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The Journal of Biological Chemistry Nov 2019Several antidepressant drugs activate tropomyosin-related kinase B (TRKB) receptor, but it remains unclear whether these compounds employ a common mechanism for TRKB...
Several antidepressant drugs activate tropomyosin-related kinase B (TRKB) receptor, but it remains unclear whether these compounds employ a common mechanism for TRKB activation. Here, using MS, we found that a single intraperitoneal injection of fluoxetine disrupts the interaction of several proteins with TRKB in the hippocampus of mice. These proteins included members of adaptor protein complex-2 (AP-2) involved in vesicular endocytosis. The interaction of TRKB with the cargo-docking μ subunit of the AP-2 complex (AP2M) was confirmed to be disrupted by both acute and repeated fluoxetine treatments. Of note, fluoxetine disrupted the coupling between full-length TRKB and AP2M, but not the interaction between AP2M and the TRKB C-terminal region, indicating that the fluoxetine-binding site in TRKB lies outside the TRKB:AP2M interface. ELISA experiments revealed that in addition to fluoxetine, other chemically diverse antidepressants, such as imipramine, rolipram, phenelzine, ketamine, and its metabolite 2,6-hydroxynorketamine, also decreased the interaction between TRKB and AP2M Silencing the expression of AP2M in a TRKB-expressing mouse fibroblast cell line (MG87.TRKB) increased cell-surface expression of TRKB and facilitated its activation by brain-derived neurotrophic factor (BDNF), observed as levels of phosphorylated TRKB. Moreover, animals haploinsufficient for the gene displayed increased levels of active TRKB, along with enhanced cell-surface expression of the receptor in cultured hippocampal neurons. Taken together, our results suggest that disruption of the TRKB:AP2M interaction is a common mechanism underlying TRKB activation by several chemically diverse antidepressants.
Topics: Adaptor Protein Complex 2; Animals; Antidepressive Agents; Cell Line; Endocytosis; Enzyme Activation; Fibroblasts; Hippocampus; Male; Membrane Glycoproteins; Mice; Neurons; Protein-Tyrosine Kinases
PubMed: 31631060
DOI: 10.1074/jbc.RA119.008837 -
ACS Omega Oct 2019A ligand-promoted iridium-catalyzed transfer hydrogenation of terminal alkynes with ethanol and its application has been developed. Highly chemical selectivity control...
A ligand-promoted iridium-catalyzed transfer hydrogenation of terminal alkynes with ethanol and its application has been developed. Highly chemical selectivity control is achieved based on ligand regulation. 1,2-Bis(diphenylphosphino)ethane was found to be critical for the transfer hydrogenation of alkynes. The general applicability of this procedure is highlighted by the synthesis of 30 terminal alkenes with a good yield. In addition, we conducted drug effect studies of phenelzine using zebrafish as the vertebrate model. Phenelzine shows a significant effect on promoting vascular proliferation and inhibiting nerve growth. The results of these studies have an important reference value for promoting drug research in cerebrovascular diseases, epilepsy, mania, and psychosis.
PubMed: 31592175
DOI: 10.1021/acsomega.9b02191 -
International Journal of Molecular... Sep 2019Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care... (Review)
Review
Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care patients. Mortality from acute kidney injury remains high, particularly in critically ill patients, where it can be more than 50%. The primary causes of AKI include ischemia/reperfusion (I/R), sepsis, or nephrotoxicity; however, AKI patients may present with a complicated etiology where many of the aforementioned conditions co-exist. Multiple bio-markers associated with renal damage, as well as metabolic and signal transduction pathways that are involved in the mediation of renal dysfunction have been identified as a result of the examination of models, patient samples, and clinical data of AKI of disparate etiologies. These discoveries have enhanced our ability to diagnose AKIs and to begin to elucidate the mechanisms involved in their pathogenesis. Studies in our laboratory revealed that the expression and activity of spermine/spermidine N-acetyltransferase (SAT1), the rate-limiting enzyme in polyamine back conversion, were enhanced in kidneys of rats after I/R injury. Additional studies revealed that the expression of spermine oxidase (SMOX), another critical enzyme in polyamine catabolism, is also elevated in the kidney and other organs subjected to I/R, septic, toxic, and traumatic injuries. The maladaptive role of polyamine catabolism in the mediation of AKI and other injuries has been clearly demonstrated. This review will examine the biochemical and mechanistic basis of tissue damage brought about by enhanced polyamine degradation and discuss the potential of therapeutic interventions that target polyamine catabolic enzymes or their byproducts for the treatment of AKI.
Topics: Acetyltransferases; Acute Kidney Injury; Animals; Biomarkers; Gene Expression; Gene Expression Regulation, Enzymologic; Humans; Metabolic Networks and Pathways; Oxidoreductases Acting on CH-NH Group Donors; Polyamines; Polyamine Oxidase
PubMed: 31561575
DOI: 10.3390/ijms20194790 -
Frontiers in Immunology 2019Macrophages play an important role in regulating the tumor microenvironment (TME). Here we show that classical (M1) macrophage polarization reduced expression of LSD1,...
Macrophages play an important role in regulating the tumor microenvironment (TME). Here we show that classical (M1) macrophage polarization reduced expression of LSD1, nuclear REST corepressor 1 (CoREST), and the zinc finger protein SNAIL. The LSD1 inhibitor phenelzine targeted both the flavin adenine dinucleotide (FAD) and CoREST binding domains of LSD1, unlike the LSD1 inhibitor GSK2879552, which only targeted the FAD domain. Phenelzine treatment reduced nuclear demethylase activity and increased transcription and expression of M1-like signatures both and in a murine triple-negative breast cancer model. Overall, the LSD1 inhibitors phenelzine and GSK2879552 are useful tools for dissecting the contribution of LSD1 demethylase activity and the nuclear LSD1-CoREST complex to switching macrophage polarization programs. These findings suggest that inhibitors must have dual FAD and CoREST targeting abilities to successfully initiate or prime macrophages toward an anti-tumor M1-like phenotype in triple-negative breast cancer.
Topics: Animals; Cell Differentiation; Co-Repressor Proteins; Cytokines; Disease Models, Animal; Flavin-Adenine Dinucleotide; Histone Demethylases; Humans; Macrophage Activation; Macrophages; Mice; Nerve Tissue Proteins; Phenelzine; RAW 264.7 Cells; RNA, Small Interfering; Snail Family Transcription Factors; Th1 Cells; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 31249575
DOI: 10.3389/fimmu.2019.01351 -
Chemico-biological Interactions May 2019Phenelzine (β-phenylethylhydrazine) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. It possesses a number of important... (Review)
Review
Phenelzine (β-phenylethylhydrazine) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. It possesses a number of important pharmacological properties which may alter the effects of oxidative stress. After conducting a comprehensive literature search, the authors of this review paper aim to provide an overview and discussion of the mechanisms by which phenelzine may attenuate oxidative stress. It inhibits γ-aminobutyric acid (GABA) transaminase, resulting in elevated brain GABA levels, inhibits both MAO and primary amine oxidase and, due to its hydrazine-containing structure, reacts chemically to sequester a number of reactive aldehydes (e.g. acrolein and 4-hydroxy-2-nonenal) proposed to be implicated in oxidative stress in a number of neurodegenerative disorders. Phenelzine is unusual in that it is both an inhibitor of and a substrate for MAO, the latter action producing at least one active metabolite, β-phenylethylidenehydrazine (PEH). This metabolite inhibits GABA transaminase, is a very weak inhibitor of MAO but a strong inhibitor of primary amine oxidase, and sequesters aldehydes. Phenelzine may ameliorate the effects of oxidative stress by reducing formation of reactive metabolites (aldehydes, hydrogen peroxide, ammonia/ammonia derivatives) produced by the interaction of MAO with biogenic amines, by sequestering various other reactive aldehydes and by inhibiting primary amine oxidase. In PC12 cells treated with the neurotoxin MPP, phenelzine has been reported to reduce several adverse effects of MPP. It has also been reported to reduce lipid peroxidative damage induced in plasma and platelet proteins by peroxynitrite. In animal models, phenelzine has a neuroprotective effect in global ischemia and in cortical impact traumatic brain injury. Recent studies reported in the literature on the possible involvement of acrolein in spinal cord injury and multiple sclerosis indicate that phenelzine can attenuate adverse effects of acrolein in these models. Results from studies in our laboratories on effects of phenelzine and PEH on primary amine oxidase (which catalyzes formation of toxic aldehydes and is overexpressed in Alzheimer's disease), on sequestration of the toxic aldehyde acrolein, and on reduction of acrolein-induced toxicity in mouse cortical neurons are also reported.
Topics: Animals; Antidepressive Agents; Free Radical Scavengers; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Oxidative Stress; Phenelzine
PubMed: 30857888
DOI: 10.1016/j.cbi.2019.03.003 -
Drug Metabolism and Disposition: the... Apr 2019Clopidogrel acyl--d-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8 in human liver microsomes (HLMs). However, time-dependent inactivation (TDI) of...
Clopidogrel acyl--d-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8 in human liver microsomes (HLMs). However, time-dependent inactivation (TDI) of CYP2C8 could not be detected in an earlier study in human recombinant CYP2C8 (Supersomes). Here, we investigate whether different enzyme sources exhibit differences in detection of CYP2C8 TDI under identical experimental conditions. Inactivation of CYP2C8 by amiodarone (100 M), clopidogrel acyl--d-glucuronide (100 M), gemfibrozil 1-glucuronide (100 M), and phenelzine (100 M) was investigated in HLMs and three recombinant human CYP2C8 preparations (Supersomes, Bactosomes, and EasyCYP Bactosomes) using amodiaquine -deethylation as the marker reaction. Furthermore, the inactivation kinetics of CYP2C8 by clopidogrel glucuronide (5-250 M) was determined in Supersomes and Bactosomes. Amiodarone caused weak TDI in all enzyme preparations tested, while the extent of inactivation by clopidogrel glucuronide, gemfibrozil glucuronide, and phenelzine varied markedly between preparations, and even different Supersome lots. Both glucuronides caused strong inactivation of CYP2C8 in HLMs, Bactosomes and in one Supersome lot (>50% inhibition), but significant inactivation could not be reliably detected in other Supersome lots or EasyCYP Bactosomes. In Bactosomes, the concentration producing half of k (K) and maximal inactivation rate (k) of clopidogrel glucuronide (14 M and 0.054 minute) were similar to those determined previously in HLMs. Phenelzine caused strong inactivation of CYP2C8 in one Supersome lot (91% inhibition) but not in HLMs or other recombinant CYP2C8 preparations. In conclusion, different enzyme sources and different lots of the same recombinant enzyme preparation are not equally sensitive to detect inactivation of CYP2C8, suggesting that recombinant CYPs should be avoided when identifying mechanism-based inhibitors.
Topics: Amiodarone; Clopidogrel; Cytochrome P-450 CYP2C8; Gemfibrozil; Glucuronides; Humans; Kinetics; Microsomes, Liver; Phenelzine; Sensitivity and Specificity
PubMed: 30709838
DOI: 10.1124/dmd.118.085498 -
The Prostate May 2019Monoamine oxidase A (MAOA) is best known for its role in neuro-transmitter regulation. Monoamine oxidase inhibitors are used to treat atypical depression. MAOA is highly...
BACKGROUND
Monoamine oxidase A (MAOA) is best known for its role in neuro-transmitter regulation. Monoamine oxidase inhibitors are used to treat atypical depression. MAOA is highly expressed in high grade prostate cancer and modulates tumorigenesis and progression in prostate cancer. Here, we investigated the potential role of MAOA inhibitors (MAOAIs) in relation to the androgen receptor (AR) pathway and resistance to antiandrogen treatment in prostate cancer.
METHODS
We examined MAOA expression and the effect of MAOI treatment in relation to AR-targeted treatments using the LNCaP, C4-2B, and 22Rv1 human prostate cancer cell lines. MAOA, AR-full length (AR-FL), AR splice variant 7 (AR-V7), and PSA expression was evaluated in the presence of MAOAIs (clorgyline, phenelzine), androgenic ligand (R1881), and antiandrogen (enzalutamide) treatments. An enzalutamide resistance cell line was generated to test the effect of MAOAI treatment in this model.
RESULTS
We observed that MAOAIs, particularly clorgyline and phenelzine, were effective at decreasing MAOA activity in human prostate cancer cells. MAOAIs significantly decreased growth of LNCaP, C4-2B, and 22Rv1 cells and produced additive growth inhibitory effects when combined with enzalutamide. Clorgyline decreased expression of AR-FL and AR-V7 in 22Rv1 cells and was effective at decreasing growth of an enzalutamide-resistant C4-2B cell line with increased AR-V7 expression.
CONCLUSIONS
MAOAIs decrease growth and proliferation of androgen-sensitive and castration-resistant prostate cancer cells. Clorgyline, in particular, decreases expression of AR-FL and AR-V7 expression and decreases growth of an enzalutamide-resistant cell line. These findings provide preclinical validation of MAOA inhibitors either alone or in combination with antiandrogens for therapeutic intent in patients with advanced forms of prostate cancer.
Topics: Androgen Antagonists; Benzamides; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Clorgyline; Drug Resistance, Neoplasm; Humans; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neoplasm Grading; Nitriles; Phenelzine; Phenylthiohydantoin; Prostate; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 30693539
DOI: 10.1002/pros.23774 -
Medicines (Basel, Switzerland) Jan 2019Two classes of amine oxidases are found in mammals: those with a flavin adenine dinucleotide as a cofactor, such as monoamine oxidases (MAO) and lysine-specific... (Review)
Review
Two classes of amine oxidases are found in mammals: those with a flavin adenine dinucleotide as a cofactor, such as monoamine oxidases (MAO) and lysine-specific demethylases (LSD), and those with copper as a cofactor, including copper-containing amine oxidases (AOC) and lysyl oxidases (LOX). All are expressed in adipose tissue, including a semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) strongly present on the adipocyte surface. Previously, irreversible MAO inhibitors have been reported to limit food intake and/or fat extension in rodents; however, their use for the treatment of depressed patients has not revealed a clear anti-obesity action. Semicarbazide and other molecules inhibiting SSAO/VAP-1 also reduce adiposity in obese rodents. Recently, a LOX inhibitor and a subtype-selective MAO inhibitor have been shown to limit fattening in high-fat diet-fed rats. Phenelzine, which inhibits MAO and AOC, limits adipogenesis in cultured preadipocytes and impairs lipogenesis in mature adipocytes. When tested in rats or mice, phenelzine reduces food intake and/or fat accumulation without cardiac adverse effects. Novel amine oxidase inhibitors have been recently characterized in a quest for promising anti-inflammatory or anti-cancer approaches; however, their capacity to mitigate obesity has not been studied so far. The present review of the diverse effects of amine oxidase inhibitors impairing adipocyte differentiation or limiting excessive fat accumulation indicates that further studies are needed to reveal their potential anti-obesity properties.
PubMed: 30650583
DOI: 10.3390/medicines6010009 -
Journal of Neurochemistry Mar 2019Inflammatory insult to the central nervous system (CNS) can lead to development of depression, and subsequently depression is the most frequent psychiatric comorbidity...
Inflammatory insult to the central nervous system (CNS) can lead to development of depression, and subsequently depression is the most frequent psychiatric comorbidity following ischemic stroke, often limiting recovery and rehabilitation in patients. The initiators of inflammatory pathways in the CNS are microglia activated in response to acute ischemic stress, and anti-depressants have been shown to have anti-inflammatory effects in the CNS, promoting neuronal survival following ischemic insult. We have previously shown that the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and citalopram promote neuronal survival after oxygen-glucose deprivation, an in vitro model of ischemia, by attenuating the release of glutamate and D-serine from activated microglia. Interestingly, we found that fluoxetine-treated microglial cultures contained fewer numbers of cells compared to other groups and hypothesized that fluoxetine and citalopram attenuated the release of glutamate and D-serine by promoting the apoptosis of microglia. The present study aimed to test and compare antidepressants from three distinct classes (tricyclics, monoamine oxidase inhibitors, and SSRIs) on microglial apoptosis. Primary microglia were treated with 1 μg/mL lipopolysaccharide and/or 10 μM antidepressants, and various apoptotic markers were assayed. Fluoxetine and its metabolite norfluoxetine decreased protein levels in cell lysates, decreased cell viability of microglia, and increased the expression of the apoptotic marker cleaved-caspase 3 in microglia. Live/dead nuclear staining also showed that fluoxetine- or norfluoxetine-treated cultures contained greater numbers of dying microglial cells compared to vehicle-treated cultures. Cultures treated with citalopram, phenelzine, or imipramine showed no evidence of inducing microglial apoptosis. Our results demonstrate that fluoxetine and norfluoxetine induce the apoptotic death of microglia, which may serve as a mechanism to attenuate the release of glutamate and D-serine from activated microglia. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
Topics: Animals; Antidepressive Agents, Second-Generation; Apoptosis; Cell Survival; Fluoxetine; Microglia; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors
PubMed: 30613984
DOI: 10.1111/jnc.14661 -
Journal of Neurotrauma Apr 2019Traumatic brain injury (TBI) results in the production of peroxynitrite (PN), leading to oxidative damage of lipids and protein. PN-mediated lipid peroxidation (LP)...
Traumatic brain injury (TBI) results in the production of peroxynitrite (PN), leading to oxidative damage of lipids and protein. PN-mediated lipid peroxidation (LP) results in production of reactive aldehydes 4-hydroxynonenal (4-HNE) and acrolein. The goal of these studies was to explore the hypothesis that interrupting secondary oxidative damage following a TBI via phenelzine (PZ), analdehyde scavenger, would protect against LP-mediated mitochondrial and neuronal damage. Male Sprague-Dawley rats received a severe (2.2 mm) controlled cortical impact (CCI)-TBI. PZ was administered subcutaneously (s.c.) at 15 min (10 mg/kg) and 12 h (5 mg/kg) post-injury and for the therapeutic window/delay study, PZ was administered at 1 h (10 mg/kg) and 24 h (5 mg/kg). Mitochondrial and cellular protein samples were obtained at 24 and 72 h post-injury (hpi). Administration of PZ significantly improved mitochondrial respiration at 24 and 72 h compared with vehicle-treated animals. These results demonstrate that PZ administration preserves mitochondrial bioenergetics at 24 h and that this protection is maintained out to 72 hpi. Additionally, delaying the administration still elicited significant protective effects. PZ administration also improved mitochondrial Ca buffering (CB) capacity and mitochondrial membrane potential parameters compared with vehicle-treated animals at 24 h. Although PZ treatment attenuated aldehyde accumulation post-injury, the effects were insignificant. The amount of α-spectrin breakdown in cortical tissue was reduced by PZ administration at 24 h, but not at 72 hpi compared with vehicle-treated animals. In conclusion, these results indicate that acute PZ treatment successfully attenuates LP-mediated oxidative damage eliciting multiple neuroprotective effects following TBI.
Topics: Animals; Brain Injuries, Traumatic; Calcium Signaling; Cytoskeleton; Male; Mitochondria; Neuroprotective Agents; Oxidative Stress; Phenelzine; Rats; Rats, Sprague-Dawley
PubMed: 30358485
DOI: 10.1089/neu.2018.5946