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1.
CNS Neurosci Ther ; 30(2): e14419, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37622292

RESUMO

AIMS: To investigate the role of mGluR1α in cerebellar unipolar brush cells (UBC) in mediating vestibular compensation (VC), using mGluR1α agonist and antagonist to modulate ON UBC neurons, and explore the mGluR1/IP3/extracellular signal-regulated kinase (ERK) signaling pathway. METHODS: First, AAV virus that knockdown ON UBC (mGluR1α) were injected into cerebellar UBC by stereotactic, and verified by immunofluorescence and western blot. The effect on VC was evaluated after unilateral labyrinthectomy (UL). Second, saline, (RS)-3,5-dihydroxyphenylglycine (DHPG), and LY367385 were injected into tubes implanted in rats at different time points after UL separately. The effect on ON UBC neuron activity was evaluated by immunofluorescence. Then, Phosphoinositide (PI) and p-ERK1/2 levels of mGluR1α were analyzed by ELISA after UL. The protein levels of p-ERK and total ERK were verified by western blot. In addition, the effect of mGluR1α activation or inhibition on VC-related behavior was observed. RESULTS: mGluR1α knockdown induced VC phenotypes. DHPG increased ON UBC activity, while LY367385 reduced ON UBC activity. DHPG group showed an increase in PI and p-ERK1/2 levels, while LY367385 group showed a decrease in PI and p-ERK1/2 levels in cerebellar UBC of rats. The western blot results of p-ERK and total ERK confirm and support the observations. DHPG alleviated VC-related behavior phenotypes, while LY367385 exacerbated vestibular decompensation-like behavior induced by UL. CONCLUSION: mGluR1α activity in cerebellar ON UBC is crucial for mediating VC through the mGluR1/IP3/ERK signaling pathway, which affects ON UBC neuron activity and contributes to the pathogenesis of VC.


Assuntos
Benzoatos , MAP Quinases Reguladas por Sinal Extracelular , Glicina/análogos & derivados , Metoxi-Hidroxifenilglicol/análogos & derivados , Receptores de Glutamato Metabotrópico , Transdução de Sinais , Ratos , Animais
2.
J Neurovirol ; 29(4): 440-448, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37289360

RESUMO

Depression is a common illness in people with HIV (PWH) and is associated with substantial morbidity and mortality. The mechanisms that underpin depression in PWH remain incompletely elucidated, and more research is therefore needed to develop effective treatments. One hypothesis is that neurotransmitter levels may be altered. These levels could be influenced by the chronic inflammation and viral persistence that occurs in PWH. We examined a panel of cerebrospinal fluid (CSF) neurotransmitters in PWH on suppressive antiretroviral therapy (ART), many of whom had a current depression diagnosis. CSF monoamine neurotransmitters and their metabolites were measured from participants in studies at the Emory Center for AIDS Research (CFAR). Only participants on stable ART with suppressed HIV RNA from both plasma and CSF were analyzed. Neurotransmitter levels were measured with high-performance liquid chromatography (HPLC). Neurotransmitters and their metabolites included dopamine (DA), homovanillic acid (HVA, a major metabolite of dopamine), serotonin (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA, a major metabolite of serotonin), and 4-hydroxy-3-methoxyphenylglycol (MHPG, a major metabolite of norepinephrine). Multivariable logistic regression was used to evaluate factors associated with depression. There were 79 PWH with plasma and CSF HIV RNA levels < 200 copies/mL at the time of the visit, and 25 (31.6%) carried a current diagnosis of depression. Participants with depression were significantly older (median age 53 years versus 47 years, P = 0.014) and were significantly less likely to be African American (48.0% versus 77.8%, P = 0.008). Participants with depression had significantly lower dopamine levels (median 0.49 ng/mL versus 0.62 ng/mL, P = 0.03) and significantly lower 5-HIAA levels (median 12.57 ng/mL versus 15.41 ng/mL, P = 0.015). Dopamine and 5-HIAA were highly correlated. In the multivariable logistic regression models, lower 5-HIAA was significantly associated with the depression diagnosis when accounting for other significant demographic factors. The associations between lower 5-HIAA, lower dopamine, and depression in PWH suggest that altered neurotransmission may contribute to these comorbid conditions. However, the effects of antidepressants on neurotransmitters cannot be ruled out as a factor in the 5-HIAA results.


Assuntos
Dopamina , Serotonina , Humanos , Pessoa de Meia-Idade , Dopamina/metabolismo , Serotonina/metabolismo , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Depressão , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Neurotransmissores
3.
Psychogeriatrics ; 23(4): 675-681, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37248036

RESUMO

BACKGROUND: The noradrenergic systems in the brain maintain cognitive functions including attention/concentration and establishment of long-term memory. In addition, hypofunction of noradrenergic systems is supposed to be involved in the pathophysiology of Alzheimer's disease. In this study, we tried to examine the possible associations of concentrations of basal salivary 3-methoxy-4-hydroxyphenylglycol (sMHPG), a major metabolite of noradrenaline, and brain volume changes during 4 years in elderly people living in a rural community. METHODS: The survey was conducted twice in Kurokawa-cho, Imari, Saga Prefecture, Japan, among people aged 65 years and older. We collected data from 226 residents. Measurements of sMHPG and brain MRIs were collected at Time 1 (2005-2007). Follow-up brain MRIs were taken at Time 2 (2009-2011). A total of 70 participants (18 men, mean age 71.9 ± 4.8 years; 52 women, mean age 72.0 ± 4.3 years) completed this survey. Concentrations of sMHPG at baseline were divided into two groups using the mean value (12.83 ng/ml). We compared the brain volumes between groups with higher and lower sMHPG concentrations over time using voxel-based morphometry implemented with statistical parametric mapping. RESULTS: In participants with higher sMHPG concentrations at baseline, brain volumes including right precuneus were significantly larger 4 years after baseline than those with lower sMHPG concentrations at baseline. No interaction between sMHPG concentration and MRI acquisition interval was found. CONCLUSION: Our results suggest that higher sMHPG concentrations in elderly people might be associated with maintenance of brain volume, especially in brain regions closely related to cognitive function.


Assuntos
Vida Independente , Metoxi-Hidroxifenilglicol , Idoso , Masculino , Humanos , Feminino , Metoxi-Hidroxifenilglicol/metabolismo , Norepinefrina/metabolismo , Imageamento por Ressonância Magnética , Lobo Parietal/metabolismo
4.
Gut ; 72(8): 1581-1591, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36788015

RESUMO

BACKGROUND AND AIMS: Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models. METHODS: Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling. RESULTS: Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality. CONCLUSIONS: Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.


Assuntos
Insuficiência Hepática Crônica Agudizada , Metoxi-Hidroxifenilglicol , Humanos , Prognóstico , Estudos Prospectivos , Cirrose Hepática/complicações , Inflamação/complicações , Metabolômica , Mitocôndrias
5.
Ageing Res Rev ; 83: 101784, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36368648

RESUMO

Some studies point locus coeruleus cell loss, the central nervous system main source of norepinephrine, to be one of the earliest neuropathological events of Alzheimer's disease (AD). However, there are conflicting reports regarding the level of norepinephrine and its metabolites (3-Methoxy-4-hydroxyphenylglycol (MHPG), 3,5-dihydroxyphenylglycine (DHPG) and 3,4 -dihydroxyphenylglycolaldehyde (DOPEGAL)) in AD patients. Uncover these alterations may be a key factor for understanding cognitive deficits and AD pathology. We review the literature that compare norepinephrine and its metabolites between AD patients and non-demented controls. A meta-analysis did not reveal significant statistical differences, but there was a trend towards a lower level of norepinephrine of AD, with almost no difference in MHPG in the cerebrospinal fluid. Regarding MHPG in plasma, DHPG and DOPEGAL we only performed a qualitative analyse due to the small or absent number of studies. These findings point to a decrease in norepinephrine, what is in line with locus coeluleus cell loss in AD. The absence of statistical difference and an equal level of MHGP could indicate a compensatory mechanism.


Assuntos
Doença de Alzheimer , Norepinefrina , Humanos , Norepinefrina/metabolismo , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Doença de Alzheimer/metabolismo
6.
Int J Mol Sci ; 23(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36233200

RESUMO

Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found that prenatal treatment with SAMe of Submissive (Sub) mice that serve as a model for depression alleviated many of the behavioral depressive symptoms. In the present study, we treated pregnant Sub mice with 20 mg/kg of SAMe on days 12-15 of gestation and studied the levels of monoamines and the expression of genes related to monoamines metabolism in their prefrontal cortex (PFC) at the age of 3 months. The data were compared to normal saline-treated Sub mice that exhibit depressive-like symptoms. SAMe increased the levels of serotonin in the PFC of female Sub mice but not in males. The levels of 5-HIAA were not changed. SAMe increased the levels of dopamine and of DOPAC in males and females but increased the levels of HVA only in females. The levels of norepinephrine and its metabolite MHPG were unchanged. SAMe treatment changed the expression of several genes involved in the metabolism of these monoamines, also in a sex-related manner. The increase in several monoamines induced by SAMe in the PFC may explain the alleviation of depressive-like symptoms. Moreover, these changes in gene expression more than 3 months after treatment probably reflect the beneficial effects of SAMe as an epigenetic modulator in the treatment of depression.


Assuntos
Dopamina , Serotonina , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Animais , Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Catecolaminas/metabolismo , Depressão/tratamento farmacológico , Depressão/genética , Dopamina/metabolismo , Epigênese Genética , Feminino , Hierarquia Social , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Metoxi-Hidroxifenilglicol , Camundongos , Norepinefrina/metabolismo , Solução Salina , Serotonina/metabolismo
7.
Zhongguo Zhong Yao Za Zhi ; 47(17): 4691-4697, 2022 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-36164876

RESUMO

To investigate the effect of Rehmanniae Radix on depression-like behavior and monoamine neurotransmitters of chronic unpredictable mild stress(CUMS) model rats. CUMS combined with isolated feeding was used to induce the depression model of rats. The depression-like behavior of rats was evaluated by sucrose preference test, open field test, and forced swim test. Hematoxylin-Eosin(HE) staining was used to investigate the pathological changes of neurons in the CA1 and CA3 area of hippocampus. Ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS) was used to detect the contents of 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), 3,4-dihydroxyphenylacetic acid(DOPAC), homovanillic acid(HVA), norepinephrine(NE), and 3-methoxy-4-hydroxyphenyl glycol(MHPG) in rats. Western blot was used to detect the protein expressions of tryptophan hydroxylase 2(TPH2), serotonin transporter(SERT), and monoamine oxidase A(MAO-A) in the hippocampus of rats. Compared with the normal group, depressive-like behavior of rats was obvious in the model group. The arrangements of neurons in the CA1 and CA3 area of hippocampus were loose and disorderly. The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in the hippocampal area were decreased(P<0.01). The protein expression of TPH2 was decreased(P<0.01), but those of SERT and MAO-A were increased(P<0.01). In the Rehmanniae Radix groups with 1.8 g·kg~(-1) and 7.2 g·kg~(-1), the depression-like behavior of CUMS rats and pathological changes of neurons in CA1, CA3 area of hippocampus were improved. The protein expression of TPH2(P<0.05, P<0.01) was increased, and those of SERT and MAO-A were down-regulated(P<0.05, P<0.01). The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in hippocampus were increased(P<0.05, P<0.01). The changes in DA, DOPAC, HVA, DA/(DOPAC +HVA), NE, DHPG, and NE/DHPG were not statistically significant. The results suggested that Rehmanniae Radix improved depression-like behavior of CUMS rats, and the mechanism might be related to the regulation of synthesis, transportation, and metabolism of 5-HT neurotransmitter in the hippocampus.


Assuntos
Antidepressivos , Depressão , Hipocampo , Ácido Hidroxi-Indolacético , Rehmannia , Serotonina , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Cromatografia Líquida , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Dopamina , Amarelo de Eosina-(YS)/metabolismo , Amarelo de Eosina-(YS)/farmacologia , Hematoxilina/metabolismo , Hematoxilina/farmacologia , Hipocampo/metabolismo , Ácido Homovanílico/metabolismo , Ácido Homovanílico/farmacologia , Ácido Hidroxi-Indolacético/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/metabolismo , Metoxi-Hidroxifenilglicol/farmacologia , Monoaminoxidase/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Extratos Vegetais , Ratos , Rehmannia/química , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/farmacologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Espectrometria de Massas em Tandem , Triptofano Hidroxilase/metabolismo
8.
J Integr Neurosci ; 21(4): 123, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35864774

RESUMO

BACKGROUND: There has been increasing evidence that exercise therapy is effective in the treatment and prevention of major depression (MD). However, the basic molecular mechanisms underlying the effects of exercise on MD remain unclear. We conducted a preliminary study to clarify the effect of exercise therapy on MD, focusing on the dynamics of nitric oxide (NO) and catecholamine metabolites, which have been found to be associated with MD. METHODS: Eleven outpatients with mild to moderate MD and 37 healthy controls (HC) were included in the study. The participants' clinical records and questionnaires were screened for their past medical history. For their exercise therapy, the participants were instructed to walk the equivalent of 17.5 kcal/kg/week for 8 weeks. Blood samples were collected from all participants at baseline, 4 weeks, and 8 weeks after the start of exercise therapy, and plasma metabolites of NO (NOx), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were analyzed. We also assessed the 17-item Hamilton Rating Scale for Depression (HRSD-17) in patients with MD. A mixed-effects regression model was used to compare the mean values by time (baseline, 4, and 8 weeks) for the three corresponding groups (NOx, MHPG, and HVA). RESULTS: HRSD-17 scores decreased significantly in the MD group after 8 weeks of exercise therapy. NOx and MHPG increased, but there was no significant change in HVA in the MD group after the exercise therapy. NOx decreased after exercise, and HVA increased significantly from baseline after 4 weeks of exercise but decreased after 8 weeks of exercise in the HC group. CONCLUSIONS: The effects of exercise on NOx, MHPG, and HVA may differ between MD and HC. The potential mechanisms for the benefits of walking exercise in MD patients will be the subject for future research.


Assuntos
Transtorno Depressivo Maior , Metoxi-Hidroxifenilglicol , Catecolaminas/uso terapêutico , Depressão , Transtorno Depressivo Maior/terapia , Ácido Homovanílico/metabolismo , Ácido Homovanílico/uso terapêutico , Humanos , Metoxi-Hidroxifenilglicol/metabolismo , Metoxi-Hidroxifenilglicol/uso terapêutico , Óxido Nítrico/uso terapêutico
9.
Eur Arch Psychiatry Clin Neurosci ; 272(7): 1283-1296, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35410391

RESUMO

Neurotransmitter metabolism plays a critical role in the pathophysiology of major depressive disorder (MDD). However, whether the neurotransmitter metabolism in adolescent MDD is differentiated from adult MDD is still elusive. In the current study, plasma concentrations of monoamine and amino acid neurotransmitters as well as their metabolites, including tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), glutamine (GLN), glutamate (GLU) and gamma-aminobutyric acid (GABA), were measured and compared in two cohorts of subjects (adult cohort: 31 first-episode MDD vs. 35 healthy controls; adolescent cohort: 33 first-episode MDD vs. 30 healthy controls). To assess the effects of antidepressant treatment, we also analyzed the concentrations of these indexes pre- and post-treatment in adult and adolescent cohorts. At baseline, the deficits of neurotransmitter metabolism in adult MDD were manifested in all the neurotransmitter systems. In contrast, for adolescent MDD, the dysregulation of neurotransmission was mainly indicated in the catecholaminergic systems. After antidepressant treatment, adult MDD showed increased TRP, KYN, KYNA and GLU levels, together with decreased levels of 5-HIAA and DOPAC. Adolescent MDD illustrated an increased level of 5-HT and decreased levels of TRP and GABA. The improvements of Hamilton total scores correlated with the changes in plasma TRP and the turnover of KYN/TRP after treatment in all MDD patients. However, these correlations were only manifested in the adult MDD rather than in adolescent MDD patients. The findings highlight the shared and distinguished neurotransmitter pathways in MDD and emphasize the different antidepressant responses between adults and adolescents. Potentially, the neurotransmitters above could serve as diagnostic biomarkers and provide a novel pharmacological treatment strategy for MDD.


Assuntos
Transtorno Depressivo Maior , Cinurenina , Ácido 3,4-Di-Hidroxifenilacético , Adolescente , Adulto , Biomarcadores , Transtorno Depressivo Maior/diagnóstico , Dopamina , Ácido Glutâmico , Glutamina , Ácido Homovanílico , Humanos , Ácido Hidroxi-Indolacético , Ácido Cinurênico , Cinurenina/metabolismo , Metoxi-Hidroxifenilglicol , Neurotransmissores/metabolismo , Norepinefrina , Serotonina , Triptofano , Ácido Vanilmandélico , Ácido gama-Aminobutírico
10.
Acta Biomater ; 145: 200-209, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35430336

RESUMO

Gemcitabine (GEM) is among the most used chemotherapies for advanced malignancies including non-small cell lung cancer. The clinical efficacy of GEM is, however, downplayed by its poor bioavailability, short half-life, drug resistance, and dose-limiting toxicities (e.g. myelosuppression). In spite of many approaches exploited to improve the efficacy and safety of GEM, limited success was achieved. The short A6 peptide (sequence: Ac-KPSSPPEE-NH2) is clinically validated for specific binding to CD44 on metastatic tumors. Here, we designed a robust and CD44-specific GEM nanotherapeutics by encapsulating hydrophobic phosphorylated gemcitabine prodrug (HPG) into the core of A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG), which exhibited reduction-triggered HPG release and specific targetability to CD44 overexpressing tumor cells. Interestingly, A6 greatly enhanced the internalization and inhibitory activity of micellar HPG (mHPG) in CD44 positive A549 cells, and increased its accumulation in A549 cancerous lung, leading to potent repression of orthotopic tumor growth, depleted toxicity, and marked survival benefits compared to free HPG and mHPG (median survival time: 59 days versus 30 and 45 days, respectively). The targeted delivery of gemcitabine prodrug with disulfide-crosslinked biodegradable micelles appears to be a highly appealing strategy to boost gemcitabine therapy for advance tumors. STATEMENT OF SIGNIFICANCE: Gemcitabine (GEM) though widely used in clinics for treating advanced tumors is associated with poor bioavailability, short half-life and dose-limiting toxicities. Development of clinically translatable GEM formulations to improve its anti-tumor efficacy and safety is of great interest. Here, we report on CD44-targeting GEM nanotherapeutics obtained by encapsulating hydrophobic phosphorylated GEM prodrug (HPG), a single isomer of NUC-1031, into A6 peptide-functionalized disulfide-crosslinked micelles (A6-mHPG). A6-mHPG demonstrates stability against degradation, enhanced internalization and inhibition toward CD44+ cells, and increased accumulation in A549 lung tumor xenografts, leading to potent repression of orthotopic tumor growth, depleted toxicity and marked survival benefits. The targeted delivery of GEM prodrug using A6-mHPG is a highly appealing strategy to GEM cancer therapy.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pró-Fármacos , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Dissulfetos , Humanos , Receptores de Hialuronatos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Metoxi-Hidroxifenilglicol , Micelas , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Gencitabina
11.
Int J Mol Sci ; 23(2)2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-35054851

RESUMO

Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the ß2-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play a critical pathogenetic role in MS. CD4+ T cells obtained from twenty-five relapsing-remitting MS patients and sixteen healthy subjects were cultured ex vivo with norepinephrine and/or ß2-adrenoreceptor antagonist or agonist, followed by a cytokine production analysis using ELISA. Norepinephrine suppressed IL-17 and IFN-γ production by the anti-CD3/anti-CD28-microbead-stimulated CD4+ T cells in both groups. Blockade of the ß2-adrenoreceptor with the specific antagonist ICI 118.551 enhanced norepinephrine-mediated IL-17 suppression but decreased its inhibitory effect on IFN-γ production in MS patients. In contrast, the ß2-adrenoreceptor agonist formoterol did not influence norepinephrine's inhibitory effect on cytokine production in both groups. The blockade of the ß2-adrenoreceptor, even in the absence of exogenous norepinephrine, suppressed IL-17 production but did not influence IFN-γ production in both groups. Conversely, ß2-adrenoreceptor activation by formoterol decreased IFN-γ production and did not affect IL-17 production in both groups. These data illustrate the inhibitory effect of norepinephrine on IL-17 and IFN-γ production by CD4+ T cells in MS. The inhibitory effect of norepinephrine on IFN-γ production by CD4+ T cells in MS could be mediated via ß2-adrenoreceptor activation.


Assuntos
Interferon gama/biossíntese , Interleucina-17/biossíntese , Esclerose Múltipla/imunologia , Receptores Adrenérgicos beta 2/metabolismo , Linfócitos T/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Citocinas/metabolismo , Epinefrina/sangue , Feminino , Humanos , Masculino , Metoxi-Hidroxifenilglicol , Esclerose Múltipla/sangue , Norepinefrina/sangue
12.
Psychoneuroendocrinology ; 136: 105598, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34894424

RESUMO

Anxiety and depression are linked to both explicit and implicit memory biases, which are defined as the tendency to preferentially recall emotionally negative information at conscious and subconscious levels, respectively. Functional connectivity (FC) of the basolateral amygdala (BLA) and related stress hormones (i.e., cortisol and norepinephrine) are purportedly implicated in these biases. However, previous findings on memory biases in anxiety and depression have been inconsistent, likely due to their symptomatic complications. Therefore, the underlying neurobiological mechanism remains unclear. We thus investigated whether anxiety and depression as premorbid predispositions are related to the memory biases, and whether FC of BLA, cortisol, and 3-methoxy-4-hydroxyphenylglycol (MHPG: a major metabolite of norepinephrine) would affect the anxiety/depression-related biased memory recall in 100 participants without psychiatric symptomatology. Psycho-behavioral assessment, resting-state fMRI scans, and saliva collection at 10-points-in-time across two days were conducted. Correlations of memory biases with anxiety/depression and neurobiological markers were explored. As a result, neither anxiety nor depression were correlated with explicit memory bias to negative (vs. positive) information, although depression was associated with better recall of the negative stimuli only when they were perceived as self-relevant. In contrast, both anxiety and depression were correlated with implicit memory bias; however, the effects were solely explained by anxiety. Furthermore, FC of the BLA with subgenual anterior cingulate cortex (sgACC) and the synergetic effect of cortisol and MHPG uniquely affected the implicit memory bias. These findings suggest that anxiety facilitates an initial snapshot of negative information and can be accompanied by depression when the information creates negative semantic associations with the self. The BLA-sgACC neural connectivity and cortisol-norepinephrine interaction that are associated with the implicit memory bias might be one of the important neurobiological targets in the prevention and treatment for comorbid anxiety and depressive disorders.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Hidrocortisona , Ansiedade , Depressão , Humanos , Imageamento por Ressonância Magnética , Metoxi-Hidroxifenilglicol , Norepinefrina
13.
Cell Rep ; 37(9): 110076, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34852231

RESUMO

A core network of widely expressed proteins within the glutamatergic post-synapse mediates activity-dependent synaptic plasticity throughout the brain, but the specific proteomic composition of synapses differs between brain regions. Here, we address the question, how does proteomic composition affect activity-dependent protein-protein interaction networks (PINs) downstream of synaptic activity? Using quantitative multiplex co-immunoprecipitation, we compare the PIN response of in vivo or ex vivo neurons derived from different brain regions to activation by different agonists or different forms of eyeblink conditioning. We report that PINs discriminate between incoming stimuli using differential kinetics of overlapping and non-overlapping PIN parameters. Further, these "molecular logic rules" differ by brain region. We conclude that although the PIN of the glutamatergic post-synapse is expressed widely throughout the brain, its activity-dependent dynamics show remarkable stimulus-specific and brain-region-specific diversity. This diversity may help explain the challenges in developing molecule-specific drug therapies for neurological disorders.


Assuntos
Piscadela/efeitos dos fármacos , Encéfalo/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , N-Metilaspartato/farmacologia , Mapas de Interação de Proteínas , Proteoma/metabolismo , Sinapses/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Condicionamento Palpebral , Agonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Plasticidade Neuronal , Proteoma/análise , Sinapses/efeitos dos fármacos
14.
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
15.
Neurobiol Dis ; 159: 105466, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34390832

RESUMO

Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, in the spinal cord are implicated in nociceptive transmission and plasticity through G protein-mediated second messenger cascades leading to the activation of various protein kinases such as extracellular signal-regulated kinase (ERK). In this study, we demonstrated that cytohesin-2, a guanine nucleotide exchange factor for ADP ribosylation factors (Arfs), is abundantly expressed in subsets of excitatory interneurons and projection neurons in the superficial dorsal horn. Cytohesin-2 is enriched in the perisynapse on the postsynaptic membrane of dorsal horn neurons and forms a protein complex with mGluR5 in the spinal cord. Central nervous system-specific cytohesin-2 conditional knockout mice exhibited reduced mechanical allodynia in inflammatory and neuropathic pain models. Pharmacological blockade of cytohesin catalytic activity with SecinH3 similarly reduced mechanical allodynia and inhibited the spinal activation of Arf6, but not Arf1, in both pain models. Furthermore, cytohesin-2 conditional knockout mice exhibited reduced mechanical allodynia and ERK1/2 activation following the pharmacological activation of spinal mGluR1/5 with 3,5-dihydroxylphenylglycine (DHPG). The present study suggests that cytothesin-2 is functionally associated with mGluR5 during the development of mechanical allodynia through the activation of Arf6 in spinal dorsal horn neurons.


Assuntos
Fator 6 de Ribosilação do ADP/metabolismo , Proteínas Ativadoras de GTPase/genética , Hiperalgesia/genética , Neuralgia/genética , Células do Corno Posterior/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Medula Espinal/metabolismo , Fator 1 de Ribosilação do ADP/efeitos dos fármacos , Fator 1 de Ribosilação do ADP/metabolismo , Fator 6 de Ribosilação do ADP/efeitos dos fármacos , Animais , Proteínas Ativadoras de GTPase/antagonistas & inibidores , Proteínas Ativadoras de GTPase/metabolismo , Hiperalgesia/metabolismo , Inflamação/genética , Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Camundongos Knockout , Neuralgia/metabolismo , Densidade Pós-Sináptica/metabolismo , Células do Corno Posterior/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5/agonistas , Receptores de Glutamato Metabotrópico/agonistas , Medula Espinal/efeitos dos fármacos , Corno Dorsal da Medula Espinal , Triazóis/farmacologia
16.
J Neurosci ; 41(35): 7340-7349, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34290083

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles. Aß oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP61). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aß toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aß-oligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP61, prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca2+-permeable GluA2-lacking AMPA receptors along with higher STEP61 levels, resulting in occlusion of DHPG-induced LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration.SIGNIFICANCE STATEMENT Reelin is an important neuromodulator, which in the adult brain controls synaptic plasticity and protects against neurodegeneration. Amyloid-ß has been shown to use mGluRs to induce synaptic depression through endocytosis of NMDA and AMPA receptors, a mechanism referred to as LTD, a paradigm of forgetfulness. Our results show that Reelin regulates the phosphatase STEP, which plays an important role in neurodegeneration, as well as the expression of calcium-permeable AMPA receptors, which play a role in memory formation. These data suggest that Reelin uses mGluR LTD pathways to regulate memory formation as well as neurodegeneration.


Assuntos
Depressão Sináptica de Longo Prazo/fisiologia , Neurônios/fisiologia , Proteínas Tirosina Fosfatases não Receptoras/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Proteína Reelina/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/efeitos dos fármacos , Cálcio/fisiologia , Células Cultivadas , Córtex Cerebral/citologia , Indução Enzimática/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Memória/fisiologia , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Degeneração Neural/fisiopatologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Fosforilação/efeitos dos fármacos , Picrotoxina/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Proteínas Recombinantes/metabolismo , Proteína Reelina/deficiência , Proteína Reelina/genética
17.
Asian J Psychiatr ; 62: 102711, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34090249

RESUMO

AIM: The purpose of this meta-analysis was to critically examine the data from individual studies on CSF neurotransmitter metabolites to see whether there were consistencies in the results of the comparison of suicide attempters and psychiatric controls and of the comparison of attempted suicides using violent versus nonviolent methods. METHOD: Systematic literature search across different electronic databases using PubMed/Google Scholar/EMBASE/Cochrane library was conducted for studies that reported concentration of CSF-neurotransmitter metabolites: 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxy phenylglycol (MHPG) in suicide attempters, from January'1981 to November'2020. Standardized mean differences (SMDs) and corresponding 95 % confidence interval (CIs) were deduced for outcome measures. I2 statistics were used to assess heterogeneity within studies. Data were analyzed using STATA software. RESULTS: A total of 36 studies (N = 1987 attempted suicide and N = 1235 psychiatry control) were included for the meta-analysis. We found CSF levels of all the 3 metabolites i.e. 5-HIAA (SMD= -0.43; 95 %CI: -0.61, -0.24), HVA (SMD= -0.16; 95 %CI: -0.33, -0.00) and MHPG (SMD= -0.33; 95 %CI: -0.71, -0.05) were lower in suicide attempters. While the findings were consistent for 5-HIAA, they were inconsistent for the HVA and MHPG. CSF levels of 5-HIAA (SMD= -0.66; 95 %; CI: -1.01, -0.31), HVA (SMD= -0.14; 95 %CI: -0.45, 0.16) and MHPG (SMD= -0.12; 95 %CI: -0.56, 0.31) were significantly lower in violent suicide attempters than non-violent attempters. No significant publication bias found in any study. CONCLUSION: We found a significant association between lower levels of CSF 5-HIAA in suicide attempters, particularly the violent ones, compared to psychiatric controls, whereas findings from CSF HVA and MHPG were inconsistent.


Assuntos
Metoxi-Hidroxifenilglicol , Tentativa de Suicídio , Agressão , Ácido Homovanílico , Humanos , Ácido Hidroxi-Indolacético
18.
J Neurochem ; 158(2): 554-568, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33894018

RESUMO

The synucleinopathies Parkinson's disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF) are characterized by intra-cytoplasmic deposition of the protein alpha-synuclein and by catecholamine depletion. PAF, which manifests with neurogenic orthostatic hypotension (nOH) and no motor signs of central neurodegeneration, can evolve into PD+nOH. The cerebrospinal fluid (CSF) levels of catecholamine metabolites may indicate central catecholamine deficiency in these synucleinopathies, but the literature is inconsistent and incomplete. In this retrospective cohort study we reviewed data about CSF catecholamines, the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the norepinephrine metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG). The compounds were measured in 36 patients with PD, 37 patients with MSA, and 19 patients with PAF and in 38 controls. Compared to the control group, the PD, MSA, and PAF groups had decreased CSF MHPG (p < .0001 each by Dunnett's post hoc test), DHPG (p = .004; p < .0001; p < .0001) and norepinephrine (p = .017; p = .0003; p = .044). CSF HVA and DOPAC were decreased in PD (p < .0001 each) and MSA (p < .0001 each) but not in PAF. The three synucleinopathies therefore have in common in vivo evidence of central noradrenergic deficiency but differ in the extents of central dopaminergic deficiency-prominent in PD and MSA, less apparent in PAF. Data from putamen 18 F-DOPA and cardiac 18 F-dopamine neuroimaging in the same patients, post-mortem tissue catecholamines in largely separate cohorts, and review of the neuropathology literature fit with these distinctions. The results suggest a 'norepinephrine first' ascending pathogenetic sequence in synucleinopathies, with degeneration of pontine locus ceruleus noradrenergic neurons preceding the loss of midbrain substantia nigra dopaminergic neurons.


Assuntos
Dopamina/líquido cefalorraquidiano , Norepinefrina/líquido cefalorraquidiano , Sinucleinopatias/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Idoso , Estudos de Coortes , Neurônios Dopaminérgicos/patologia , Feminino , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Masculino , Metoxi-Hidroxifenilglicol/análogos & derivados , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Atrofia de Múltiplos Sistemas/patologia , Neurônios/patologia , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/patologia , Insuficiência Autonômica Pura/líquido cefalorraquidiano , Insuficiência Autonômica Pura/patologia , Estudos Retrospectivos , Sinucleinopatias/patologia
19.
Reprod Domest Anim ; 56(7): 1004-1014, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33908088

RESUMO

Supplementing the extender with antioxidants with low molecular weight can enhance the quality of the post-thaw sperm during the freezing process. This study was aimed at determining the impacts of 3,4-dihydroxyphenyl glycol (DHPG) on the spermatozoa of the canine undergoing freeze-thawing process. In this study, 24 ejaculates were obtained from three mixed-breed dogs and were diluted in a Tris-based extender. The diluted semen was divided into aliquots for supplementation of 10, 30, 50 and 70 µg/ml of DHPG, control (without antioxidant) and control sham (DMSO). After being extended, the semen was equilibrated at a temperature of 4°C and then transferred to the straws and kept 4 cm above the liquid nitrogen for 20 min and was finally immersed in the liquid nitrogen. They were cryopreserved for seven days; then, sperm parameters including sperm motility evaluation, motility characteristics, viability, DNA and plasma membrane integrity, total antioxidant capacity (TAC), reduced glutathione content (GSH), antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT] and glutathione peroxidase [GPx]) activity malondialdehyde (MDA) levels were evaluated. This study showed that spermatozoa cryopreservation with 50, 30 and 70 µg/ml of DHPG concentrations had better progressive motility, Curvilinear Velocity, Linearity, viability, intact plasma membrane and the levels of TAC, GPx and GSH were higher than the control group. The 50, 30 and 70 µg/ml of DHPG concentrations led to the significant decrease of DNA damage compared to the control group. Total motility, average path velocity, straight-line velocity and CAT activity were significantly improved in 30 and 50 µg/ml of DHPG concentrations, compared to the control group. Also, the 50 and 30 µg/ml of DHPG concentrations, decreased MDA levels compared to the other groups, significantly. In conclusion, our study showed that the addition 50 µg/ml of DHPG to the canine semen extender improved the semen characteristics and oxidative markers in the cryopreservation process.


Assuntos
Criopreservação/veterinária , Crioprotetores/farmacologia , Cães , Metoxi-Hidroxifenilglicol/farmacologia , Animais , Antioxidantes , Criopreservação/métodos , Dano ao DNA , Congelamento , Masculino , Análise do Sêmen/veterinária , Preservação do Sêmen/métodos , Preservação do Sêmen/veterinária , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos
20.
Clin Auton Res ; 31(3): 395-403, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33782836

RESUMO

PURPOSE: Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population. METHODS: Patients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine. RESULTS: Thirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6-9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001). CONCLUSIONS: Persistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with nOH.


Assuntos
Hipotensão Ortostática , Sistema Nervoso Autônomo , Humanos , Hipotensão Ortostática/tratamento farmacológico , Metoxi-Hidroxifenilglicol , Norepinefrina
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