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Molekuliarnaia Biologiia 2020Striatal-enriched protein tyrosine phosphatase (STEP), which was initially identified in the striatum, is encoded by the Ptpn5 gene and is expressed in neurons of...
Striatal-enriched protein tyrosine phosphatase (STEP), which was initially identified in the striatum, is encoded by the Ptpn5 gene and is expressed in neurons of various structures of the brain. STEP is involved in regulating neuroplasticity, and its expression abnormalities are associated with human neurodegenerative disorders. The STEP inhibitor 8-trifluoromethyl-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) has been shown to affect the serotoninergic system of the brain. However, the influence of the serotoninergic system on the STEP regulation has not been studied yet. The aim of the study was to investigate how pharmacologically induced changes in the brain serotonin (5-HT) level affect Ptpn5 expression and STEP activity in adult male C57BL/6J mice. To modulate the 5-HT level in the brain, the 5-HT synthesis inhibitor p-chlorophenylalanine or 5-HT degradation inhibitor pargyline was administered intraperitoneally for three successive days. Changes in 5-HT concentration in the brain were assayed using high-performance liquid chromatography. The STEP activity was determined spectrophotometrically in the supernatant by the rate of p-nitrophenyl phosphate dephosphorylation in the absence and presence of the selective STEP inhibitor TC-2153. The Ptpn5 mRNA level was determined using quantitative RT-PCR. The Ptpn5 expression level in the striatum was three times higher than in the cortex and hippocampus. Both increases and decreases in brain 5-HT were for the first time associated with a decrease in Ptpn5 mRNA in the striatum. STEP activity in the striatum and cortex was significantly higher than in the hippocampus. However, p-chlorophenylalanine and pargyline did not affect the STEP activity in the brain structures tested. Thus, a new method was proposed to study the STEP activity in the brain and p-chlorophenylalanine and pargyline were shown to decrease Ptpn5 expression in the striatum in mice.
Topics: Alanine; Animals; Chloramines; Corpus Striatum; Male; Mice; Mice, Inbred C57BL; Neurons; Pargyline; Protein Tyrosine Phosphatases, Non-Receptor; Serotonin
PubMed: 32392202
DOI: 10.31857/S0026898420020093 -
Pharmaceuticals (Basel, Switzerland) Mar 2020Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical...
Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control.
Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.
PubMed: 32151075
DOI: 10.3390/ph13030041 -
Current Opinion in Chemical Biology Apr 2020One of the challenges of modern inorganic chemistry is translating the potential of metal catalysts to living systems to achieve controlled non-natural transformations.... (Review)
Review
One of the challenges of modern inorganic chemistry is translating the potential of metal catalysts to living systems to achieve controlled non-natural transformations. This field poses numerous issues associated with the metal compounds biocompatibility, stability, and reactivity in complex aqueous environment. Moreover, it should be noted that although referring to 'metal catalysis', turnover has not yet been fully demonstrated in most of the examples within living systems. Nevertheless, transition metal catalysts offer an opportunity of modulating bioprocesses through reactions that are complementary to enzymes. In this context, gold complexes, both coordination and organometallic, have emerged as promising tools for bio-orthogonal transformations, endowed with excellent reactivity and selectivity, compatibility within aqueous reaction medium, fast kinetics of ligand exchange reactions, and mild reaction conditions. Thus, a number of examples of gold-templated reactions in a biologically relevant context will be presented and discussed here in relation to their potential applications in biological and medicinal chemistry.
Topics: Alkynes; Animals; Catalysis; Coordination Complexes; Cycloaddition Reaction; Fluorescent Dyes; Gold; Humans; Hydrogenation; Kinetics; Ligands; Optical Imaging; Oxidation-Reduction; Pargyline; Propylamines; Rhodamines; Substrate Specificity
PubMed: 32086166
DOI: 10.1016/j.cbpa.2019.12.007 -
Chemical Communications (Cambridge,... Mar 2020We have developed a propargylamine-selective dual fluorescence turn-on system, using ylidenemalononitrile enamines, for post-synthetic DNA labeling, allowing the direct...
We have developed a propargylamine-selective dual fluorescence turn-on system, using ylidenemalononitrile enamines, for post-synthetic DNA labeling, allowing the direct monitoring of DNA using dual emission in living cells.
Topics: Cell Line, Tumor; DNA; Fluorescence; Fluorescent Dyes; Humans; Molecular Structure; Optical Imaging; Pargyline; Propylamines; Staining and Labeling
PubMed: 32068200
DOI: 10.1039/d0cc00255k -
Neurotoxicity Research Mar 2020Serotoninergic nerves are known to modulate sensitization of dopamine receptors (DA-R) in a rodent model of Parkinson's disease (PD). However, serotoninergic nerves are...
Serotoninergic nerves are known to modulate sensitization of dopamine receptors (DA-R) in a rodent model of Parkinson's disease (PD). However, serotoninergic nerves are not known to have a prominent role on DA exocytosis in intact rats. The current study was undertaken to explore the possible influence of serotoninergic nerves on DA exocytosis in Parkinsonian rats. Rat pups were treated at 3 days after birth with the neurotoxin 6-hydroxydopamine (6-OHDA; 134 μg icv, half into each lateral ventricle; desipramine, 1 h pretreatment), in order to produce marked long-lasting destruction of neostriatal dopaminergic innervation, as evidenced by the 90-95% depletion of DA (p < 0.001) [HPLC/ED] into adulthood. Controls received vehicle/desipramine in place of 6-OHDA. Other groups received the serotoninergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 25 μg base, icv, half in each lateral ventricle; desipramine, 1 h; 75 mg/kg pargyline HCl, 30 min) at 3 days post-birth; or both 6-OHDA+5,7-DHT treatments. In adulthood, an in vivo microdialysis study was undertaken to ascertain that p-chloroamphetamine (PCA, 1 mM in the microdialysate)-evoked DA release in the neostriatum was reduced approximately 50% in the 6-OHDA group, while PCA-evoked DA release in the 6-OHDA+5,7-DHT group was substantially increased, to a level equivalent to that of the vehicle control. The baseline neostriatal microdialysate level of 3,4-dihydroxyphenylacetic acid (DOPAC) was also higher in the 6-OHDA+5,7-DHT group vs 6-OHDA group; also, during the 2nd hour of PCA infusion. PCA-enhanced DA exocytosis occurred in the absence of changes in hydroxyl radical (HO·) in the microdialysate (i.e., assay of 2,3- and 2,5-dihydroxybenzoic acid, 2,3-DHBA; 2,5-DHBA). The overall findings demonstrate that an adulthood serotoninergic nerve lesion enhanced PCA-evoked DA exocytosis in a rodent model of severe PD, while susceptibility to oxidative stress was unchanged. The implication is that serotoninergic nerves may normally suppress the release of DA and/or act as an uptake site and storage sink for accumulated DA in parkinsonian-like neostriatum. Potentially, serotoninergic agonists or antagonists, targeting subtype-selective serotonin receptors, may be viable therapeutic adjuncts in PD.
Topics: 3,4-Dihydroxyphenylacetic Acid; 5,7-Dihydroxytryptamine; Animals; Animals, Newborn; Dopamine; Exocytosis; Female; Male; Microdialysis; Neostriatum; Oxidopamine; Parkinson Disease; Rats; Serotonin; p-Chloroamphetamine
PubMed: 31939043
DOI: 10.1007/s12640-019-00145-4 -
Physiological Research Dec 2019Increased activity of the sympathetic nervous system (SNS) has been proposed as a risk factor for increased cardiovascular mortality in patients with chronic kidney...
Increased activity of the sympathetic nervous system (SNS) has been proposed as a risk factor for increased cardiovascular mortality in patients with chronic kidney disease (CKD). Information on the activity of cardiac sympathetic innervation is non-homogeneous and incomplete. The aim of our study was to evaluate the tonic effect of SNS on heart rate, norepinephrine turnover and direct and indirect effects of norepinephrine in left ventricles of subtotally nephrectomized rats (SNX) in comparison with sham-operated animals (SHAM). Renal failure was verified by measuring serum creatinine and urea levels. SNX rats developed increased heart rates and blood pressure (BP). The increase in heart rate was not caused by sympathetic overactivity as the negative chronotropic effect of metipranolol did not differ between the SNX and SHAM animals. The positive inotropic effects of norepinephrine and tyramine on papillary muscle were not significantly different. Norepinephrine turnover was measured after the administration of tyrosine hydroxylase inhibitor, pargyline, tyramine, desipramine, and KCl induced depolarization. The absolute amount of released norepinephrine was comparable in both groups despite a significantly decreased norepinephrine concentration in the cardiac tissue of the SNX rats. We conclude that CKD associated with renal denervation in rats led to adaptive changes characterized by an increased reuptake and intracellular norepinephrine turnover which maintained normal reactivity of the heart to sympathetic stimulation.
Topics: Animals; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Disease Models, Animal; Heart Rate; Heart Ventricles; Kidney; Male; Nephrectomy; Neuropeptide Y; Norepinephrine; Rats, Wistar; Renal Insufficiency, Chronic; Sympathetic Nervous System
PubMed: 31928041
DOI: 10.33549/physiolres.934354 -
The Journal of Organic Chemistry Feb 2020Decarboxylative A-coupling of -hydroxybenzaldehydes, secondary amines, and alkynoic acids is performed under catalyst and solvent-free conditions. The developed...
Decarboxylative A-coupling of -hydroxybenzaldehydes, secondary amines, and alkynoic acids is performed under catalyst and solvent-free conditions. The developed methodology provided a waste-free method for the synthesis of hydroxylated propargylamines which are versatile precursors for various bioactive heterocyclic scaffolds. The experimental and density functional theory studies revealed that the in situ-formed -quinonoid intermediate (formed from -hydroxybenzaldehyde and amine) undergoes a concerted Eschweiler-Clarke type decarboxylation with alkynoic acids. The synthesized compounds were evaluated for MAO-A, MAO-B, and AChE inhibitory activities as potential drug candidates for the treatment of various neurological disorders. Compound was found to be the most potent and selective MAO-B (high selectivity over MAO-A) and AChE inhibitor in the series with IC values of 4.27 ± 0.07 and 0.79 ± 0.03 μM, respectively.
Topics: Monoamine Oxidase Inhibitors; Pargyline; Propylamines; Solvents; Structure-Activity Relationship
PubMed: 31877044
DOI: 10.1021/acs.joc.9b02806 -
Bioorganic & Medicinal Chemistry Letters Feb 2020Current options for the treatment of Alzheimeŕs disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor... (Review)
Review
Current options for the treatment of Alzheimeŕs disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aβ expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Cholinesterases; Humans; Ligands; Monoamine Oxidase; Neuroprotective Agents; Oxidative Stress; Pargyline; Propylamines
PubMed: 31864798
DOI: 10.1016/j.bmcl.2019.126880 -
Organic Letters Dec 2019A diastereo- and enantioselective propargylic substitution reaction between propargylic carbonates and α-substituted nitroacetates catalyzed by a Cu-pybox complex is...
A diastereo- and enantioselective propargylic substitution reaction between propargylic carbonates and α-substituted nitroacetates catalyzed by a Cu-pybox complex is described. This method allows the preparation of a series of non-proteinogenic quaternary α-amino acid precursors featuring two contiguous stereogenic centers and a terminal alkyne moiety in high yields with good to excellent diastereo- and enantioselectivities in most cases. The propargylated adducts were elaborated into a diverse set of quaternary α-amino acid derivatives.
Topics: Amino Acids; Catalysis; Copper; Molecular Structure; Pargyline; Stereoisomerism
PubMed: 31820655
DOI: 10.1021/acs.orglett.9b03894 -
Nucleic Acids Research Jan 2020One of the major hurdles in RNAi research has been the development of safe and effective delivery systems for siRNAs. Although various chemical modifications have been...
One of the major hurdles in RNAi research has been the development of safe and effective delivery systems for siRNAs. Although various chemical modifications have been proposed to improve their pharmacokinetic behaviour, their delivery to target cells and tissues presents many challenges. In this work, we implemented a receptor-targeting strategy to selectively deliver siRNAs to cancer cells using folic acid as a ligand. Folic acid is capable of binding to cell-surface folate receptors with high affinity. These receptors have become important molecular targets for cancer research as they are overexpressed in numerous cancers despite being expressed at low levels in normal tissues. Employing a post-column copper-catalyzed alkyne-azide cycloaddition (CuAAC), we report the synthesis of siRNAs bearing folic acid modifications at different positions within the sense strand. In the absence of a transfection carrier, these siRNAs were selectively taken up by cancer cells expressing folate receptors. We show that centrally modified folic acid-siRNAs display enhanced gene-silencing activity against an exogenous gene target (∼80% knockdown after 0.75 μM treatment) and low cytotoxicity. In addition, these siRNAs achieved potent dose-dependent knockdown of endogenous Bcl-2, an important anti-apoptotic gene.
Topics: Carbonates; Cell Survival; Folate Receptors, GPI-Anchored; Folic Acid; Gene Silencing; Gene Targeting; Genes, Reporter; HT29 Cells; HeLa Cells; Humans; Luciferases; Pargyline; Potassium; Protein Binding; Proto-Oncogene Proteins c-bcl-2; RNA, Small Interfering; Transfection
PubMed: 31777918
DOI: 10.1093/nar/gkz1115