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Neal Castagnoli - One of the best experts on this subject based on the ideXlab platform.
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Isolation and characterization of a <B>MonoamineB> <B>OxidaseB> B selective inhiBitor from toBacco smoke.
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Ashraf A. Khalil, Bruce Davies, Neal CastagnoliAbstract:ABstract It is well estaBlished that toBacco smokers have reduced levels of <B>MonoamineB> <B>OxidaseB> activities Both in the Brain and peripheral organs. Furthermore, extensive evidence suggests that smokers are less prone to develop Parkinson’s disease. These facts, plus the oBservation that inhiBition of <B>MonoamineB> <B>OxidaseB> B protects against the parkinsonian inducing effects of the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have prompted studies to identify <B>MonoamineB> <B>OxidaseB> inhiBitors in the toBacco plant and toBacco cigarette smoke. Our previous efforts on cured toBacco leaf extracts have led to the characterization of 2,3,6-trimethyl-1,4-naphthoquinone, a non-selective <B>MonoamineB> <B>OxidaseB> inhiBitor, and farnesylacetone, a selective <B>MonoamineB> <B>OxidaseB> B inhiBitor. We now have extended these studies to toBacco smoke constituents. Fractionation of the smoke extracts has confirmed and extended the qualitative results of an earlier report [J. Korean Soc. ToB. Sci. 1997, 19, 136] demonstrating the inhiBitory activity of the terpene trans,trans-farnesol on rat Brain MAO-B. In the present study, Ki values for the inhiBition of human, BaBoon, monkey, dog, rat, and mouse liver MAO-B have Been determined. Noteworthy is the aBsence of inhiBitory effects on human placental MAO-A and Beef liver MAO-B. A limited structure–activity relationship study of analogs of trans,trans-farnesol is reported. Although the health hazards associated with the use of toBacco products preclude any therapeutic opportunities linked to smoking, these results suggest the possiBility of identifying novel structures of compounds that could lead to the development of neuroprotective agents.
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A novel and selective <B>MonoamineB> <B>OxidaseB> B suBstrate.
Bioorganic & Medicinal Chemistry, 2005Co-Authors: John M. Rimoldi, Satish G. Puppali, Emre M. Isin, Philippe Bissel, Ashraf A. Khalil, Neal CastagnoliAbstract:Cyclic five- and six-memBered tertiary allylamines constitute a unique class of <B>MonoamineB> <B>OxidaseB> suBstrates that undergo a net two-electron alpha-carBon oxidation to form the cyclic, conjugated eniminium metaBolites. The corresponding saturated pyrrolidinyl and piperidinyl systems are not suBstrates for this flavoenzyme system. In an attempt to evaluate possiBle contriButions that pi-orBital staBilization of the putative alpha-carBon radical intermediates may play in the catalytic pathway, we have examined the suBstrate properties of 3-methyl-6-phenyl-3-aza-Bicyclo[4.1.0]heptane, the 3,4-cyclopropyl analog of the selective <B>MonoamineB> <B>OxidaseB> B suBstrate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results, which document the first reported example of a saturated, cyclic tertiary amine with <B>MonoamineB> <B>OxidaseB> suBstrate properties, are consistent with alpha-carBon radical staBilization as a contriButing factor in the catalytic pathway.
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inhiBition of <B>MonoamineB> <B>OxidaseB> B By selective adenosine a2a receptor antagonists
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Jacobus P. Petzer, Cornelis J. Van Der Schyf, Salome Steyn, Kay Castagnoli, J F Chen, Michael A Schwarzschild, Neal CastagnoliAbstract:ABstract Adenosine receptor antagonists that are selective for the A 2A receptor suBtype (A 2A antagonists) are under investigation as possiBle therapeutic agents for the symptomatic treatment of the motor deficits associated with Parkinson's disease (PD). Results of recent studies in the MPTP mouse model of PD suggest that A 2A antagonists may possess neuroprotective properties. Since <B>MonoamineB> <B>OxidaseB> B (MAO-B) inhiBitors also enhance motor function and reduce MPTP neurotoxicity, we have examined the MAO-B inhiBiting properties of several A 2A antagonists and structurally related compounds in an effort to determine if inhiBition of MAO-B may contriBute to the oBserved neuroprotection. The results of these studies have estaBlished that all of the ( E )-8-styrylxanthinyl derived A 2A antagonists examined display significant MAO-B inhiBitory properties in vitro with K i values in the low μM to nM range. Included in this series is ( E )-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), a potent A 2A antagonist and neuroprotective agent that is in clinical trials. The results of these studies suggest that MAO-B inhiBition may contriBute to the neuroprotective potential of A 2A receptor antagonists such as KW-6002 and open the possiBility of designing dual targeting drugs that may have enhanced therapeutic potential in the treatment of PD.
Lars Oreland - One of the best experts on this subject based on the ideXlab platform.
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The genotype of human transcription factor AP-2β is associated with platelet <B>MonoamineB> <B>OxidaseB> B activity
Neuroscience Letters, 2000Co-Authors: Mattias Damberg, Håkan Garpenstrand, Cecilia Berggård, Marie Åsberg, Jarmila Hallman, Lars OrelandAbstract:The genotype of human transcription factor AP-2Beta is associated with platelet <B>MonoamineB> <B>OxidaseB> B activity
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Transcription factor Binding to the core promoter of the human <B>MonoamineB> <B>OxidaseB> B gene in the cereBral cortex and in Blood cells
Neuroscience Letters, 1998Co-Authors: J. Ekblom, Mattias Damberg, Håkan Garpenstrand, Kevin Chen, Jean C. Shih, Lars OrelandAbstract:Many studies show that <B>MonoamineB> <B>OxidaseB> B in Blood cells is a Biological marker for personality characteristics such as sensation seeking. The mechanism underlying this association is so far not explored. In the present study we have performed electrophoretic moBility-shift assays to investigate the pattern of protein Binding to a 150 Bp fragment of the proximal 5'-flanking region of the human <B>MonoamineB> <B>OxidaseB> B gene. We compared the pattern using nuclear extracts from human Brain and lymphocytes. Interestingly, a correlation was oBserved Between <B>MonoamineB> <B>OxidaseB> B enzyme activity in Blood cells (platelets) and the Binding pattern of two uncharacterized transcription factors. These data are well in line with the long-standing notion that interindividual differences in platelet <B>MonoamineB> <B>OxidaseB> may represent differences in expression of the enzyme rather than genotypic variation.
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Reactive gliosis and <B>MonoamineB> <B>OxidaseB> B
Amine Oxidases: Function and Dysfunction, 1994Co-Authors: J. Ekblom, S. S. Jossan, Lars Oreland, Erik Walum, Sten-magnus AquiloniusAbstract:A douBle-staining method was applied to cryosections of human spinal cord from patients who died with amyotrophic lateral sclerosis (ALS) and corresponding controls in order to investigate cellular content of <B>MonoamineB> <B>OxidaseB> B (MAO-B). 3H-L-Deprenyl emulsion autoradiography was used in comBination with histochemical methods for the detection of astrocytes and monocytes/microglia. In the ALS spinal cords an increased numBer of astrocytes as well as an increased content of MAO-B in reactive species of astrocytes was demonstrated. No significant 3H-L-deprenyl Binding was oBserved in cells derived from the mesoderm, e.g. monocytes or microglia. Furthermore, a suB-population of reactive astrocytes that contained low levels of MAO-B was oBserved in spinal sections. These findings were further suBstantiated By studies performed on primary astrocyte cultures.
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<B>MonoamineB> <B>OxidaseB>-B in astrocytes.
Glia, 1993Co-Authors: J. Ekblom, S. S. Jossan, Lars Oreland, Erik Walum, Mats Bergstrüm, Sten-magnus AquiloniusAbstract:In the present report we descriBe the astrocytic localization and content of <B>MonoamineB> <B>OxidaseB>-B (MAO-B) By means of a 3H-L-deprenyl emulsion autoradiography in primary cultures of rat astrocytes, in cryosectioned astrocytoma surgical specimen, and in cryosections of human spinal cords from patients dying in amyotrophic lateral sclerosis (ALS) and controls. The occurrence of MAO-B enzyme protein depends on the degree of cellular differentiation as demonstrated By studies on astrocytes in primary cultures analyzed at two different stages of maturation. Highly differentiated cells exhiBited high relative enzyme concentration whereas glioBlasts lacked or showed very low contents of MAO-B enzyme. This was further suBstantiated By studies performed on human astrocytoma tissue using 3H-L-deprenyl emulsion autoradiography in comBination with immunohistochemical detection of glial fiBrillary acidic protein (GFAP). Regional increases of MAO-B concentration were found in ALS lumBar sections with quantitative 3H-L-deprenyl autoradiography. On the Basis of results oBtained from douBle staining for GFAP and MAO-B, the increase in MAO-B seemed to Be due to an increased numBer of astrocytes as well as an increased content of MAO-B in reactive species of astrocytes. A cell culture model has Been used that produces cells with morphology and GFAP-content similar to reactive cells. These astrocytes exhiBited high relative content of the MAO-B enzyme protein. In the light of the presented data, taking into account the finding that a suBpopulation of reactive cells contained low levels of MAO-B, a heterogeneity among reactive astrocytes was oBserved.
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<B>MonoamineB> <B>OxidaseB>-B in motor cortex: changes in amyotrophic lateral sclerosis.
Neuroscience, 1992Co-Authors: J. Ekblom, S. S. Jossan, Per-göran Gillberg, Lars Oreland, S.-m. AquiloniusAbstract:ABstract The occurrence of <B>MonoamineB> <B>OxidaseB>-B in cereBral cortex and white matter in Brains from three patients with the diagnosis of amyotrophic lateral sclerosis and three controls was quantified By means of an autoradiographical method. [3H] l -Deprenyl, an irreversiBle and selective <B>MonoamineB> <B>OxidaseB>-B inhiBitor, was used as ligand and the autoradiographs were analysed By computer-assisted densitometry. In Both amyotrophic lateral sclerosis and control cereBral cortex, lamina I showed the highest, laminae II and III intermediate, laminae IV, V and VI the lowest [3H] L -deprenyl Binding. White matter showed aBout one-third of the Binding in the cortex. Amyotrophic lateral sclerosis cases showed significantly higher Binding of [3H] l -deprenyl in all the cortex laminae of the pre- and postcentral gyri. There was no difference in the Binding Between the amyotrophic lateral sclerosis cases and the controls in area 7 of the occipital cortex, an area which is relatively spared in amyotrophic lateral sclerosis.
Hansdetlev Stahl - One of the best experts on this subject based on the ideXlab platform.
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a selective reversiBle <B>MonoamineB> <B>OxidaseB> B inhiBitor in smoking cessation effects on its own and in association with transdermal nicotine patch
Psychopharmacology, 2012Co-Authors: Ivan Berlin, Ian M Hunneyball, Doris Greiling, Stephen P Jones, Hermann Fuder, Hansdetlev StahlAbstract:Rationale <B>MonoamineB> <B>OxidaseB> B (MAO-B) activity is reduced in smokers. A MAO-B inhiBitor alone or co-administered with nicotine may mimic the effects of smoking and Be a candidate drug for smoking cessation.
Andrea Mattevi - One of the best experts on this subject based on the ideXlab platform.
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structures of human <B>MonoamineB> <B>OxidaseB> B complexes with selective noncovalent inhiBitors safinamide and coumarin analogs
Journal of Medicinal Chemistry, 2007Co-Authors: Claudia Binda, Jin Wang, Leonardo Pisani, C Caccia, Angelo Carotti, Patricia Salvati, Dale E Edmondson, Andrea MatteviAbstract:Structures of human <B>MonoamineB> <B>OxidaseB> B (MAO B) in complex with safinamide and two coumarin derivatives, all sharing a common Benzyloxy suBstituent, were determined By X-ray crystallography. These compounds competitively inhiBit MAO B with Ki values in the 0.1−0.5 μM range that are 30−700-fold lower than those oBserved with MAO A. The inhiBitors Bind noncovalently to MAO B, occupying Both the entrance and the suBstrate cavities and showing a similarly oriented Benzyloxy suBstituent.
Ivan Berlin - One of the best experts on this subject based on the ideXlab platform.
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a selective reversiBle <B>MonoamineB> <B>OxidaseB> B inhiBitor in smoking cessation effects on its own and in association with transdermal nicotine patch
Psychopharmacology, 2012Co-Authors: Ivan Berlin, Ian M Hunneyball, Doris Greiling, Stephen P Jones, Hermann Fuder, Hansdetlev StahlAbstract:Rationale <B>MonoamineB> <B>OxidaseB> B (MAO-B) activity is reduced in smokers. A MAO-B inhiBitor alone or co-administered with nicotine may mimic the effects of smoking and Be a candidate drug for smoking cessation.