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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 -
The Journal of Neuroscience : the... Apr 2005The synapses formed by the olfactory nerve (ON) convey sensory information to olfactory glomeruli, the first stage of central odor processing. Morphological and... (Comparative Study)
Comparative Study
The synapses formed by the olfactory nerve (ON) convey sensory information to olfactory glomeruli, the first stage of central odor processing. Morphological and behavioral studies suggest that glomerular odor processing is plastic in neonate rodents. However, long-term synaptic plasticity, a cellular correlate of functional and structural plasticity, has not yet been demonstrated in this system. Here, we report that ON-->mitral cell (MC) synapses of 5- to 8-d-old mice express long-term depression (LTD) after brief low-frequency ON stimulation. Pharmacological techniques and imaging of presynaptic calcium signals demonstrate that ON-MC LTD is expressed presynaptically and requires the activation of metabotropic glutamate receptors but does not require fast synaptic transmission. LTD at the ON--> MC synapse is potentially relevant for the establishment, maintenance, and experience-dependent refinement of odor maps in the olfactory bulb.
Topics: Animals; Animals, Newborn; Calcium; Diagnostic Imaging; Dopamine Antagonists; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Evoked Potentials; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glycine; In Vitro Techniques; Long-Term Synaptic Depression; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred ICR; N-Methylaspartate; Neurons; Olfactory Bulb; Patch-Clamp Techniques; Quinoxalines; Sodium Channel Blockers; Sulpiride; Synapses; Tetrodotoxin; Time Factors; Valine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 15858051
DOI: 10.1523/JNEUROSCI.4721-04.2005 -
Journal of Neurophysiology Aug 2005
How good vibes turn bad: rise of ictal events from oscillatory network activity. Focus on "transient depression of excitatory synapses on interneurons contributes to epileptogenesis during gamma oscillations in the mouse hippocampal slice".
Topics: Animals; Epilepsy; Hippocampus; In Vitro Techniques; Interneurons; Methoxyhydroxyphenylglycol; Mice; Nerve Net; Oscillometry; Synaptic Transmission
PubMed: 16061488
DOI: 10.1152/jn.00210.2005 -
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 -
Neurobiology of Disease Nov 2021Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, in the spinal cord are implicated in nociceptive transmission and plasticity through G...
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.
Topics: ADP-Ribosylation Factor 1; ADP-Ribosylation Factor 6; Animals; GTPase-Activating Proteins; Hyperalgesia; Inflammation; MAP Kinase Signaling System; Methoxyhydroxyphenylglycol; Mice; Mice, Knockout; Neuralgia; Post-Synaptic Density; Posterior Horn Cells; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Spinal Cord; Spinal Cord Dorsal Horn; Triazoles
PubMed: 34390832
DOI: 10.1016/j.nbd.2021.105466 -
Clinical Autonomic Research : Official... Jun 2021Ampreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic...
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.
Topics: Autonomic Nervous System; Humans; Hypotension, Orthostatic; Methoxyhydroxyphenylglycol; Norepinephrine
PubMed: 33782836
DOI: 10.1007/s10286-021-00800-x -
Molecular Autism Oct 2020Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability. TSC2 regulates mRNA...
BACKGROUND
Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD) and behavior, but the identity of mRNAs responsive to mGluR-LTD signaling is largely unknown.
METHODS
We utilized Tsc2 mice as a mouse model of TSC and prepared hippocampal slices from these animals. We induced mGluR-LTD synaptic plasticity in slices and processed the samples for RNA-seq and ribosome profiling to identify differentially expressed genes in Tsc2 and following mGluR-LTD synaptic plasticity.
RESULTS
Ribosome profiling reveals that in Tsc2 mouse hippocampal slices, the expression of several mRNAs was dysregulated: terminal oligopyrimidine (TOP)-containing mRNAs decreased, while FMRP-binding targets increased. Remarkably, we observed the opposite changes of FMRP binding targets in Fmr1 hippocampi. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady-state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in TSC mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in TSC mice.
CONCLUSION
These results suggest a molecular basis for bidirectional regulation of synaptic plasticity and behavior by TSC2 and FMRP. Our study also suggests that altered mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2 mice.
Topics: Animals; Fragile X Mental Retardation Protein; Fragile X Syndrome; Hippocampus; Methoxyhydroxyphenylglycol; Mice, Inbred C57BL; Neuronal Plasticity; Peptide Elongation Factor 2; Protein Binding; Protein Biosynthesis; RNA 5' Terminal Oligopyrimidine Sequence; Receptors, Metabotropic Glutamate; Ribosomes; Signal Transduction; Tuberous Sclerosis Complex 2 Protein
PubMed: 33054857
DOI: 10.1186/s13229-020-00384-9 -
Life Sciences 1988A recent neuropathological study has reported decreased levels of dynorphin A immunoreactivity in striato-pallidal fibers in the brain of a patient with severe Gilles de... (Comparative Study)
Comparative Study
A recent neuropathological study has reported decreased levels of dynorphin A immunoreactivity in striato-pallidal fibers in the brain of a patient with severe Gilles de la Tourette's syndrome (TS). This observation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS. We report on the presence of elevated concentrations of dynorphin A [1-8] in the CSF of 7 TS patients, aged 20 to 45 years. The increase in CSF dynorphin was found to be associated with the severity of the obsessive compulsive symptoms but not with tic severity in these patients. Although CSF studies lack the precision necessary to address questions of selective involvement of neuronal system in specific CNS locations, these findings suggest that endogenous opioids are involved in the pathobiology of TS and related disorders. Tourette's syndrome (TS) is a chronic neuropsychiatric disorder of childhood onset that is characterized by multiple motor and phonic tics that wax and wane in severity and an array of behavioral problems including some forms of obsessive compulsive disorder (OCD) (1). Once thought to be a rare condition, the prevalence of TS is now estimated to be one case per 1,000 boys and one case per 10,000 girls, and milder variants of the syndrome are likely to occur in a sizeable percentage of the population (2). Although the etiology of TS remains unknown, the vertical transmission of TS within families follows a pattern consistent with an autosomal dominant form of inheritance (3,4). Neurobiologic and pharmacological data have implicated central monoaminergic and neuropeptidergic systems in the pathophysiology of TS, and basal ganglia structures remain the prime candidates as the neuroanatomical origin for TS and related conditions (1). Endogenous opioids, including dynorphin and met-enkephalin are concentrated in structures of the basal ganglia (5), are known to interact with central dopaminergic neurons (6, 7), and may play an important role in the control of motor functions (8). Post-mortem brain studies have directly implicated opioids in the pathophysiology of Parkinson's disease (9), Huntington's disease (10), and most recently in TS (11). The neuropathological study of Haber et al. (11) reported decreased levels of dynorphin A [1-17] immunoreactivity in striatal fibers projecting to the globus pallidus in the brain of a patient with severe TS. This ovservation, taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects, has led to speculation concerning its role in the pathobiology of TS.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Dynorphins; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Methoxyhydroxyphenylglycol; Peptide Fragments; Reference Values; Tourette Syndrome; Tryptophan; Tyrosine
PubMed: 2463450
DOI: 10.1016/0024-3205(88)90575-9 -
Journal of Neurology, Neurosurgery, and... Aug 2000Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery... (Clinical Trial)
Clinical Trial
OBJECTIVES
Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression.
METHODS
In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes.
RESULTS
Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls.
CONCLUSIONS
Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.
Topics: Adult; Biogenic Monoamines; Blood Cell Count; Body Weight; Depression; Erythrocytes; Female; Folic Acid; Folic Acid Deficiency; Homocysteine; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Methylation; Middle Aged; S-Adenosylmethionine; Vitamin B 12
PubMed: 10896698
DOI: 10.1136/jnnp.69.2.228