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  1. Article ; Online: NMDAR activation regulates the daily rhythms of sleep and mood.

    Burgdorf, Jeffrey S / Vitaterna, Martha H / Olker, Christopher J / Song, Eun Joo / Christian, Edward P / Sørensen, Laurits / Turek, Fred W / Madsen, Torsten M / Khan, M Amin / Kroes, Roger A / Moskal, Joseph R

    Sleep

    2019  Volume 42, Issue 10

    Abstract: Study objectives: The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion.: Methods: Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and non-sleep- ... ...

    Abstract Study objectives: The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion.
    Methods: Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and non-sleep-deprived rats. In addition, the day-night cycle of both activity and mood was measured using home cage ultrasonic-vocalization recordings.
    Results: NYX-2925 significantly facilitated non-REM (NREM) sleep during the lights-on (sleep) period, and this effect persisted for 3 days following a single dose in sleep-deprived rats. Sleep-bout duration and REM latencies were increased without affecting total REM sleep, suggesting better sleep quality. In addition, delta power during wake was decreased, suggesting less drowsiness. NYX-2925 also rescued learning and memory deficits induced by sleep deprivation, measured using an NMDAR-dependent learning task. Additionally, NYX-2925 increased positive affect and decreased negative affect, primarily by facilitating the transitions from sleep to rough-and-tumble play and back to sleep. In contrast to NYX-2925, the NMDAR antagonist ketamine acutely (1-4 hours post-dosing) suppressed REM and non-REM sleep, increased delta power during wake, and blunted the amplitude of the sleep-wake activity rhythm.
    Discussion: These data suggest that NYX-2925 could enhance behavioral plasticity via improved sleep quality as well as vigilance during wake. As such, the facilitation of sleep by NYX-2925 has the potential to both reduce symptom burden on neurological and psychiatric disorders as well as serve as a biomarker for drug effects through restoration of sleep architecture.
    MeSH term(s) Affect/drug effects ; Affect/physiology ; Animals ; Circadian Rhythm/drug effects ; Circadian Rhythm/physiology ; Electroencephalography/methods ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/agonists ; Receptors, N-Methyl-D-Aspartate/physiology ; Sleep/drug effects ; Sleep/physiology ; Sleep Deprivation/drug therapy ; Sleep Deprivation/physiopathology ; Spiro Compounds/pharmacology ; Spiro Compounds/therapeutic use ; Wakefulness/drug effects ; Wakefulness/physiology
    Chemical Substances NYX-2925 ; Receptors, N-Methyl-D-Aspartate ; Spiro Compounds
    Language English
    Publishing date 2019-09-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 424441-2
    ISSN 1550-9109 ; 0161-8105
    ISSN (online) 1550-9109
    ISSN 0161-8105
    DOI 10.1093/sleep/zsz135
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  2. Article ; Online: NYX-2925 induces metabotropic N-methyl-d-aspartate receptor (NMDAR) signaling that enhances synaptic NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.

    Bowers, M Scott / Cacheaux, Luisa P / Sahu, Srishti U / Schmidt, Mary E / Sennello, Joseph A / Leaderbrand, Katherine / Khan, M Amin / Kroes, Roger A / Moskal, Joseph R

    Journal of neurochemistry

    2019  Volume 152, Issue 5, Page(s) 523–541

    Abstract: N-methyl-d-aspartate receptors (NMDARs) mediate both physiological and pathophysiological processes, although selective ligands lack broad clinical utility. NMDARs are composed of multiple subunits, but N-methyl-d-aspartate receptor subunit 2 (GluN2) is ... ...

    Abstract N-methyl-d-aspartate receptors (NMDARs) mediate both physiological and pathophysiological processes, although selective ligands lack broad clinical utility. NMDARs are composed of multiple subunits, but N-methyl-d-aspartate receptor subunit 2 (GluN2) is predominately responsible for functional heterogeneity. Specifically, the GluN2A- and GluN2B-containing subtypes are enriched in adult hippocampus and cortex and impact neuronal communication via dynamic trafficking into and out of the synapse. We sought to understand if ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3,4]octan-2-yl) butanamide (NYX-2925), a novel NMDAR modulator, alters synaptic levels of GluN2A- or GluN2B-containing NMDARs. Low-picomolar NYX-2925 increased GluN2B colocalization with the excitatory post-synaptic marker post-synaptic density protein 95 (PSD-95) in rat primary hippocampal neurons within 30 min. Twenty-four hours following oral administration, 1 mg/kg NYX-2925 increased GluN2B in PSD-95-associated complexes ex vivo, and low-picomolar NYX-2925 regulated numerous trafficking pathways in vitro. Because the NYX-2925 concentration that increases synaptic GluN2B was markedly below that which enhances long-term potentiation (mid-nanomolar), we sought to elucidate the basis of this effect. Although NMDAR-dependent, NYX-2925-mediated colocalization of GluN2B with PSD-95 occurred independent of ion flux, as colocalization increased in the presence of either the NMDAR channel blocker (5R,10S)-(-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate or glycine site antagonist 7-chlorokynurenic acid. Moreover, while mid-nanomolar NYX-2925 concentrations, which do not increase synaptic GluN2B, enhanced calcium transients, functional plasticity was only enhanced by picomolar NYX-2925. Thus, NYX-2925 concentrations that increase synaptic GluN2B facilitated the chemical long-term potentiation induced insertion of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA1 subunit levels. Basal (unstimulated by chemical long-term potentiation) levels of synaptic GluA1 were only increased by mid-nanomolar NYX-2925. These data suggest that NYX-2925 facilitates homeostatic plasticity by initially increasing synaptic GluN2B via metabotropic-like NMDAR signaling. Cover Image for this issue: doi: 10.1111/jnc.14735.
    MeSH term(s) Animals ; Hippocampus/drug effects ; Hippocampus/metabolism ; Long-Term Potentiation/drug effects ; Long-Term Potentiation/physiology ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/drug effects ; Receptors, AMPA/metabolism ; Receptors, N-Methyl-D-Aspartate/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; Signal Transduction/drug effects ; Spiro Compounds/pharmacology ; Synapses/drug effects ; Synapses/metabolism
    Chemical Substances NR2B NMDA receptor ; NYX-2925 ; Receptors, AMPA ; Receptors, N-Methyl-D-Aspartate ; Spiro Compounds ; glutamate receptor ionotropic, AMPA 1 (TFZ3H25BS1) ; N-methyl D-aspartate receptor subtype 2A (VH92ICR8HX)
    Language English
    Publishing date 2019-10-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80158-6
    ISSN 1471-4159 ; 0022-3042 ; 1474-1644
    ISSN (online) 1471-4159
    ISSN 0022-3042 ; 1474-1644
    DOI 10.1111/jnc.14845
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  3. Article ; Online: Cellular diamine levels in cancer chemoprevention: modulation by ibuprofen and membrane plasmalogens.

    Wood, Paul L / Khan, M Amin / Smith, Tara / Goodenowe, Dayan B

    Lipids in health and disease

    2011  Volume 10, Page(s) 214

    Abstract: Background: To develop effective strategies in cancer chemoprevention, an increased understanding of endogenous biochemical mediators that block metastatic processes is critically needed. Dietary lipids and non-steroidal anti-inflammatory drugs (NSAIDs) ...

    Abstract Background: To develop effective strategies in cancer chemoprevention, an increased understanding of endogenous biochemical mediators that block metastatic processes is critically needed. Dietary lipids and non-steroidal anti-inflammatory drugs (NSAIDs) have a published track record of providing protection against gastrointestinal malignancies. In this regard, we examined the effects of membrane plasmalogens and ibuprofen on regulation of cellular levels of diamines, polyamine mediators that are augmented in cancer cells. For these studies we utilized Chinese hamster ovary (CHO) cells and NRel-4 cells, a CHO cell line with defective plasmalogen synthesis.
    Results: NRel-4 cells, which possess cellular plasmalogen levels that are 10% of control CHO cells, demonstrated 2- to 3-fold increases in cellular diamine levels. These diamine levels were normalized by plasmalogen replacement and significantly reduced by ibuprofen. In both cases the mechanism of action appears to mainly involve increased diamine efflux via the diamine exporter. The actions of ibuprofen were not stereospecific, supporting previous studies that cyclooxygenase (COX) inhibition is unlikely to be involved in the ability of NSAIDs to reduce intracellular diamine levels.
    Conclusions: Our data demonstrate that ibuprofen, a drug known to reduce the risk of colorectal cancer, reduces cellular diamine levels via augmentation of diamine efflux. Similarly, augmentation of membrane plasmalogens can increase diamine export from control and plasmalogen-deficient cells. These data support the concept that membrane transporter function may be a therapeutic point of intervention for dietary and pharmacological approaches to cancer chemoprevention.
    MeSH term(s) Amino Acids/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; CHO Cells ; Cadaverine/metabolism ; Cell Membrane/metabolism ; Cricetinae ; Fusion Regulatory Protein 1, Heavy Chain/metabolism ; Ibuprofen/pharmacology ; Neoplasms/prevention & control ; Plasmalogens/pharmacology ; Plasmalogens/physiology ; Putrescine/metabolism
    Chemical Substances Amino Acids ; Anti-Inflammatory Agents, Non-Steroidal ; Fusion Regulatory Protein 1, Heavy Chain ; Plasmalogens ; Cadaverine (L90BEN6OLL) ; Putrescine (V10TVZ52E4) ; Ibuprofen (WK2XYI10QM)
    Language English
    Publishing date 2011-11-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1476-511X
    ISSN (online) 1476-511X
    DOI 10.1186/1476-511X-10-214
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  4. Article ; Online: The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant.

    Moskal, Joseph R / Burgdorf, Jeffrey S / Stanton, Patric K / Kroes, Roger A / Disterhoft, John F / Burch, Ronald M / Khan, M Amin

    Current neuropharmacology

    2016  Volume 15, Issue 1, Page(s) 47–56

    Abstract: Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans.: Methods: ... ...

    Abstract Background: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans.
    Methods: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide (threonine-proline-proline-threonine-amide) obtained from amino acid sequence information obtained from sequencing one of the hypervariable regions of the light chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined.
    Results: Rapastinel was found to be a robust cognitive enhancer in a variety of learning and memory paradigms and shows marked antidepressant-like properties in multiple models including the forced swim (Porsolt), learned helplessness and chronic unpredictable stress. Rapastinel's rapid-acting antidepressant properties appear to be mediated by its ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover, ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing.
    Conclusion: These data suggest that rapastinel has significant effects on metaplasticity processes that may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.
    MeSH term(s) Age Factors ; Animals ; Antidepressive Agents/pharmacology ; Antidepressive Agents/therapeutic use ; Depression/drug therapy ; Depression/pathology ; Depression/physiopathology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Exploratory Behavior/drug effects ; Long-Term Potentiation/drug effects ; Maze Learning/drug effects ; Memory/drug effects ; Neuronal Plasticity/drug effects ; Oligopeptides/chemistry ; Oligopeptides/pharmacology ; Oligopeptides/therapeutic use ; Rats ; Receptors, N-Methyl-D-Aspartate/metabolism ; Swimming ; Synapses/drug effects ; Synapses/ultrastructure ; Vocalization, Animal/drug effects
    Chemical Substances Antidepressive Agents ; Oligopeptides ; Receptors, N-Methyl-D-Aspartate ; GLYX-13 peptide (6A1X56B95E)
    Language English
    Publishing date 2016-03-21
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 2192352-8
    ISSN 1875-6190 ; 1570-159X
    ISSN (online) 1875-6190
    ISSN 1570-159X
    DOI 10.2174/1570159x14666160321122703
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  5. Article: Mechanism of action of the disease-modifying anti-arthritic thiol agents D-penicillamine and sodium aurothiomalate: restoration of cellular free thiols and sequestration of reactive aldehydes.

    Wood, Paul L / Khan, M Amin / Moskal, Joseph R

    European journal of pharmacology

    2008  Volume 580, Issue 1-2, Page(s) 48–54

    Abstract: While new anti-cytokine disease-modifying anti-arthritic drugs for rheumatoid arthritis have been designed via mechanistic approaches, the mechanism of action of a number of more established disease-modifying anti-arthritic drugs has not been elucidated. ...

    Abstract While new anti-cytokine disease-modifying anti-arthritic drugs for rheumatoid arthritis have been designed via mechanistic approaches, the mechanism of action of a number of more established disease-modifying anti-arthritic drugs has not been elucidated. In the case of d-penicillamine and sodium aurothiomalate, the key structural feature appears to be a free thiol group. However, the role thiol groups play in the therapeutic efficacy of these drugs has not been defined. A number of lines of evidence have demonstrated increased generation of reactive aldehydes and the associated depletion of free thiol pools in rheumatoid arthritis. These observations have led to the suggestion that reactive aldehydes may be the ultimate mediators of cell destruction in rheumatoid arthritis joints. Our data clearly demonstrate that thiol-containing disease-modifying anti-arthritic agents both directly sequester reactive aldehydes and augment intracellular thiol pools, which also can buffer increased aldehyde load and oxidative stress. These data are consistent with clinical data that penicillamine lowers synovial aldehyde levels and augments plasma thiols. We suggest that these actions are the pivotal mechanism of action of thiol-containing disease-modifying anti-arthritic drugs. Understanding the mechanism of action of these drugs provides the opportunity for the design of more potent and safer thiol drug candidates.
    MeSH term(s) Aldehydes/toxicity ; Animals ; Antirheumatic Agents/pharmacology ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/physiopathology ; Cell Line ; Gold Sodium Thiomalate/pharmacology ; Mice ; Oxidative Stress/drug effects ; Penicillamine/pharmacology ; Sulfhydryl Compounds/metabolism
    Chemical Substances Aldehydes ; Antirheumatic Agents ; Sulfhydryl Compounds ; Gold Sodium Thiomalate (12244-57-4) ; Penicillamine (GNN1DV99GX)
    Language English
    Publishing date 2008-02-02
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80121-5
    ISSN 1879-0712 ; 0014-2999
    ISSN (online) 1879-0712
    ISSN 0014-2999
    DOI 10.1016/j.ejphar.2007.10.066
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  6. Article ; Online: NYX-2925 Is a Novel

    Ghoreishi-Haack, Nayereh / Priebe, Jessica M / Aguado, Jacqueline D / Colechio, Elizabeth M / Burgdorf, Jeffrey S / Bowers, M Scott / Cearley, Cassia N / Khan, M Amin / Moskal, Joseph R

    The Journal of pharmacology and experimental therapeutics

    2018  Volume 366, Issue 3, Page(s) 485–497

    Abstract: NYX-2925 [(2S,3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide] is a ... ...

    Abstract NYX-2925 [(2S,3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide] is a novel
    MeSH term(s) Analgesics/pharmacology ; Analgesics/therapeutic use ; Animals ; Disease Models, Animal ; Male ; Neuralgia/drug therapy ; Neuralgia/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; Spiro Compounds/pharmacology ; Spiro Compounds/therapeutic use ; Vocalization, Animal/drug effects
    Chemical Substances Analgesics ; NYX-2925 ; Receptors, N-Methyl-D-Aspartate ; Spiro Compounds
    Language English
    Publishing date 2018-07-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3106-9
    ISSN 1521-0103 ; 0022-3565
    ISSN (online) 1521-0103
    ISSN 0022-3565
    DOI 10.1124/jpet.118.249409
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  7. Article: The concept of "aldehyde load" in neurodegenerative mechanisms: cytotoxicity of the polyamine degradation products hydrogen peroxide, acrolein, 3-aminopropanal, 3-acetamidopropanal and 4-aminobutanal in a retinal ganglion cell line.

    Wood, Paul L / Khan, M Amin / Moskal, Joseph R

    Brain research

    2007  Volume 1145, Page(s) 150–156

    Abstract: In neurodegenerative diseases augmented polyamine metabolism results in the generation of hydrogen peroxide and a number of reactive aldehydes that participate in the death of compromised tissue. The major aldehydes produced by polyamine oxidase and ... ...

    Abstract In neurodegenerative diseases augmented polyamine metabolism results in the generation of hydrogen peroxide and a number of reactive aldehydes that participate in the death of compromised tissue. The major aldehydes produced by polyamine oxidase and amine oxidases include the 2-alkenal acrolein, the acetoamidoaldehyde 3-acetamidopropanal (3-AAP) and the aminoaldehydes 3-aminopropanal (3-AP) and 4-aminobutanal (4-AB). Using retinal ganglion cell (E1A-NR.3) cultures, we confirmed the cytotoxicity of acrolein and 3-AP. For the first time we also demonstrated the cytotoxicity of 4-AB and the lack of toxicity of 3-AAP. Our data with 3-AAP, a product of N-acetylspermine and N-acetylspermidine metabolism, indicate that the aldehyde function of aminoaldehydes is insufficient to express toxicity since the free amino group of aminoaldehydes is also required to gain access to lysosomes where their cytotoxic actions are expressed via leakage of cathepsins that compromise mitochondrial integrity. Metabolism of 3-AP to beta-alanine by aldehyde dehydrogenase was also evaluated in retinal ganglion cell cultures and found to proceed at a linear rate of 24.3+/-1 nmol/mg protein/h. These are the first data demonstrating the dynamic cellular detoxification of 3-AP by neural cells and support the concept that decrements in aldehyde elimination leading to an increase in "aldehyde load" may play pivotal roles in the development and progression of neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis and Parkinson's disease.
    MeSH term(s) Acrolein/metabolism ; Acrolein/toxicity ; Aldehyde Dehydrogenase/metabolism ; Aldehydes/metabolism ; Aldehydes/toxicity ; Animals ; Biogenic Polyamines/metabolism ; Biogenic Polyamines/toxicity ; Brain Chemistry/physiology ; Cell Death/drug effects ; Cell Death/physiology ; Cell Line ; Hydrogen Peroxide/metabolism ; Hydrogen Peroxide/toxicity ; Metabolic Clearance Rate/physiology ; Nerve Degeneration/chemically induced ; Nerve Degeneration/metabolism ; Nerve Degeneration/physiopathology ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/physiopathology ; Neurotoxins/metabolism ; Neurotoxins/toxicity ; Propylamines/metabolism ; Propylamines/toxicity ; Rats ; Retinal Ganglion Cells/drug effects ; Retinal Ganglion Cells/metabolism ; beta-Alanine/metabolism
    Chemical Substances Aldehydes ; Biogenic Polyamines ; Neurotoxins ; Propylamines ; beta-Alanine (11P2JDE17B) ; Acrolein (7864XYD3JJ) ; Hydrogen Peroxide (BBX060AN9V) ; Aldehyde Dehydrogenase (EC 1.2.1.3) ; 3-aminopropionaldehyde (ML707Y407U)
    Language English
    Publishing date 2007-05-11
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2006.10.004
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  8. Article: Cellular thiol pools are responsible for sequestration of cytotoxic reactive aldehydes: central role of free cysteine and cysteamine.

    Wood, Paul L / Khan, M Amin / Moskal, Joseph R

    Brain research

    2007  Volume 1158, Page(s) 158–163

    Abstract: Cellular thiol pools have been shown to be important in the regulation of the redox status of cells, providing a large antioxidant pool consisting of free thiols, thiols bound in the disulfide form and thiols bound to proteins. However, experimental ... ...

    Abstract Cellular thiol pools have been shown to be important in the regulation of the redox status of cells, providing a large antioxidant pool consisting of free thiols, thiols bound in the disulfide form and thiols bound to proteins. However, experimental studies with the thiol cysteamine and its disulfide cystamine have demonstrated dramatic cytoprotection in experimental models where antioxidants provide only minor protection. These data suggest that an alternate action of thiols is important in their cytoprotective actions. A common feature of the in vitro and in vivo models, where these thiol agents demonstrate cytoprotection, is the generation of cytotoxic aldehydes. We therefore studied the actions of cystamine, cysteamine and several reference thiol agents as cytoprotectants against cell death induced by increased "aldehyde load". We found that all the thiol agents examined provided dramatic protection against aldehyde-induced cell death in SN56 cholinergic neurons, under conditions in which acrolein induced 100% cell death. With regard to mechanism of action, the reference thiols cysteine, N-acetylcysteine, 2-mercaptoethanesulfonic acid, mercapto-propionyglycine, and cysteamine can directly sequester aldehydes. In addition, these thiols were all found to augment intracellular cysteine levels via disulfide interchange reactions. Cysteamine and cystamine also augmented basal intracellular cysteamine levels. Our data, for the first time, demonstrate the importance of intracellular thiols in sequestering toxic reactive aldehyde products of lipid peroxidation and polyamine metabolism. In addition it appears that pharmacological manipulation of intracellular thiol pools might offer a new approach in the design of neuroprotective drug candidates.
    MeSH term(s) Aldehydes/toxicity ; Animals ; Cell Death/drug effects ; Cell Line ; Cysteamine/metabolism ; Cysteamine/pharmacology ; Cysteine/metabolism ; Cysteine/pharmacology ; Drug Interactions ; Extracellular Fluid/drug effects ; Extracellular Fluid/metabolism ; Mice ; Models, Biological ; Neurons/drug effects ; Neurons/metabolism ; Septum of Brain/cytology ; Sulfhydryl Compounds/metabolism ; Time Factors
    Chemical Substances Aldehydes ; Sulfhydryl Compounds ; Cysteamine (5UX2SD1KE2) ; Cysteine (K848JZ4886)
    Language English
    Publishing date 2007-07-16
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1200-2
    ISSN 1872-6240 ; 0006-8993
    ISSN (online) 1872-6240
    ISSN 0006-8993
    DOI 10.1016/j.brainres.2007.05.007
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  9. Article: Neurochemical analysis of amino acids, polyamines and carboxylic acids: GC-MS quantitation of tBDMS derivatives using ammonia positive chemical ionization.

    Wood, Paul L / Khan, M Amin / Moskal, Joseph R

    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

    2006  Volume 831, Issue 1-2, Page(s) 313–319

    Abstract: The GC-MS quantitation of a large number of neurochemicals utilizing a single derivatization step is not common but is provided by the reagent N-(tert-butyldimethylsilyl)-N-methyltrifluro-acetamide (MTBSTFA). Previous workers have utilized this ... ...

    Abstract The GC-MS quantitation of a large number of neurochemicals utilizing a single derivatization step is not common but is provided by the reagent N-(tert-butyldimethylsilyl)-N-methyltrifluro-acetamide (MTBSTFA). Previous workers have utilized this derivative for GC-MS analyses of amino acids, carboxylic acids and urea with electron impact (EI) and with positive chemical ionization (PCI; methane as reagent gas). However, these conditions yield significant fragmentation, decreasing sensitivity and in some cases reducing specificity for quantitation with selected ion monitoring (SIM). Additionally, the majority of studies have used a single internal standard to quantitate many compounds. In this study we demonstrate that using isotopic dilution combined with ammonia as the reagent gas for PCI analyses, results in high precision and sensitivity in analyzing complex neurochemical mixes. We also demonstrate for the first time the utility of this derivative for the analysis of brain polyamines and the dipeptide cysteinyl glycine. In the case of ammonia as the reagent gas, all amino acids, polyamines and urea yielded strong [MH](+) ions with little or no fragmentation. In the case of carboxylic acids, [M+18](+) ions predominated but [MH](+) ions were also noted. This approach was used to analyze superfusates from hippocampal brain slices and brain tissue extracts from brain lesion studies. The advantages of this methodology include: (i) simple sample preparation; (ii) a single derivatization step; (iii) direct GC-MS analysis of the reaction mix; (iv) high precision as a result of isotopic dilution analyses; (v) high sensitivity and specificity as a result of strong [MH](+) ions with ammonia reagent gas; (vi) no hydrolysis of glutamine to glutamate or asparagine to aspartate; and (vii) applicability to a wide range of neurochemicals.
    MeSH term(s) Acetamides ; Amino Acids/analysis ; Ammonia ; Animals ; Carbon Isotopes ; Carboxylic Acids/analysis ; Deuterium ; Fluoroacetates ; Gas Chromatography-Mass Spectrometry/methods ; Hippocampus/chemistry ; Hippocampus/drug effects ; Male ; Neurotransmitter Agents/secretion ; Nitrogen Isotopes ; Organosilicon Compounds/analysis ; Organosilicon Compounds/chemistry ; Polyamines/analysis ; Rats ; Rats, Sprague-Dawley ; Trifluoroacetic Acid/chemistry ; Trimethyltin Compounds/toxicity
    Chemical Substances Acetamides ; Amino Acids ; Carbon Isotopes ; Carboxylic Acids ; Fluoroacetates ; Neurotransmitter Agents ; Nitrogen Isotopes ; Organosilicon Compounds ; Polyamines ; Trimethyltin Compounds ; t-butyldimethylsilyl compounds ; trimethyltin (1631-73-8) ; Ammonia (7664-41-7) ; N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (77377-52-7) ; Deuterium (AR09D82C7G) ; Trifluoroacetic Acid (E5R8Z4G708)
    Language English
    Publishing date 2006-02-02
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1570-0232
    ISSN 1570-0232
    DOI 10.1016/j.jchromb.2005.12.031
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Oral bioavailability of the ether lipid plasmalogen precursor, PPI-1011, in the rabbit: a new therapeutic strategy for Alzheimer's disease.

    Wood, Paul L / Smith, Tara / Lane, Nina / Khan, M Amin / Ehrmantraut, Greg / Goodenowe, Dayan B

    Lipids in health and disease

    2011  Volume 10, Page(s) 227

    Abstract: Introduction: Docosahexaenoic acid (DHA) and DHA-containing ethanolamine plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer's disease. Decreased supply of plasmalogen precursors to the brain by the liver, as a ... ...

    Abstract Introduction: Docosahexaenoic acid (DHA) and DHA-containing ethanolamine plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer's disease. Decreased supply of plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing ether lipid precursor of plasmalogens. PPI-1011 is an alkyl-diacyl plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines (PtdEtn).
    Methods: Rabbits were dosed orally with PPI-1011 in hard gelatin capsules for time-course and dose response studies. Incorporation into PlsEtn and PtdEtn was monitored by LC-MS/MS. Metabolism of released lipoic acid was monitored by GC-MS. To monitor the metabolic fate of different components of PPI-1011, we labeled the sn-1 palmitic acid, sn-2 DHA and glycerol backbone with (13)C and monitored their metabolic fates by LC-MS/MS.
    Results: PPI-1011 was not detected in plasma suggesting rapid release of sn-3 lipoic acid via gut lipases. This conclusion was supported by peak levels of lipoic acid metabolites in the plasma 3 hours after dosing. While PPI-1011 did not gain access to the plasma, it increased circulating levels of DHA-containing PlsEtn and PtdEtn. Labeling experiments demonstrated that the PtdEtn increases resulted from increased availability of DHA released via remodeling at sn-2 of phospholipids derived from PPI-1011. This release of DHA peaked at 6 hrs while increases in phospholipids peaked at 12 hr. Increases in circulating PlsEtn were more complex. Labeling experiments demonstrated that increases in the target PlsEtn, 16:0/22:6, consisted of 2 pools. In one pool, the intact precursor received a sn-3 phosphoethanolamine group and desaturation at sn-1 to generate the target plasmalogen. The second pool, like the PtdEtn, resulted from increased availability of DHA released during remodeling of sn-2. In the case of sn-1 18:0 and 18:1 plasmalogens with [(13)C(3)]DHA at sn-2, labeling was the result of increased availability of [(13)C(3)]DHA from lipid remodeling. Isotope and repeated dosing (2 weeks) experiments also demonstrated that plasmalogens and/or plasmalogen precursors derived from PPI-1011 are able to cross both the blood-retinal and blood-brain barriers.
    Conclusions: Our data demonstrate that PPI-1011, an ether lipid precursor of plasmalogens is orally bioavailable in the rabbit, augmenting the circulating levels of unesterified DHA and DHA-containing PlsEtn and PtdEtn. Other ethanolamine plasmalogens were generated from the precursor via lipid remodeling (de-acylation/re-acylation reactions at sn-2) and phosphatidylethanolamines were generated via de-alkylation/re-acylation reactions at sn-1. Repeated oral dosing for 2 weeks with PPI-1011 resulted in dose-dependent increases in circulating DHA and DHA-containing plasmalogens. These products and/or precursors were also able to cross the blood-retinal and blood-brain barriers.
    MeSH term(s) Administration, Oral ; Alzheimer Disease/drug therapy ; Animals ; Biological Availability ; Caproates/blood ; Diglycerides/administration & dosage ; Diglycerides/pharmacokinetics ; Docosahexaenoic Acids/blood ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Female ; Phosphatidylethanolamines/blood ; Plasmalogens/blood ; Rabbits ; Tissue Distribution
    Chemical Substances Caproates ; Diglycerides ; Phosphatidylethanolamines ; Plasmalogens ; glycerophosphoethanolamine (1190-00-7) ; Docosahexaenoic Acids (25167-62-8)
    Language English
    Publishing date 2011-12-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1476-511X
    ISSN (online) 1476-511X
    DOI 10.1186/1476-511X-10-227
    Database MEDical Literature Analysis and Retrieval System OnLINE

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