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Neurobiology of Aging Jun 2021Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the...
Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), Aβ42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of Aβ42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Cerebral Cortex; Cognition; Female; Humans; Locus Coeruleus; Male; Methoxyhydroxyphenylglycol; Middle Aged; Nerve Degeneration; Norepinephrine; Organ Size; Peptide Fragments; tau Proteins
PubMed: 33667876
DOI: 10.1016/j.neurobiolaging.2021.01.024 -
The Journal of Neuroscience : the... Dec 2018GABA synapses in the brain undergo depolarization-induced suppression of inhibition (DSI) that requires activation of presynaptic cannabinoid type 1 receptors (CBRs)....
GABA synapses in the brain undergo depolarization-induced suppression of inhibition (DSI) that requires activation of presynaptic cannabinoid type 1 receptors (CBRs). The brevity of DSI, lasting ∼1 min in most brain regions, has been ascribed to the transient production of 2-arachidonoylglycerol (2-AG). Here, we propose that the duration of DSI is controlled by heterologous interactions between presynaptic mGluRs and CBRs. By examining GABA synapses on parvocellular corticotropin-releasing hormone-expressing neurons in the paraventricular nucleus of the hypothalamus (PVN) of male and female mice, we show that DSI decays quickly in experimental conditions in which both GABA and glutamate are released from adjacent nerve terminals. Pharmacological inhibition of group I mGluRs prolongs DSI, whereas prior activation of mGluRs inhibits DSI, collectively suggesting that group I mGluRs quench presynaptic CBR signaling. When photostimulation of genetically identified terminals is used to release only GABA, CBR-dependent DSI persists for many minutes. Under the same conditions, activation of group I mGluRs reestablishes classical, transient DSI. The long-lasting DSI observed when GABA synapses are independently recruited functionally uncouples inhibitory input to PVN neurons. These observations suggest that heterologous interactions between mGluRs and CBRs control the temporal window of DSI at GABA synapses, providing evidence for a powerful new way to affect functional circuit connectivity in the brain. Postsynaptic depolarization liberates endocannabinoids, resulting in a rapid and transient decrease in release probability at GABA synapses. We discovered that mGluRs control the duration of depolarization-induced suppression of inhibition (DSI), most likely through heterologous desensitization of cannabinoid type 1 receptors by presynaptic mGluR By shortening the duration of DSI, mGluRs control the temporal window for retrograde signaling at GABA synapses. Physiological or pathological changes that affect glutamate spillover may profoundly affect network excitability by shifting the duration of cannabinoid inhibition at GABA synapses.
Topics: Animals; Endocannabinoids; Female; Glutamic Acid; Inhibitory Postsynaptic Potentials; Male; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Mice, Transgenic; Optogenetics; Receptor, Cannabinoid, CB1; Receptors, Metabotropic Glutamate; Receptors, Presynaptic; gamma-Aminobutyric Acid
PubMed: 30355625
DOI: 10.1523/JNEUROSCI.1097-18.2018 -
Journal of Psychiatric Research Oct 2018Altered monoaminergic functions have been implicated in the pathophysiology of depressive disorder. However, previously reported cerebrospinal fluid (CSF) monoamine... (Meta-Analysis)
Meta-Analysis
Altered monoaminergic functions have been implicated in the pathophysiology of depressive disorder. However, previously reported cerebrospinal fluid (CSF) monoamine metabolite concentrations in major depression have been inconsistent. We performed a meta-analysis of historic evidence to determine whether CSF monoamine metabolite levels were different between patients with depression and normal controls, and could be used as depression biomarkers. Relevant studies that investigated CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with depression and normal controls were identified in PubMed, Web of Science, PsycINFO, and Embase databases through September 5, 2017, using a synonymous search for depression, CSF, normal, control, and each monoamine metabolite name, and in the reference lists of the acquired articles. Obtained records were individually scrutinized for eligibility. Our search strategy identified 26 studies, including our own. We employed random effects modeling and adopted "Hedges's g" as an index of effect size. In the meta-analyses, no significant difference was observed in CSF 5-HIAA or MHPG levels between patients with depressive disorder and controls. In contrast, CSF HVA was significantly decreased in patients with depression (Hedges's g = -0.30, P = 0.0000025), and these results remained significant after patients with bipolar disorder were excluded (Hedges's g = -0.37, P = 0.000061). In the meta-regression, sex was significantly associated with the Hedges's g of CSF HVA (Q = 4.41, P = 0.036). This meta-analysis revealed that only CSF HVA, and not 5-HIAA or MHPG, levels were decreased in depressive disorder. The reduction in the CSF HVA concentration in patients with depression may guide future studies on depression and serve as a useful biomarker of depressive disorder.
Topics: Biomarkers; Depressive Disorder, Major; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Methoxyhydroxyphenylglycol
PubMed: 30219563
DOI: 10.1016/j.jpsychires.2018.08.028 -
Molecules (Basel, Switzerland) Sep 2019Hydroxytyrosol and two other polyphenols of olive tree, hydroxytyrosol acetate and 3,4-dihydroxyphenylglycol, are known for a wide range of beneficial activities in...
Hydroxytyrosol and two other polyphenols of olive tree, hydroxytyrosol acetate and 3,4-dihydroxyphenylglycol, are known for a wide range of beneficial activities in human health and prevention from diseases. The inability to isolate high, pure amounts of these natural compounds and the difficult and laborious procedures for the synthesis of them led us to describe herein an efficient, easy, cheap, and scaling up synthetic procedure, from catechol, via microwave irradiation.
Topics: Chemistry Techniques, Synthetic; Humans; Methoxyhydroxyphenylglycol; Molecular Structure; Phenylethyl Alcohol
PubMed: 31492013
DOI: 10.3390/molecules24183239 -
BMC Psychiatry Dec 2014Treatments of eating disorders result too often in partial psychological and physical remission, chronicization, dropout, relapse and death, with no fully known... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Treatments of eating disorders result too often in partial psychological and physical remission, chronicization, dropout, relapse and death, with no fully known explanations for this failure. In order to clarify this problem, we conducted three studies to identify the biochemical background of cognitive-behavioural psychotherapy (CBT), individual psychology brief psychotherapy (IBPP), and psychotherapy-pharmacotherapy with CBT + olanzapine in anorexics (AN) and bulimics (BN) by measuring the levels of plasma homovanillic acid (HVA) for dopamine secretion, plasma 3-methoxy-4-hydroxy-phenylglycol (MHPG) for noradrenalin secretion, and platelet [3H]-Paroxetin-binding Bmax and Kd for serotonin transporter function. The data were then compared with psychopathological and physical alterations.
METHODS
Study 1 investigated the effects of 4 months of CBT on plasma HVA, MHPG and [3H]-Par-binding in 14 AN-restricted, 14 AN-bingeing/purging, and 22 BN inpatients. Study 2 investigated the effects of 4 months of IBPP on plasma HVA in 15 AN and 17 BN outpatients. Study 3 investigated the effect of 3 months of CBT + olanzapine (5 mg/day) in 30 AN outpatients. The data were analyzed using one-way ANOVA for repeated measures for the changes between basal and post-treatment biological and psychological parameters, two-way ANOVA for repeated measures for the differences in the psychobiological data in the 3 groups, Spearman's test for the correlations between basal and final changes in the psychological and biological scores.
RESULTS
Study 1 revealed significant amelioration of the psychopathology in the AN and BN patients, no effects on HVA, MHPG or Paroxetin binding Kd, and a significant increase in Par-binding Bmax only in the BN patients. Study 2 revealed a significant effect of IBPP on psychopathology in the AN and BN patients, and a significant increase in HVA only in the BN patients. Study 3 revealed a significant positive effect of CBT + olanzapine therapy on the psychopathology and increased HVA values. No correlations were observed in the 3 groups between biological and psychological effects of the three treatments.
CONCLUSIONS
Our data advance suggestions on the mechanism of action of the three therapies; however, the lack of correlations between biochemical and psychological effects casts doubt on their significance. Clinical Trials.gov. Identifier NCT01990755 .
Topics: Administration, Oral; Adult; Analysis of Variance; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Bulimia Nervosa; Cognitive Behavioral Therapy; Combined Modality Therapy; Double-Blind Method; Female; Homovanillic Acid; Humans; Male; Methoxyhydroxyphenylglycol; Olanzapine; Paroxetine; Psychotherapy, Brief; Serotonin Plasma Membrane Transport Proteins; Treatment Failure
PubMed: 25539757
DOI: 10.1186/s12888-014-0376-7 -
Scientific Reports Aug 2021Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. Traumatic stress during adolescence increases the risk of IBS in adults. The aim...
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.
Topics: Abdominal Pain; Age Factors; Animals; Anxiety; Avoidance Learning; Behavior, Animal; Colon; Disease Models, Animal; Irritable Bowel Syndrome; Male; Methoxyhydroxyphenylglycol; Mice; Norepinephrine; Serotonin; Social Behavior; Social Defeat; Stress, Psychological
PubMed: 34381165
DOI: 10.1038/s41598-021-95916-5 -
Clinical Drug Investigation Feb 2016Dasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of...
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.
Topics: 1-Naphthylamine; Administration, Oral; Adrenergic Uptake Inhibitors; Attention Deficit Disorder with Hyperactivity; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dopamine Uptake Inhibitors; Female; Half-Life; Humans; Male; Methoxyhydroxyphenylglycol; Models, Biological; Norepinephrine Plasma Membrane Transport Proteins; Randomized Controlled Trials as Topic
PubMed: 26597180
DOI: 10.1007/s40261-015-0358-7 -
Journal of Neurochemistry Nov 2015In 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...
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).
Topics: 3,4-Dihydroxyphenylacetic Acid; Aged; Aged, 80 and over; Chromatography, High Pressure Liquid; Chromatography, Liquid; Female; Humans; Locus Coeruleus; Male; Mandelic Acids; Mass Spectrometry; Melanins; Methoxyhydroxyphenylglycol; Norepinephrine; Substantia Nigra
PubMed: 26156066
DOI: 10.1111/jnc.13237 -
Translational Psychiatry May 2018Cancer-related fatigue (CRF) is a common burden in cancer patients and little is known about its underlying mechanism. The primary aim of this study was to identify gene...
Cancer-related fatigue (CRF) is a common burden in cancer patients and little is known about its underlying mechanism. The primary aim of this study was to identify gene signatures predictive of post-radiotherapy fatigue in prostate cancer patients. We employed Fisher Linear Discriminant Analysis (LDA) to identify predictive genes using whole genome microarray data from 36 men with prostate cancer. Ingenuity Pathway Analysis was used to determine functional networks of the predictive genes. Functional validation was performed using a T lymphocyte cell line, Jurkat E6.1. Cells were pretreated with metabotropic glutamate receptor 5 (mGluR5) agonist (DHPG), antagonist (MPEP), or control (PBS) for 20 min before irradiation at 8 Gy in a Mark-1 γ-irradiator. NF-κB activation was assessed using a NF-κB/Jurkat/GFP Transcriptional Reporter Cell Line. LDA achieved 83.3% accuracy in predicting post-radiotherapy fatigue. "Glutamate receptor signaling" was the most significant (p = 0.0002) pathway among the predictive genes. Functional validation using Jurkat cells revealed clustering of mGluR5 receptors as well as increased regulated on activation, normal T cell expressed and secreted (RANTES) production post irradiation in cells pretreated with DHPG, whereas inhibition of mGluR5 activity with MPEP decreased RANTES concentration after irradiation. DHPG pretreatment amplified irradiation-induced NF-κB activation suggesting a role of mGluR5 in modulating T cell activation after irradiation. These results suggest that mGluR5 signaling in T cells may play a key role in the development of chronic inflammation resulting in fatigue and contribute to individual differences in immune responses to radiation. Moreover, modulating mGluR5 provides a novel therapeutic option to treat CRF.
Topics: Aged; Fatigue; Genome-Wide Association Study; Humans; Jurkat Cells; Machine Learning; Male; Methoxyhydroxyphenylglycol; Middle Aged; NF-kappa B; Prostatic Neoplasms; Pyridines; Radiotherapy; Radiotherapy Dosage; Receptor, Metabotropic Glutamate 5; T-Lymphocytes; Transcriptome
PubMed: 29849049
DOI: 10.1038/s41398-018-0161-3 -
Molecular & Cellular Proteomics : MCP Dec 2020At neuronal synapses, activation of group I metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein...
At neuronal synapses, activation of group I metabotropic glutamate receptors (mGluR1/5) triggers a form of long-term depression (mGluR-LTD) that relies on new protein synthesis and the internalization of AMPA-type glutamate receptors. Dysregulation of these processes has been implicated in the development of mental disorders such as autism spectrum disorders and therefore merit a better understanding on a molecular level. Here, to study mGluR-induced signaling pathways, we integrated quantitative phosphoproteomics with the analyses of newly synthesized proteins via bio-orthogonal amino acids (azidohomoalanine) in a pulsed labeling strategy in cultured hippocampal neurons stimulated with DHPG, a specific agonist for group I mGluRs. We identified several kinases with important roles in DHPG-induced mGluR activation, which we confirmed using small molecule kinase inhibitors. Furthermore, changes in the AMPA receptor endocytosis pathway in both protein synthesis and protein phosphorylation were identified, whereby Intersectin-1 was validated as a novel player in this pathway. This study revealed several new insights into the molecular pathways downstream of group I mGluR activation in hippocampal neurons, and provides a rich resource for further analyses.
Topics: Amino Acid Sequence; Animals; Endocytosis; Hippocampus; Methoxyhydroxyphenylglycol; Neurons; Phosphorylation; Protein Biosynthesis; Proteomics; Rats; Receptors, AMPA; Receptors, Metabotropic Glutamate; Signal Transduction; Time Factors
PubMed: 32912969
DOI: 10.1074/mcp.RA120.002199