mass spectrometer using negative electrospray ionization, without the use of derivatization reagents. Results: Modulation of DHPG levels was observed following administration of selective and nonselective MAO inhibitors and results were in correlation with historical MAO inhibition potential of compounds. Conclusion: The proposed method is sensitive enough to measure plasma DHPG levels and DHPG can be used as a biomarker to assess MAO inhibition potential of new therapeutic agents.


Assuntos
Análise Química do Sangue/métodos , Encéfalo/metabolismo , Cromatografia Líquida/métodos , Metoxi-Hidroxifenilglicol/análogos & derivados , Norepinefrina/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Encéfalo/efeitos dos fármacos , Humanos , Masculino , Metoxi-Hidroxifenilglicol/sangue , Metoxi-Hidroxifenilglicol/metabolismo , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Ratos , Ratos Sprague-Dawley
4.
Int J Dev Neurosci ; 76: 1-5, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31125683

RESUMO

One of the reasons for using paracetamol during pregnancy is fever. The brain structure responsible for maintaining proper body temperature, but also for controlling some endocrine aspects is hypothalamus. In this study we examined the effect of early pretreatment of paracetamol on hypothalamic neurotransmission in rats' offspring. We used two-month old rats previously exposed to paracetamol at doses of 5 (P5) and 15 mg/kg (P15) during gestational development and next postnatally. The concentration of monoamines, their metabolites and amino acids in hypothalamus was chromatographically determined. The results of biochemical analysis were compared with the Control animals (Con). We found differences between groups in the concentration of main noradrenaline metabolite in hypothalamus. The control group had significantly higher level of 3-methoxy-4-hydroxyphenylglycol (MHPG) compared with rats exposed to paracetamol (F(2,27) = 7.96, p < 0.005). Simultaneously the level of dopamine (DA) (F(2,27) = 4.33, p < 0.05) and its metabolite - homovanillic acid (HVA) (F(2,27) = 17.03, p < 0.005) was increased in the hypothalamus of animals treated with lower dose of the drug. Biochemical analyses show an increase in 3,4-dihydroxyphenyl acetic acid (DOPAC) concentration in P5 group compared to the control rats and group treated with higher dose of paracetamol (F(2,27) = 7.37, p < 0.005). In the hypothalamus significant decrease of glutamic acid concentration was also observed in the group treated with paracetamol at dose of 5 mg. These results demonstrated that paracetamol had a significant effect on dopaminergic and noradrenergic neurotransmission and changed the concentration of glutamic acid in hypothalamus - heat-regulating center and important element of hypothalamic-pituitary- gonadal axis.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Narcóticos/toxicidade , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Aminoácidos/metabolismo , Animais , Animais Recém-Nascidos , Química Encefálica/efeitos dos fármacos , Dopamina/metabolismo , Feminino , Glutamatos/metabolismo , Ácido Homovanílico/metabolismo , Hipotálamo/metabolismo , Masculino , Metoxi-Hidroxifenilglicol/metabolismo , Norepinefrina/metabolismo , Gravidez , Ratos , Ratos Wistar , Transmissão Sináptica/efeitos dos fármacos
5.
Nutrients ; 11(1)2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30577513

RESUMO

Hops, the immature inflorescences of the female hop plant (Humulus lupulus L.) are one of the main components of beer and provides flavor and bitterness. ß-Eudesmol, an oxygenated sesquiterpene, is reported to accumulate in a particular hop cultivar. Recently, we revealed that ß-Eudesmol ingestion affected autonomic nerve activity in an animal model. The effect on humans has not been elucidated, therefore, we investigated the effects of ß-Eudesmol on reducing objective and subjective markers related to sympathetic nerve activity after the application of mental stress in healthy participants. Fifty participants (male and female aged 20 to 50 years) were randomly assigned to two groups. Five minutes before taking the Trier Social Stress Test (TSST) as a mental stressor, participants in each group ingested a beverage containing ß-Eudesmol, the active beverage, or a placebo beverage that did not contain ß-Eudesmol. Saliva 3-methoxy-4-hydroxyphenylglycol (MHPG), a major product of noradrenaline breakdown and a representative marker of sympathetic nerve activity, was significantly lower just after the TSST in the active group compared with the placebo group. Saliva cortisol, a marker of the endocrine stress response system, was not significantly different between the two groups. No adverse events related to test beverage ingestion were observed. This is the first experimental evidence of ß-Eudesmol effect for mental stress in human.


Assuntos
Humulus , Metoxi-Hidroxifenilglicol/metabolismo , Saliva/efeitos dos fármacos , Sesquiterpenos de Eudesmano/farmacologia , Estresse Psicológico/metabolismo , Adulto , Bebidas/análise , Estudos Cross-Over , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
J Nutr Sci Vitaminol (Tokyo) ; 64(5): 329-334, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381622

RESUMO

The effect of soy and casein peptide intake on the metabolism of amino acids and monoamine neurotransmitters in the serum and brain were examined in C57BL/6 mice. Acute oral administration of soy peptide (0.026 g/30 g body weight) caused a notable increase in tyrosine, a catecholamine precursor, in the serum and cerebral cortex, whereas casein peptide administration at the same dose led to an increase in tyrosine in the serum, but not in the cerebral cortex. In addition to tyrosine, soy peptide administration also led to an effective augmentation of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), a principal metabolite of noradrenaline, and significant facilitation of noradrenergic turnover in the cerebral cortex, brainstem, and hippocampus compared to the vehicle control. Casein peptide administration also led to an increase in MHPG only in the cerebral cortex, and caused facilitation of noradrenergic turnover in the cerebral cortex and brainstem. These in vivo observations suggest that both soy and casein peptide intake at this concentration can lead to an increased availability of tyrosine and stimulation of noradrenergic turnover in the brain.


Assuntos
Encéfalo/metabolismo , Caseínas/farmacologia , Metoxi-Hidroxifenilglicol/metabolismo , Norepinefrina/metabolismo , Peptídeos/farmacologia , Proteínas de Soja/farmacologia , Tirosina/metabolismo , Animais , Tronco Encefálico/metabolismo , Catecolaminas/metabolismo , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurotransmissores/farmacologia
8.
Auton Neurosci ; 208: 165-169, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29029974

RESUMO

Baseline sympathetic activity was found to be elevated in rheumatoid arthritis (RA) patients and it is related to increased cardiovascular risk in these patients. Although many studies have highlighted the association between RA and increased cardiac sympathetic activity, the underlying mechanistic links remain unclear. The aim of the present study was to understand how diseases-triggered changes in gene expression may result in maladaptive physiological changes. Our results suggest that the equilibrium between noradrenaline synthesis, release and reuptake was disrupted in the ventricles of arthritic rats. In the acute phase of the arthritic process, decreased gene expression of MAO-A might lead to accumulation of noradrenaline in myocardial interstitial space, whereas increased gene expression of NET protected cardiomyocytes from the deleterious effects of enhanced noradrenaline. During the chronic phase, reduced expression of ß1-adrenoceptor and decreased efficiency of noradrenaline reuptake contribute to progressive damage of the myocardium and limits heart efficiency.


Assuntos
Artrite Reumatoide/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , Miocárdio/metabolismo , Norepinefrina/metabolismo , Receptores Adrenérgicos beta/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Expressão Gênica , Masculino , Metoxi-Hidroxifenilglicol/metabolismo , Monoaminoxidase/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Terpenos , Tirosina 3-Mono-Oxigenase/metabolismo
9.
Andrologia ; 49(2)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27167778

RESUMO

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.


Assuntos
Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Metanfetamina/efeitos adversos , Metoxi-Hidroxifenilglicol/análogos & derivados , Norepinefrina/metabolismo , Testículo/efeitos dos fármacos , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Drogas Ilícitas/efeitos adversos , Masculino , Metanfetamina/administração & dosagem , Metoxi-Hidroxifenilglicol/metabolismo , Ratos , Reprodução/efeitos dos fármacos , Testículo/metabolismo
10.
Physiol Behav ; 169: 82-89, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27884589

RESUMO

Cohabitation with Ehrlich ascitic tumor-injected conspecifics induces behavioral, neurochemical, endocrine and immune changes indicative of stress and immune impairment in female mice. The present work analyzed the effects of similar cohabitation in Swiss and Balb/C male mice. At least 12 pairs of male mice were divided into a control group and an experimental group. On experimental day 1 (ED1), one animal within each experimental pair was inoculated with 5×106 Ehrlich tumor cells intraperitoneally (i.p.); the other animal was kept undisturbed and was referred to as the CSP (companion of a sick partner). One male mouse of each control pair was treated i.p. with 0.9% NaCl (1mL/kg); the other animal (the CHP, companion of a healthy partner) was kept undisturbed. Cohabitation with a sick partner for 11days did not induce any behavioral, hypothalamic noradrenergic, corticosterone or adrenal weight changes in the Swiss CSP male mice compared to those of the Swiss CHP group. However, impairments in neutrophil phagocytosis and oxidative burst as well as increased levels of catecholamines were observed in Swiss and Balb/C CSP mice relative to CHP male animals of the same strains on ED11 and ED14, respectively. Moreover, after a challenge with 5×106 Ehrlich tumor cells on ED11 of cohabitation, the number and concentration of tumor cells found in the ascitic fluid were higher in the Swiss CSP male mice than in the CHP mice. These data suggest that the immune changes observed in Swiss and Balb/C male CSP mice after cohabitation with a sick cagemate might, ultimately, depend on the changes induced by catecholamines, as previously reported for CSP female mice. However, contrary to that reported in Swiss CSP female mice, changes in behavioral and hypothalamic noradrenaline activity were not found in the Swiss CSP male mice analyzed in this work. This fact suggests that male and female CSP mice might use similar immune but different CNS strategies against the threats posed by the tumor-bearing animals.


Assuntos
Carcinoma de Ehrlich/imunologia , Carcinoma de Ehrlich/psicologia , Comportamento Social , Glândulas Suprarrenais/patologia , Animais , Catecolaminas/sangue , Corticosterona/sangue , Comportamento Exploratório/fisiologia , Citometria de Fluxo , Abrigo para Animais , Hipotálamo/metabolismo , Masculino , Metoxi-Hidroxifenilglicol/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Neutrófilos/patologia , Norepinefrina/metabolismo , Fatores de Tempo
11.
PLoS One ; 11(11): e0166561, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27855214

RESUMO

The chemical synthesis of new lipophilic polyphenols with improved properties presents technical difficulties. Here we describe the selection, isolation and identification of lipolytic bacteria from food-processing industrial wastes, and their use for tailoring a new set of compounds with great interest in the food industry. These bacteria were employed to produce lipolytic supernatants, which were applied without further purification as biocatalysts in the chemoselective and regioselective synthesis of lipophilic partially acetylated phenolic compounds derived from olive polyphenols. The chemoselectivity of polyphenols acylation/deacylation was analyzed, revealing the preference of the lipases for phenolic hydroxyl groups and phenolic esters. In addition, the alcoholysis of peracetylated 3,4-dihydroxyphenylglycol resulted in a series of lipophilic 2-alkoxy-2-(3,4-dihydroxyphenyl)ethyl acetate through an unexpected lipase-mediated etherification at the benzylic position. These new compounds are more lipophilic and retained their antioxidant properties. This approach can provide access to unprecedented derivatives of 3,4-dihydroxyphenylglycol with improved properties.


Assuntos
Bactérias/metabolismo , Lipólise , Polifenóis/metabolismo , Acilação , Biocatálise , Compostos de Bifenilo/metabolismo , Candida/enzimologia , Esterificação , Sequestradores de Radicais Livres/metabolismo , Hidroxibenzoatos/metabolismo , Lipase/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/química , Metoxi-Hidroxifenilglicol/metabolismo , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/química , Álcool Feniletílico/metabolismo , Filogenia , Picratos/metabolismo , Estereoisomerismo
12.
Neuropharmacology ; 108: 161-71, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27091486

RESUMO

Sleep disturbances are among the most disabling non-motor symptoms in Parkinson's disease. The pedunculopontine tegmental nucleus and basal ganglia are likely involved in these dysfunctions, as they are affected by neurodegeneration in Parkinson's disease and have a role in sleep regulation. To investigate this, we promoted a lesion in the pedunculopontine tegmental nucleus or substantia nigra pars compacta of male rats, followed by 24 h of REM sleep deprivation. Then, we administrated a dopaminergic D2 receptor agonist, antagonist or vehicle directly in the striatum. After a period of 24 h of sleep-wake recording, we observed that the ibotenic acid infusion in the pedunculopontine tegmental nucleus blocked the so-called sleep rebound effect mediated by REM sleep deprivation, which was reversed by striatal D2 receptors activation. Rotenone infusion in the substantia nigra pars compacta also blocked the sleep rebound, however, striatal D2 receptors activation did not reverse it. In addition, rotenone administration decreased the time spent in NREM sleep, which was corroborated by positive correlations between dopamine levels in both substantia nigra pars compacta and striatum and the time spent in NREM sleep. These findings suggest a new circuitry for sleep regulation in Parkinson's disease, involving the triad composed by pedunculopontine nucleus, substantia nigra pars compacta and striatum, evidencing a potential therapeutic target for the sleep disturbances associated to this pathology.


Assuntos
Corpo Estriado/metabolismo , Rede Nervosa/metabolismo , Doença de Parkinson/metabolismo , Parte Compacta da Substância Negra/metabolismo , Fases do Sono/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Rede Nervosa/efeitos dos fármacos , Parte Compacta da Substância Negra/efeitos dos fármacos , Ratos , Ratos Wistar , Fases do Sono/efeitos dos fármacos
13.
Int J Mol Sci ; 17(2)2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26828480

RESUMO

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 methides afford stable alcoholic or carbonyl products.


Assuntos
Catecolaminas/metabolismo , Quinonas/metabolismo , Proteínas Fúngicas/metabolismo , Isomerismo , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/metabolismo
14.
CNS Neurosci Ther ; 22(5): 404-12, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26849844

RESUMO

INTRODUCTION: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT. METHODS: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings. CONCLUSION: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.


Assuntos
Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/líquido cefalorraquidiano , Cloridrato de Duloxetina/farmacologia , Neurotransmissores/sangue , Neurotransmissores/líquido cefalorraquidiano , Inibidores da Captação de Neurotransmissores/farmacologia , Adulto , Monoaminas Biogênicas/sangue , Monoaminas Biogênicas/líquido cefalorraquidiano , Cromatografia Líquida de Alta Pressão , Cicloexanóis/farmacologia , Dimetilaminas/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Fatores de Tempo , Adulto Jovem
15.
Clin Drug Investig ; 36(2): 137-46, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26597180

RESUMO

BACKGROUND AND OBJECTIVES: Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of attention-deficit/hyperactivity disorder (ADHD). Uniquely, relative to current ADHD medications, dasotraline has a slow absorption and long elimination half-life. Here we relate the pharmacokinetics and pharmacodynamics of dasotraline to reduction in ADHD symptoms based on simulated clinical trial outcomes. METHODS: Dasotraline pharmacokinetics were analyzed by population pharmacokinetic methodologies using data collected from 395 subjects after single or multiple oral dose administrations ranging from 0.2 to 36 mg (three phase I studies and one phase II ADHD study). Population pharmacokinetic and pharmacodynamic models related individual dasotraline exposures to norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations, ADHD symptoms, and study discontinuation (probability of dropout). RESULTS: Dasotraline pharmacokinetics were described by a one-compartment model with dual (linear plus nonlinear) elimination. In an ADHD population treated with dasotraline 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 h and plasma concentrations reached steady-state by 10 days of dosing. A population pharmacokinetic and pharmacodynamic model of DHPG indicated clinically significant norepinephrine transporter inhibition was achieved as a function of time-matched dasotraline concentrations. Dasotraline exposure reduced ADHD symptoms in a sigmoid E max time-course model. Clinical trial simulations described the effects of dose, duration, and sample size on clinical outcomes. CONCLUSION: These results related dasotraline pharmacokinetics to pharmacological activity in ADHD, and support the novel concept that maintaining constant, steady-state dopamine and norepinephrine reuptake inhibition throughout a 24-h dosing interval is a novel pharmacological approach to the management of ADHD symptoms. Clinicaltrials.gov identifier: NCT01692782.


Assuntos
1-Naftilamina/análogos & derivados , Inibidores da Captação Adrenérgica/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Inibidores da Captação de Dopamina/farmacologia , 1-Naftilamina/farmacocinética , 1-Naftilamina/farmacologia , Administração Oral , Inibidores da Captação Adrenérgica/farmacocinética , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Inibidores da Captação de Dopamina/farmacocinética , Feminino , Meia-Vida , Humanos , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Modelos Biológicos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
J Neurochem ; 135(4): 768-76, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26156066

RESUMO

In order to elucidate the chemical structure of black to brown pigments, neuromelanins (NMs), in the substantia nigra (SN) and the locus coeruleus (LC) in the central nervous system of humans and other mammalian species during aging, chemical degradative methods are powerful tools. HPLC analysis after hydroiodic acid hydrolysis detected aminohydroxyphenylethylamines, aminohydroxyphenylacetic acids, and aminohydroxyethylbenzenes, which confirmed that SN-NM and LC-NM contain melanin derived not only from dopamine and norepinephrine (NE) but also from several other catecholic metabolites, such as 3,4-dihydroxyphenylalanine, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxymandelic acid, 3,4-dihydroxyphenylethanol, and 3,4-dihydroxyphenylethylene glycol, in addition to the corresponding Cys-derivatives in varying degrees. However, hydroiodic acid hydrolysis showed that LC-NM produced the same degradation products as were detected in SN-NM. Thus, we needed to develop a new chemical detection method to validate the existence of NE in LC-NM. In the present study, we report that HCl hydrolysis of LC-NM in the presence of thioglycolic acid yields new products arising from substitution of the hydroxyl group by thioglycolic acid at the benzyl position of NE and cysteinyl-NE. This is the first chemical evidence showing that NE and cysteinyl-NE are incorporated into LC-NM. Using the chemical degradation methods for the determination of catechols in neuromelanin (NM), we have shown that dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), 3,4-dihydroxyphenylethanol (DOPE), and 3,4-dihydroxyphenylalanine (DOPA) are mainly responsible for the structure of NM from substantia nigra (SN), while norepinephrine (NE), 3,4-dihydroxymandelic acid (DOMA), and 3,4-dihydroxyphenylethylene glycol (DOPEG) are additionally responsible for the structure of NM from locus coeruleus (LC).


Assuntos
Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Locus Cerúleo/metabolismo , Melaninas/metabolismo , Norepinefrina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Feminino , Humanos , Masculino , Ácidos Mandélicos/metabolismo , Espectrometria de Massas , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Substância Negra/metabolismo
17.
J Clin Pharmacol ; 55(12): 1422-31, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26011686

RESUMO

Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker.


Assuntos
Cloridrato de Atomoxetina/farmacologia , Cloridrato de Duloxetina/farmacologia , Metoxi-Hidroxifenilglicol/análogos & derivados , Morfolinas/farmacologia , Norepinefrina/metabolismo , Álcool Feniletílico/análogos & derivados , Adolescente , Inibidores da Captação Adrenérgica/sangue , Inibidores da Captação Adrenérgica/farmacologia , Adulto , Idoso , Cloridrato de Atomoxetina/sangue , Cloridrato de Atomoxetina/farmacocinética , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Cloridrato de Duloxetina/sangue , Feminino , Humanos , Masculino , Metoxi-Hidroxifenilglicol/sangue , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Morfolinas/sangue , Morfolinas/farmacocinética , Álcool Feniletílico/sangue , Álcool Feniletílico/farmacocinética , Álcool Feniletílico/farmacologia , Adulto Jovem
18.
Biosci Biotechnol Biochem ; 79(9): 1542-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25996770

RESUMO

In this study, we examined the effect of orally administrated dipeptides containing Tyr (Y) on the metabolism of catecholamines in mouse brains. We found that among eight synthetic dipeptides whose sequences are present frequently in soy proteins, Ser-Tyr (SY), Ile-Tyr, and Tyr-Pro had the highest apparent permeability coefficients in monolayers of human intestinal epithelial Caco-2 cells. When administrated orally, SY markedly increased tyrosine content in the cerebral cortex compared to the vehicle control, Ile-Tyr, Tyr-Pro, and Y alone. The oral administration of SY more effectively increased 3-methoxy-4-hydroxyphenylethyleneglycol, the principal metabolite of noradrenaline, in the cerebral cortex and hippocampus than did Ile-Tyr, Tyr-Pro, or Y alone. Central noradrenergic turnover was also markedly stimulated by SY administration. These in vivo observations strongly suggest that SY is more potent in boosting central catecholamine transmission, particularly the noradrenergic system, than Y alone or other dipeptides that include Y.


Assuntos
Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Tirosina/administração & dosagem , Administração Oral , Animais , Células CACO-2 , Catecolaminas/metabolismo , Córtex Cerebral/efeitos dos fármacos , Dipeptídeos/administração & dosagem , Hipocampo/efeitos dos fármacos , Humanos , Metoxi-Hidroxifenilglicol/metabolismo , Camundongos , Norepinefrina/metabolismo , Tirosina/metabolismo
19.
Parkinsonism Relat Disord ; 21(6): 567-72, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25829070

RESUMO

BACKGROUND: Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic features (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not others (Lewy bodies in PD, glial cytoplasmic inclusions in MSA). In PD evidence has accrued for a vesicular storage defect and decreased aldehyde dehydrogenase (ALDH) activity in residual dopaminergic terminals, resulting in accumulation of the toxic dopamine (DA) metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). In this study we asked whether MSA entails a similar abnormal neurochemical pattern. METHODS: DA and its main neuronal metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its main neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG), the catecholamine precursor DOPA, and DOPAL were measured in striatal and frontal cortical tissue from patients with pathologically proven end-stage MSA (N = 15), sporadic PD (N = 17), and control subjects (N = 18). RESULTS: Compared to the control group, the MSA and PD groups had similarly decreased putamen DA (by 96% and 93%, p < 0.0001), DOPAC (97% and 95%, p < 0.0001), NE (91% and 74%, p < 0.0001), and DHPG (81% and 74%, p < 0.0001). In the MSA and PD groups, ratios of DOPAL:DA were 2.3 and 3.5 times control and DHPG:NE 3.1 and 2.6 times control, while DOPAC:DOPAL ratios were decreased by 61% and 74%. In both diseases cortical NE and DHPG were decreased, while DA and DOPAC were not. CONCLUSIONS: MSA and PD entail a catecholamine metabolic profile indicating impaired vesicular storage, decreased ALDH activity, and DOPAL buildup, which might be part of a common pathway in catecholamine neuronal death. Targeting this pathway by interfering with catecholaldehyde production or effects constitutes a novel treatment approach.


Assuntos
Aldeído Desidrogenase/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Lobo Frontal/metabolismo , Atrofia de Múltiplos Sistemas/metabolismo , Doença de Parkinson/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Idoso , Idoso de 80 Anos ou mais , Di-Hidroxifenilalanina/metabolismo , Feminino , Humanos , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo
20.
BMC Complement Altern Med ; 14: 476, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25495725

RESUMO

BACKGROUND: In this study, we investigate the effects of valerian root extracts (VE) on physical and psychological stress responses by utilizing a communication box. METHODS: Eight-week-old ICR mice received oral administration of VE (100 mg/kg/0.5 ml) or equal volume of distilled water in every day for 3 weeks prior to being subjected to physical or psychological stress for 3 days, which are induced by communication box developed for physical electric shock and psychological stress by nociceptive stimulation-evoked responses. The stress condition was assessed by forced swimming test and serum corticosterone levels. In addition, norepinephrine (NE), serotonin (5-HT), and their metabolites such as 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and amygdala at 1 h after final stress condition, respectively. RESULTS: Immobility time and corticosterone levels were significantly increased in both the physical and psychological stress groups compared to the control group. The administration of VE significantly reduced these parameters in both the physical and psychological stress groups. In addition, compared to the control group, physical and psychological stress groups showed significantly increased levels of MHPG-SO4 and 5-HIAA in the hippocampus and amygdala, respectively. The administration of VE significantly suppressed the increase of MHPG-SO4 and 5-HIAA in the two stress groups. CONCLUSION: These results suggest that VE can suppress physical and psychological stress responses by modulating the changes in 5-HT and NE turnover in the hippocampus and amygdala.


Assuntos
Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Neurotransmissores/uso terapêutico , Dor/tratamento farmacológico , Fitoterapia , Estresse Psicológico/tratamento farmacológico , Valeriana , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/metabolismo , Corticosterona/sangue , Eletrochoque , Hipocampo/metabolismo , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Dor/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas , Serotonina/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Estresse Psicológico/metabolismo , Natação
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