The Experts below are selected from a list of 222 Experts worldwide ranked by ideXlab platform
Motohiko Takemura - One of the best experts on this subject based on the ideXlab platform.
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low dose pretreatment with Clorgyline decreases the levels of 3 methoxy 4 hydroxyphenylglycol in the striatum and nucleus accumbens and attenuates methamphetamine induced conditioned place preference in rats
Neuroscience, 2010Co-Authors: Nobue Kitanaka, Kaname Watabe, Jun-ichi Kitanaka, Motohiko TakemuraAbstract:The effect of treating rats with Clorgyline, an irreversible monoamine oxidase-A (MAO-A) inhibitor, on methamphetamine (METH)-induced conditioned place preference (CPP) was investigated. Administering rats with METH (1.0 mg/kg i.p.) every other day during two conditioning sessions (i.e., saline/METH conditioning with no Clorgyline pretreatment) induced a significant CPP compared with saline/saline conditioning. Pretreatment of the rats with Clorgyline at a dose of 0.1 mg/kg (i.p.), but not 1.0 or 10 mg/kg, attenuated the METH-induced CPP. Neurochemical analysis using high-performance liquid chromatography revealed that the tissue levels of monoamines and their metabolites were not significantly affected by treatment with 0.1 mg/kg Clorgyline except for the levels of 3-methoxy4-hydroxyphenylglycol (MHPG) in the striatum and nucleus accumbens (NAc). Clorgyline at doses of 1.0 or 10 mg/kg significantly affected the tissue levels of 3,4-dihydroxyphenylacetic acid, norepinephrine (NE), MHPG, and serotonin in the cerebral cortex and those of all monoamines and metabolites examined in the striatum and NAc. A significant decrease in the MHPG/NE ratio in the striatum and NAc was apparent in the rats pretreated with 0.1 mg/kg Clorgyline. Overall, the present study demonstrated that low-dose Clorgyline attenuated METH-induced CPP in rats.
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modification of morphine induced hyperlocomotion and antinociception in mice by Clorgyline a monoamine oxidase a inhibitor
Neurochemical Research, 2006Co-Authors: Nobue Kitanaka, Jun-ichi Kitanaka, Motohiko TakemuraAbstract:We evaluated the effects of pretreatment with Clorgyline, an irreversible monoamine oxidase (MAO)-A inhibitor, on morphine-induced hyperlocomotion and antinociception. A single administration of morphine (30 mg/kg, i.p.) to male ICR mice induced a hyperlocomotion. ANOVA analysis revealed the statistical significance of the morphine effect on horizontal locomotion and of the Clorgyline pretreatment × morphine interaction effect, but not of the effect of Clorgyline pretreatment. The initial (5 min after challenge) phase of morphine actions vs. saline challenge appeared as if morphine had a strong inhibitory effect on locomotor activity in combination with different doses of Clorgyline. The mice administered with morphine in combination of Clorgyline (1 and 10 mg/kg) did not show any stereotypic behaviors. Clorgyline at a dose of 0.1 mg/kg but not other doses tested significantly potentiated morphine-induced antinociception evaluated by tail flick but not hot plate test. During the measurements of locomotor activity and antinociception, Clorgyline at doses of 1 and 10 mg/kg significantly inhibited monoamine metabolism through MAO. These results suggest that Clorgyline showed an inhibitory effect on morphine-induced hyperlocomotion, but not antinociception, through MAO inhibition. There is not a possibility that Clorgyline pretreatment enhanced morphine action on motor activity, resulting in the abnormal behavior from hyperlocomotion to stereotypic movements.
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Methamphetamine Reward in Mice as Assessed by Conditioned Place Preference Test with Supermex® Sensors: Effect of Subchronic Clorgyline Pretreatment
Neurochemical Research, 2006Co-Authors: Nobue Kitanaka, Tomohiro Tatsuta, Kaname Watabe, Jun-ichi Kitanaka, Yoshio Morita, Motohiko TakemuraAbstract:Recent studies in our laboratory have shown that methamphetamine (METH)-induced hyperlocomotion and behavioral sensitization in mice were inhibited by Clorgyline, an irreversible monoamine oxidase inhibitor. In this study, the effect of Clorgyline pretreatment on METH-induced rewarding effect was assessed by a conditioned place preference (CPP) test, using an apparatus developed with Supermex® sensors (infrared pyroelectric sensors). Although intact male ICR mice showed significant CPP for METH (0.5 mg/kg, i.p.), pretreatment with subchronic Clorgyline (0.1 and 10 mg/kg, s.c.) did not affect the magnitude of CPP. At a dose of 1 mg/kg, pretreatment of the mice with Clorgyline showed a similar CPP index in both saline/saline and METH/saline pairing groups. During the conditioning session, the mice did not express behavioral sensitization to METH. Pretreatment with Clorgyline (0.1, 1, and 10 mg/kg) decreased striatal apparent monoamine turnover in a dose-dependent manner. These results indicated that Clorgyline pretreatment (0.1 and 10 mg/kg) did not influence the METH-induced rewarding effect in mice, although pretreatment of the mice with Clorgyline at a dose of 1 mg/kg appeared to influence the CPP for METH.
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repeated Clorgyline treatment inhibits methamphetamine induced behavioral sensitization in mice
Neurochemical Research, 2005Co-Authors: Nobue Kitanaka, Jun-ichi Kitanaka, Motohiko TakemuraAbstract:Following the expression of the behavioral sensitization by repeated administration of methamphetamine (METH) (1 mg/kg, intraperitoneal (i.p.), once per day for five consecutive days), male ICR mice were treated with Clorgyline (1 mg/kg, subcutaneous, once per day for five consecutive days), a monoamine oxidase-A inhibitor. Two hours after the final treatment with Clorgyline, the mice were challenged with METH (1 mg/kg, i.p.) and locomotor activity was measured for 1 h. The mice treated with Clorgyline showed a significant decrease in both vertical locomotion and horizontal rearing, compared with those treated with saline. Clorgyline treatment altered the effect of single METH challenges on apparent dopamine turnover in the cerebral cortex of the mice sensitized to METH. These results suggested a possible association of the inhibition by Clorgyline of METH-induced behavioral sensitization with the alteration of dopamine turnover in the cerebral cortex of the mouse.
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inhibition of methamphetamine induced hyperlocomotion in mice by Clorgyline a monoamine oxidase a inhibitor through alteration of the 5 hydroxytriptamine turnover in the striatum
Neuroscience, 2005Co-Authors: Nobue Kitanaka, Jun-ichi Kitanaka, Motohiko TakemuraAbstract:The psychomotor stimulant methamphetamine (METH) has been shown to cause specific behaviors such as hyperlocomotion in rodents. Pretreatment of repeated s.c. administration of Clorgyline (1 mg/kg, once per day for 5 consecutive days), a monoamine oxidase (MAO)-A inhibitor, blocked hyperlocomotion induced by a single i.p. administration of METH (1 mg/kg) in male ICR mice, without any effect on spontaneous locomotion. The blockade was also observed when mice were pretreated with a single administration of Clorgyline (1 mg/kg, s.c.), without potentiating hyperlocomotion and rearing induced by a single challenge of METH at the range of 0.5-2 mg/kg (i.p.). In contrast, single or repeated pretreatment of selegiline (0.3 mg/kg, s.c.), a MAO-B inhibitor, had no effect on METH-induced hyperlocomotion. Clorgyline pretreatment, both single and repeated, altered the effects of single METH challenges on apparent 5-hydroxytryptamine (serotonin) turnover in the region of the striatum and accumbens. These results suggest that Clorgyline tends to oppose METH-induced hyperlocomotion through alteration of the serotonergic system in the region of the striatum and accumbens.
Donna M. Peehl - One of the best experts on this subject based on the ideXlab platform.
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targeting monoamine oxidase a in advanced prostate cancer
Journal of Cancer Research and Clinical Oncology, 2010Co-Authors: Vincent Flamand, Hongjuan Zhao, Donna M. PeehlAbstract:Purpose Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, Clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, Clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA.
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anti oncogenic and pro differentiation effects of Clorgyline a monoamine oxidase a inhibitor on high grade prostate cancer cells
BMC Medical Genomics, 2009Co-Authors: Hongjuan Zhao, Vincent Flamand, Donna M. PeehlAbstract:Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of Clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA).
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anti oncogenic and pro differentiation effects of Clorgyline a monoamine oxidase a inhibitor on high grade prostate cancer cells
BMC Medical Genomics, 2009Co-Authors: Hongjuan Zhao, Vincent Flamand, Donna M. PeehlAbstract:Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of Clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA). We systematically assessed gene expression changes induced by Clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction. The expression of 156 genes was significantly increased by Clorgyline at all time points over the time course of 6 – 96 hr identified by Significance Analysis of Microarrays (SAM). The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated ≥ 2-fold by Clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of Clorgyline. Another striking effect of Clorgyline was the induction of androgen receptor (AR) and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that Clorgyline promotes differentiation of cancer cells. Moreover, Clorgyline downregulated EZH2, a critical component of the Polycomb Group (PcG) complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by Clorgyline, suggesting that the differentiation-promoting effect of Clorgyline may be mediated by its downregulation of EZH2. Our results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.
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inhibition of monoamine oxidase a promotes secretory differentiation in basal prostatic epithelial cells
Differentiation, 2008Co-Authors: Hongjuan Zhao, Stephen Reese, Rosalie Nolley, Zuxiong Chen, Donna M. PeehlAbstract:Monoamine oxidase A (MAO-A) expression is associated with high-grade prostate cancer. Immunohistochemistry showed that MAO-A is also expressed in the basal epithelial cells of normal prostate glands. Using cultured primary prostatic epithelial cells as a model, we showed that MAO-A prevents basal epithelial cells from differentiating into secretory cells. Under differentiation-promoting conditions, Clorgyline, an irreversible MAO-A inhibitor, induced secretory cell-like morphology and repressed expression of cytokeratin 14, a basal cell marker. More importantly, Clorgyline induced mRNA and protein expression of androgen receptor (AR), a hallmark of secretory epithelial cells. In Clorgyline-treated cells, androgen induced luciferase activity controlled by the promoter of prostate-specific antigen, an AR target gene, in a dose-dependent manner. This activity was blocked by the AR antagonist Casodex, showing that AR is functional. In turn, androgen decreased MAO-A expression in Clorgyline-treated, secretory-like cells. Our results demonstrated that cultured basal epithelial cells have the potential to differentiate into secretory cells, and that inhibition of MAO-A is a key factor in promoting this process. Increased expression of MAO-A in high-grade prostate cancer may be an important contributor to its de-differentiated phenotype, raising the possibility that MAO-A inhibition may restore differentiation and reverse the aggressive behavior of high-grade cancer.
Gregory F Oxenkrug - One of the best experts on this subject based on the ideXlab platform.
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Clorgyline effect on pineal melatonin biosynthesis in rats with lesioned suprachiasmatic nuclei
Journal of Neural Transmission-supplement, 1998Co-Authors: Gregory F Oxenkrug, Pura J RequintinaAbstract:We have reported that Clorgyline-induced stimulation of pineal melatonin biosynthesis could be augmented by the exposure to 24 h of constant light in young but not in aged rats. Aging is associated with the declined integrity of the suprachiasmatic nuclei (SCN), the major station of the light signal passage from the retina to the pineal gland. The present study aimed to investigate whether SCN integrity is essential for Clorgyline effects on pineal melatonin biosynthesis in light-primed rats. Clorgyline (2.5mg/kg, s.c.) was administered to sham-operated and SCN-lesioned Sprague-Dawley rats kept under regular light/dark cycle or exposed to 24 h of constant light. Pineal melatonin and related indoles were evaluated by HPLC-fluorimetric procedure.
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Clorgyline effect on pineal melatonin biosynthesis in adrenalectomized rats pretreated with 6 hydroxydopamine
Journal of Neural Transmission-supplement, 1994Co-Authors: S. Reuss, P J Requintina, R Riemann, Gregory F OxenkrugAbstract:The response to administration of the specific monoamine oxidase A (MAO-A) blocker Clorgyline was investigated in adult male Sprague-Dawley rats which were adrenalectomized four days prior to treatment or were additionally sympathectomized as newborns by injection of 6-hydroxydopamine. In both groups, the contents of pineal indoles melatonin and N-acetylserotonin were augmented, and the contents of 5-hydroxyindoleacetic acid and 5-hydroxyindoletryptophol decreased 90 min following Clorgyline injections when compared to rats receiving saline. The observed responses were less pronounced in rats both adrenalectomized and sympathectomized. The results are in line with the hypothesis that preservation from oxidation of both MAO-A substrates, noradrenaline and serotonin, upon Clorgyline administration contributes to the observed increase in melatonin biosynthesis thought to be associated with the antidepressant effects of MAO inhibition.
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Clorgyline effect on pineal melatonin biosynthesis in roman high and low avoidance rats
Journal of Neural Transmission-supplement, 1994Co-Authors: P J Requintina, P Driscoll, Gregory F OxenkrugAbstract:Pineal melatonin and related indoles levels were higher in Roman high- than in Roman low-avoidance rats, while 5-HIAA/5-HT ratio, as an index of MAO activity was higher in low- than in high-avoidance rats. Clorgyline stimulated pineal melatonin biosynthesis in both lines of rats. However, melatonin and N-acetylserotonin levels remained higher and 5-HIAA levels remained lower in the high avoidance rats treated with low dose (0.5 mg/kg) while treatment with 1.0 mg/kg of Clorgyline eliminated the differences in melatonin production between high- and low-avoidance rats.
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the response of the pineal melatonin miosynthesis to the selective mao a inhibitor Clorgyline in young and middle aged rats
Progress in Neuro-psychopharmacology & Biological Psychiatry, 1991Co-Authors: Gregory F Oxenkrug, Iain M Mcintyre, P J Requintina, James D DuffyAbstract:Abstract 1. Clorgyline increased pineal melatonin and N-acetylserotonin (NAS) and decreased 5-hydroxyindoleacetic add (5-HIAA) content in 3 and 12 months of age male Sprague-Dawley rats kept under 12:12 h light: dark schedule. Exposure to light for 24 h before Clorgyline administration resulted in additonal elevation of NAS and melatonin.NAS and melatonin levels after Clorgyline injections were significantly higher while 5-HIAA levels were significantly lower in young than in middle-aged rats. 2.The 5-HIAA/5-HT ratio (index of monoamine oxidase activity) was higher in middle-aged than in young rats suggesting the lesser degree of Clorgyline-induced inhibition of MAO-A in old than in young rats. 3. It is suggested that melatonin response to a single dose of the selective MAO-A inhibitor might be used for the assessment of the aging changes of the rat (and human) pineals.
Nobue Kitanaka - One of the best experts on this subject based on the ideXlab platform.
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low dose pretreatment with Clorgyline decreases the levels of 3 methoxy 4 hydroxyphenylglycol in the striatum and nucleus accumbens and attenuates methamphetamine induced conditioned place preference in rats
Neuroscience, 2010Co-Authors: Nobue Kitanaka, Kaname Watabe, Jun-ichi Kitanaka, Motohiko TakemuraAbstract:The effect of treating rats with Clorgyline, an irreversible monoamine oxidase-A (MAO-A) inhibitor, on methamphetamine (METH)-induced conditioned place preference (CPP) was investigated. Administering rats with METH (1.0 mg/kg i.p.) every other day during two conditioning sessions (i.e., saline/METH conditioning with no Clorgyline pretreatment) induced a significant CPP compared with saline/saline conditioning. Pretreatment of the rats with Clorgyline at a dose of 0.1 mg/kg (i.p.), but not 1.0 or 10 mg/kg, attenuated the METH-induced CPP. Neurochemical analysis using high-performance liquid chromatography revealed that the tissue levels of monoamines and their metabolites were not significantly affected by treatment with 0.1 mg/kg Clorgyline except for the levels of 3-methoxy4-hydroxyphenylglycol (MHPG) in the striatum and nucleus accumbens (NAc). Clorgyline at doses of 1.0 or 10 mg/kg significantly affected the tissue levels of 3,4-dihydroxyphenylacetic acid, norepinephrine (NE), MHPG, and serotonin in the cerebral cortex and those of all monoamines and metabolites examined in the striatum and NAc. A significant decrease in the MHPG/NE ratio in the striatum and NAc was apparent in the rats pretreated with 0.1 mg/kg Clorgyline. Overall, the present study demonstrated that low-dose Clorgyline attenuated METH-induced CPP in rats.
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modification of morphine induced hyperlocomotion and antinociception in mice by Clorgyline a monoamine oxidase a inhibitor
Neurochemical Research, 2006Co-Authors: Nobue Kitanaka, Jun-ichi Kitanaka, Motohiko TakemuraAbstract:We evaluated the effects of pretreatment with Clorgyline, an irreversible monoamine oxidase (MAO)-A inhibitor, on morphine-induced hyperlocomotion and antinociception. A single administration of morphine (30 mg/kg, i.p.) to male ICR mice induced a hyperlocomotion. ANOVA analysis revealed the statistical significance of the morphine effect on horizontal locomotion and of the Clorgyline pretreatment × morphine interaction effect, but not of the effect of Clorgyline pretreatment. The initial (5 min after challenge) phase of morphine actions vs. saline challenge appeared as if morphine had a strong inhibitory effect on locomotor activity in combination with different doses of Clorgyline. The mice administered with morphine in combination of Clorgyline (1 and 10 mg/kg) did not show any stereotypic behaviors. Clorgyline at a dose of 0.1 mg/kg but not other doses tested significantly potentiated morphine-induced antinociception evaluated by tail flick but not hot plate test. During the measurements of locomotor activity and antinociception, Clorgyline at doses of 1 and 10 mg/kg significantly inhibited monoamine metabolism through MAO. These results suggest that Clorgyline showed an inhibitory effect on morphine-induced hyperlocomotion, but not antinociception, through MAO inhibition. There is not a possibility that Clorgyline pretreatment enhanced morphine action on motor activity, resulting in the abnormal behavior from hyperlocomotion to stereotypic movements.
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Methamphetamine Reward in Mice as Assessed by Conditioned Place Preference Test with Supermex® Sensors: Effect of Subchronic Clorgyline Pretreatment
Neurochemical Research, 2006Co-Authors: Nobue Kitanaka, Tomohiro Tatsuta, Kaname Watabe, Jun-ichi Kitanaka, Yoshio Morita, Motohiko TakemuraAbstract:Recent studies in our laboratory have shown that methamphetamine (METH)-induced hyperlocomotion and behavioral sensitization in mice were inhibited by Clorgyline, an irreversible monoamine oxidase inhibitor. In this study, the effect of Clorgyline pretreatment on METH-induced rewarding effect was assessed by a conditioned place preference (CPP) test, using an apparatus developed with Supermex® sensors (infrared pyroelectric sensors). Although intact male ICR mice showed significant CPP for METH (0.5 mg/kg, i.p.), pretreatment with subchronic Clorgyline (0.1 and 10 mg/kg, s.c.) did not affect the magnitude of CPP. At a dose of 1 mg/kg, pretreatment of the mice with Clorgyline showed a similar CPP index in both saline/saline and METH/saline pairing groups. During the conditioning session, the mice did not express behavioral sensitization to METH. Pretreatment with Clorgyline (0.1, 1, and 10 mg/kg) decreased striatal apparent monoamine turnover in a dose-dependent manner. These results indicated that Clorgyline pretreatment (0.1 and 10 mg/kg) did not influence the METH-induced rewarding effect in mice, although pretreatment of the mice with Clorgyline at a dose of 1 mg/kg appeared to influence the CPP for METH.
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repeated Clorgyline treatment inhibits methamphetamine induced behavioral sensitization in mice
Neurochemical Research, 2005Co-Authors: Nobue Kitanaka, Jun-ichi Kitanaka, Motohiko TakemuraAbstract:Following the expression of the behavioral sensitization by repeated administration of methamphetamine (METH) (1 mg/kg, intraperitoneal (i.p.), once per day for five consecutive days), male ICR mice were treated with Clorgyline (1 mg/kg, subcutaneous, once per day for five consecutive days), a monoamine oxidase-A inhibitor. Two hours after the final treatment with Clorgyline, the mice were challenged with METH (1 mg/kg, i.p.) and locomotor activity was measured for 1 h. The mice treated with Clorgyline showed a significant decrease in both vertical locomotion and horizontal rearing, compared with those treated with saline. Clorgyline treatment altered the effect of single METH challenges on apparent dopamine turnover in the cerebral cortex of the mice sensitized to METH. These results suggested a possible association of the inhibition by Clorgyline of METH-induced behavioral sensitization with the alteration of dopamine turnover in the cerebral cortex of the mouse.
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inhibition of methamphetamine induced hyperlocomotion in mice by Clorgyline a monoamine oxidase a inhibitor through alteration of the 5 hydroxytriptamine turnover in the striatum
Neuroscience, 2005Co-Authors: Nobue Kitanaka, Jun-ichi Kitanaka, Motohiko TakemuraAbstract:The psychomotor stimulant methamphetamine (METH) has been shown to cause specific behaviors such as hyperlocomotion in rodents. Pretreatment of repeated s.c. administration of Clorgyline (1 mg/kg, once per day for 5 consecutive days), a monoamine oxidase (MAO)-A inhibitor, blocked hyperlocomotion induced by a single i.p. administration of METH (1 mg/kg) in male ICR mice, without any effect on spontaneous locomotion. The blockade was also observed when mice were pretreated with a single administration of Clorgyline (1 mg/kg, s.c.), without potentiating hyperlocomotion and rearing induced by a single challenge of METH at the range of 0.5-2 mg/kg (i.p.). In contrast, single or repeated pretreatment of selegiline (0.3 mg/kg, s.c.), a MAO-B inhibitor, had no effect on METH-induced hyperlocomotion. Clorgyline pretreatment, both single and repeated, altered the effects of single METH challenges on apparent 5-hydroxytryptamine (serotonin) turnover in the region of the striatum and accumbens. These results suggest that Clorgyline tends to oppose METH-induced hyperlocomotion through alteration of the serotonergic system in the region of the striatum and accumbens.
Hongjuan Zhao - One of the best experts on this subject based on the ideXlab platform.
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targeting monoamine oxidase a in advanced prostate cancer
Journal of Cancer Research and Clinical Oncology, 2010Co-Authors: Vincent Flamand, Hongjuan Zhao, Donna M. PeehlAbstract:Purpose Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, Clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, Clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA.
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anti oncogenic and pro differentiation effects of Clorgyline a monoamine oxidase a inhibitor on high grade prostate cancer cells
BMC Medical Genomics, 2009Co-Authors: Hongjuan Zhao, Vincent Flamand, Donna M. PeehlAbstract:Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of Clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA).
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anti oncogenic and pro differentiation effects of Clorgyline a monoamine oxidase a inhibitor on high grade prostate cancer cells
BMC Medical Genomics, 2009Co-Authors: Hongjuan Zhao, Vincent Flamand, Donna M. PeehlAbstract:Monoamine oxidase A (MAO-A), a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated (Gleason grades 4 and 5), aggressive prostate cancer (PCa). Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of Clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa (E-CA). We systematically assessed gene expression changes induced by Clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction. The expression of 156 genes was significantly increased by Clorgyline at all time points over the time course of 6 – 96 hr identified by Significance Analysis of Microarrays (SAM). The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated ≥ 2-fold by Clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of Clorgyline. Another striking effect of Clorgyline was the induction of androgen receptor (AR) and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that Clorgyline promotes differentiation of cancer cells. Moreover, Clorgyline downregulated EZH2, a critical component of the Polycomb Group (PcG) complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by Clorgyline, suggesting that the differentiation-promoting effect of Clorgyline may be mediated by its downregulation of EZH2. Our results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.
-
inhibition of monoamine oxidase a promotes secretory differentiation in basal prostatic epithelial cells
Differentiation, 2008Co-Authors: Hongjuan Zhao, Stephen Reese, Rosalie Nolley, Zuxiong Chen, Donna M. PeehlAbstract:Monoamine oxidase A (MAO-A) expression is associated with high-grade prostate cancer. Immunohistochemistry showed that MAO-A is also expressed in the basal epithelial cells of normal prostate glands. Using cultured primary prostatic epithelial cells as a model, we showed that MAO-A prevents basal epithelial cells from differentiating into secretory cells. Under differentiation-promoting conditions, Clorgyline, an irreversible MAO-A inhibitor, induced secretory cell-like morphology and repressed expression of cytokeratin 14, a basal cell marker. More importantly, Clorgyline induced mRNA and protein expression of androgen receptor (AR), a hallmark of secretory epithelial cells. In Clorgyline-treated cells, androgen induced luciferase activity controlled by the promoter of prostate-specific antigen, an AR target gene, in a dose-dependent manner. This activity was blocked by the AR antagonist Casodex, showing that AR is functional. In turn, androgen decreased MAO-A expression in Clorgyline-treated, secretory-like cells. Our results demonstrated that cultured basal epithelial cells have the potential to differentiate into secretory cells, and that inhibition of MAO-A is a key factor in promoting this process. Increased expression of MAO-A in high-grade prostate cancer may be an important contributor to its de-differentiated phenotype, raising the possibility that MAO-A inhibition may restore differentiation and reverse the aggressive behavior of high-grade cancer.