63 results on '"T, Inoue"'
Search Results
2. The study of dopaminergic nervous system which induces hyperactive urinary bladder response in anesthetized rats
- Author
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H. Kontani, T. Inoue, T. Sakai, and M. Hayakawa
- Subjects
Pharmacology ,Nervous system ,medicine.medical_specialty ,medicine.anatomical_structure ,Urinary bladder ,business.industry ,Dopaminergic ,medicine ,Urology ,business - Published
- 1990
3. Helodermin stimulates prolactin secretion in the rat
- Author
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Yuzuru Y. Kato, Hiroyuki Koshiyama, Tatsuhide T. Inoue, Noboru Yanaihara, Hiroo Imura, and Christophe J
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,medicine.drug_class ,Vasoactive intestinal peptide ,Biology ,Peptide hormone ,Secretin ,Peptide PHI ,Internal medicine ,medicine ,Animals ,Secretion ,Injections, Intraventricular ,Pharmacology ,Biological activity ,Rats, Inbred Strains ,Prolactin ,Rats ,Endocrinology ,Injections, Intravenous ,Intercellular Signaling Peptides and Proteins ,Gonadotropin ,Peptides ,hormones, hormone substitutes, and hormone antagonists ,Vasoactive Intestinal Peptide - Abstract
The effect of helodermin, a member of the secretin/vasoactive intestinal polypeptide (VIP)/peptide histidine isoleucine (PHI) family of peptides, on pituitary prolactin (PRL) secretion was examined in the rat. Either i.c.v. or i.v. injection of helodermin resulted in a dose-related increase in plasma PRL levels in urethane-anesthetized male rats. At the doses tested the potency of helodermin to raise plasma PRL levels was greater than that of rat PHI and porcine PHI, and as great as that of VIP.
- Published
- 1987
4. Bromodomain-containing protein 4 regulates a cascade of lipid-accumulation-related genes at the transcriptional level in the 3T3-L1 white adipocyte-like cell line.
- Author
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Mochizuki K, Yamada M, Inoue T, Hariya N, Kubota T, and Goda T
- Subjects
- 3T3-L1 Cells, Acetylation, Adipocytes, White drug effects, Animals, Azepines pharmacology, Chromatin metabolism, Gene Expression Profiling, Histones metabolism, Lipid Metabolism drug effects, Mice, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins genetics, Protein Binding, RNA Interference, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Triazoles pharmacology, Adipocytes, White metabolism, Lipid Metabolism genetics, Nuclear Proteins metabolism, Transcription Factors metabolism, Transcription, Genetic drug effects
- Abstract
Our previous study demonstrated that the transfection of a short hairpin (sh)RNA targeting bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family of proteins, into 3T3-L1 cells, a white adipocyte-like cell line, reduced the expression of insulin sensitivity genes, such as Adipoq, Fabp4, Lpl, Slc2a4 and Dgat1, and that BRD4 directly bound to the Adipoq, Slc2a4 and Lpl genes. In the present study, we aimed to identify other target genes of BRD4 by microarray analysis of Brd4 shRNA- and control shRNA-transfected cells. We found that the expression of many genes related to fat metabolism, and particularly those involved in fat accumulation in the glycolytic pathway, tricarboxylic acid cycle, and triacylglycerol synthesis, such as Dgat2, Gpd1, Acsl1, Pnpla2, Pgkfb3, Pcx, Fasn, Acacb and Cidec, was reduced by Brd4 shRNA transfection 2 and 8 days after the end of adipocyte differentiation. The binding of BRD4 at the 2-day and histone acetylation at the 8-day time point, in the vicinity of the Dgat2, Gpd1, Acsl1 and Cidec genes, was also reduced by Brd4 shRNA transduction. Treatment with low doses (10-100 nM) of the BET family inhibitor (+)-JQ-1 for 2, 4 or 8 days also reduced the expression of Dgat2, Gpd1, Fasn, Acab, Acsl1, Pnpla2 and Cidec in 3T3-L1 white adipocyte-like cells. These results indicate that BRD4 regulates the expression of numerous genes involved in lipid accumulation at the transcriptional level in a white adipocyte-like cell line., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
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5. Enhancement of swallowing motor activity by the ACE inhibitor imidapril in an arterially perfused rat preparation.
- Author
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Moriya T, Nakayama K, Nakamura S, Mochizuki A, Ofuji T, Shirota T, and Inoue T
- Subjects
- Angiotensin Receptor Antagonists pharmacology, Animals, Dose-Response Relationship, Drug, Electric Stimulation, Female, Male, Perfusion, Peripheral Nerves drug effects, Peripheral Nerves physiology, Rats, Rats, Wistar, Receptors, Dopamine D1 agonists, Time Factors, Angiotensin-Converting Enzyme Inhibitors pharmacology, Arteries, Deglutition drug effects, Deglutition physiology, Imidazolidines pharmacology, Motor Activity drug effects
- Abstract
Pharmacological agents that elevate dopamine and substance P concentrations have been suggested to prevent aspiration pneumonia and improve impaired swallowing processes. However, little is known about the effects of such agents on swallowing activities induced in motor nerves innervating the pharyngeal and laryngeal muscles. In this study, we examined the effects of imidapril, cilostazol, and amantadine, which are often prescribed for swallowing disorders, on swallowing motor activity. We recorded the efferent activities of the cervical vagal nerve, hypoglossal nerve, and phrenic nerve using arterially perfused rats aged between 21-35 postnatal days. The vagal nerve activity was used for evaluation of swallowing motor activity. When 1.25 ml of distilled water was injected into the oral cavity, or the superior laryngeal nerve was electrically stimulated, synchronized swallowing bursts were evoked in the vagal and hypoglossal nerves, while inspiratory discharges were inhibited in all the recorded nerves. Administration of imidapril (60 ng/ml) but not cilostazol (2.5 μg/ml) and amantadine (200 ng/ml) to the perfusate increased the mean peak amplitude of orally evoked swallowing bursts in the vagal nerve. Such increase in the peak amplitude by imidapril was antagonized by the administration of the NK
1 receptor antagonist aprepitant (5 μg/ml) or the D1 receptor antagonist LE300 (2.5 μg/ml). In contrast, neither imidapril nor cilostazol caused a significant increase in swallowing bursts evoked by electrical stimulation of the superior laryngeal nerve. These results suggest that imidapril treatment may improve impaired swallowing by enhancing pharyngeal muscle activities via an increase in substance P and dopamine concentrations., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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6. Epigenetic regulation of lipoprotein lipase gene via BRD4, which is potentially associated with adipocyte differentiation and insulin resistance.
- Author
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Inoue T, Hariya N, Imamochi Y, Dey A, Ozato K, Goda T, Kubota T, and Mochizuki K
- Subjects
- 3T3-L1 Cells, Acetylation drug effects, Adipocytes drug effects, Adipose Tissue cytology, Adipose Tissue drug effects, Animals, Azepines pharmacology, Cell Differentiation drug effects, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Enzymologic genetics, Heterozygote, Histones metabolism, Mice, Triazoles pharmacology, Tumor Necrosis Factor-alpha pharmacology, Adipocytes cytology, Cell Differentiation genetics, Epigenesis, Genetic, Insulin Resistance genetics, Lipoprotein Lipase genetics, Nuclear Proteins metabolism, Transcription Factors metabolism
- Abstract
Lipoprotein lipase (LPL) is the rate-controlling enzyme for the accumulation of triacylglycerol into adipocytes, which acts by digesting it into glycerol and fatty acids. In this study, we found that treatment with (+)-JQ1, an inhibitor of the bromodomain and extra-terminal (BET) family proteins, for 4 days from the end of stimulation to induce adipocyte differentiation reduced binding of BRD4, a BET family member, within the gene body of Lpl. This eventually downregulated the expression of Lpl in 3T3-L1 adipocytes. Longer treatment for 8 days reduced the acetylation of histones H3 and H4 within the gene body of Lpl and subsequent Lpl expression. Lpl expression in mesenteric adipose tissues was lower in Brd4
+/- heterozygous mice at 14 days after birth than in wild-type mice at the same age. Furthermore, treatment with an inducer of insulin resistance, tumor necrosis factor-α, reduced BRD4 binding and histone acetylation in the gene body of Lpl and its expression. These results indicate that transcriptional elongation of Lpl controlled by BRD4 may be associated with adipocyte differentiation, and that its suppression is potentially associated with insulin resistance of adipocytes., (Copyright © 2019 Elsevier B.V. All rights reserved.)- Published
- 2019
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7. An anti-PLVAP antibody suppresses laser-induced choroidal neovascularization in monkeys.
- Author
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Nakagami Y, Hatano E, Chayama Y, and Inoue T
- Subjects
- Animals, Carrier Proteins genetics, Carrier Proteins metabolism, Choroidal Neovascularization etiology, Choroidal Neovascularization genetics, Choroidal Neovascularization pathology, Diabetic Retinopathy immunology, Diabetic Retinopathy metabolism, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells metabolism, Humans, Macaca fascicularis, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Oxygen metabolism, Permeability, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Retina metabolism, Retina pathology, Vascular Endothelial Growth Factor A metabolism, Antibodies immunology, Carrier Proteins immunology, Choroidal Neovascularization immunology, Lasers adverse effects, Membrane Proteins immunology
- Abstract
Plasmalemma vesicle-associated protein (PLVAP, also called PV-1) is the only protein that forms endothelial diaphragms. PLVAP expression is very low in the normal blood-retinal barrier; however, pathological factors such as high glucose and vascular endothelial growth factor (VEGF) induce its expression, leading to the exacerbation of cellular permeability. Because the new blood vessels are fragile and leaky, PLVAP could possibly be considered a therapeutic target against retinovascular diseases. VEGF inhibitors are commonly used for the treatment of such diseases; however, there are several concerns associated with their use, especially in the case of chronic suppression of VEGF. In this study, we investigated the expressional level of PLVAP mRNA in VEGF-treated endothelial cells and the retinas of 2 animal models: streptozotocin-induced diabetic Brown Norway rats and Sprague-Dawley rats with oxygen-induced retinopathy. Among transcellular transport-related genes, the induction of PLVAP mRNA is the most apparent; the increase of PLVAP mRNA levels in the retina is evident during pathological progression. Furthermore, anti-PLVAP antibodies were generated, and their efficacy against laser-induced choroidal neovascularization was tested in cynomolgus monkeys. Although the leakage was exacerbated in the saline-injected group during the progression of neovascularization, the intravitreal injection of anti-PLVAP antibodies significantly ameliorated the exudation. These data imply that the PLVAP inhibition is a promising therapeutic approach against retinal diseases such as diabetic macular edema, retinopathy of prematurity, and wet age-related macular degeneration., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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8. Mizagliflozin, a novel selective SGLT1 inhibitor, exhibits potential in the amelioration of chronic constipation.
- Author
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Inoue T, Takemura M, Fushimi N, Fujimori Y, Onozato T, Kurooka T, Asari T, Takeda H, Kobayashi M, Nishibe H, and Isaji M
- Subjects
- Amides therapeutic use, Animals, Chronic Disease drug therapy, Clinical Trials, Phase I as Topic, Constipation chemically induced, Dietary Fiber pharmacology, Dogs, Dose-Response Relationship, Drug, Glucosides therapeutic use, Humans, Loperamide pharmacology, Male, Pyrazoles therapeutic use, Rats, Amides pharmacology, Constipation drug therapy, Glucosides pharmacology, Pyrazoles pharmacology, Sodium-Glucose Transporter 1 antagonists & inhibitors
- Abstract
Chronic constipation is a highly common functional gastrointestinal disorder that adversely affects patient quality of life. At present, limited therapeutic options are available for the treatment of chronic constipation, which indicates the need for new therapeutic agents. Herein, we report the potential of mizagliflozin, a novel selective sodium glucose co-transporter 1 (SGLT1) inhibitor, for the amelioration of chronic constipation. Mizagliflozin's inhibitory activity against SGLTs was evaluated by an in vitro assay of cells transiently expressing SGLTs. The safety profile of an initial single dose (2-160mg, orally) and multiple doses (2-20mg, orally, once daily immediately prior to breakfast on Days 1 and 13, and three times daily immediately prior to every meal on Days 3-12) of mizagliflozin was determined by performing a phase I study in healthy male subjects. In addition, the effect of mizagliflozin and lubiprostone on fecal wet weight was compared using a dog model of loperamide-induced constipation and rat model of low-fiber-diet-induced constipation. Mizagliflozin potently inhibited human SGLT1 in a highly selective manner. The results of the phase I study showed mizagliflozin increased stool frequency and loosened stool consistency; these effects increased progressively with an increase in the dosage and the number of doses of mizagliflozin. In addition, the oral administration of mizagliflozin increased fecal wet weight in a dog model of loperamide-induced constipation and a rat model of low-fiber-diet-induced constipation, similar to lubiprostone. These results suggest the potential use of a novel selective SGLT1 inhibitor, mizagliflozin, for the amelioration of chronic constipation., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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9. Combined treatment with subchronic lithium and acute intracerebral mirtazapine microinjection into the median raphe nucleus exerted an anxiolytic-like effect synergistically.
- Author
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An Y, Inoue T, Kitaichi Y, Chen C, Nakagawa S, Wang C, and Kusumi I
- Subjects
- Animals, Conditioning, Psychological drug effects, Drug Synergism, Extracellular Space drug effects, Extracellular Space metabolism, Fear drug effects, Fear psychology, Male, Mianserin administration & dosage, Mianserin pharmacology, Microinjections, Mirtazapine, Neurons drug effects, Neurons metabolism, Raphe Nuclei pathology, Rats, Rats, Sprague-Dawley, Serotonin metabolism, Time Factors, Anti-Anxiety Agents pharmacology, Lithium pharmacology, Mianserin analogs & derivatives, Raphe Nuclei drug effects
- Abstract
Although preclinical and clinical studies have established the efficacy of lithium augmentation of antidepressant drugs, the mechanism of action of lithium augmentation is not fully understood. Our previous study reported that subchronic lithium treatment enhanced the anxiolytic-like effect of systemic mirtazapine. In the present study, we examined the effect of subchronic lithium in combination with acute local intracerebral injection of mirtazapine on fear-related behaviors in a contextual fear conditioning test in rats to clarify the target brain region of lithium augmentation of mirtazapine. After conditioning by footshock, diet (food pellets) containing Li2CO3 at a concentration of 0.2% was administered for 7 days. Ten min before testing and 7 days after conditioning, mirtazapine (3μg/site) in a volume of 0.5µl was acutely injected into the median raphe nucleus (MRN), hippocampus or amygdala. The combination of subchronic lithium and acute mirtazapine microinjection into the MRN but not the hippocampus or the amygdala reduced fear expression synergistically. These results suggest that intra-MRN mirtazapine treatment with subchronic lithium exerts the anxiolytic-like effect through the facilitation of the MRN-5HT pathway., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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10. Subchronic lithium treatment increases the anxiolytic-like effect of mirtazapine on the expression of contextual conditioned fear.
- Author
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An Y, Inoue T, Kitaichi Y, Nakagawa S, Wang C, Chen C, Song N, and Kusumi I
- Subjects
- Animals, Anti-Anxiety Agents therapeutic use, Anxiety psychology, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Drug Synergism, Male, Mianserin pharmacology, Mianserin therapeutic use, Mirtazapine, Motor Activity drug effects, Rats, Rats, Sprague-Dawley, Time Factors, Anti-Anxiety Agents pharmacology, Anxiety drug therapy, Conditioning, Psychological drug effects, Fear drug effects, Fear psychology, Lithium pharmacology, Mianserin analogs & derivatives
- Abstract
Lithium not only has a mood-stabilizing effect but also the augmentation effect of an antidepressant, the mechanism of which remains unclear. Although lithium may augment the effect of mirtazapine, this augmentation has not been confirmed. Using a contextual fear conditioning test in rats, an animal model of anxiety or fear, we examined the effect of subchronic lithium carbonate (in diet) in combination with systemic mirtazapine on the expression of contextual conditioned fear. Mirtazapine (10mg/kg) reduced freezing one day after fear conditioning dose-dependently, whereas the anxiolytic-like effect of mirtazapine (10mg/kg) diminished seven days after fear conditioning. When the interval between fear conditioning and testing was seven days, only the combination of subchronic 0.2% Li2CO3 but not 0.05% Li2CO3 with acute mirtazapine (10mg/kg) reduced freezing significantly. These results indicate that subchronic 0.2% Li2CO3 treatment enhanced the anxiolytic-like effect of systemic mirtazapine. This augmentation therapy might be useful for the treatment of anxiety disorders., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2015
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11. Valproate recovers the inhibitory effect of dexamethasone on the proliferation of the adult dentate gyrus-derived neural precursor cells via GSK-3β and β-catenin pathway.
- Author
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Boku S, Nakagawa S, Masuda T, Nishikawa H, Kato A, Takamura N, Omiya Y, Kitaichi Y, Inoue T, and Kusumi I
- Subjects
- Animals, Cell Proliferation drug effects, Cyclin D1 genetics, Dexamethasone pharmacology, Glucocorticoids pharmacology, Glycogen Synthase Kinase 3 beta, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Male, Neural Stem Cells metabolism, Phosphorylation drug effects, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Antimanic Agents pharmacology, Dentate Gyrus cytology, Glycogen Synthase Kinase 3 metabolism, Neural Stem Cells drug effects, Valproic Acid pharmacology, beta Catenin metabolism
- Abstract
Neurogenesis in the adult dentate gyrus (DG) is decreased in rodent models for mood disorders. Mood stabilizers including lithium (Li) and valproate (VPA) increase it. These increasing effects of Li and VPA on neurogenesis in adult DG are considered to be one of the therapeutic actions of Li and VPA, but their molecular mechanism remains unclear. We have already reported that Li recovers the inhibitory effects of dexamethasone (DEX), an agonist of glucocorticoid receptor, on the proliferation of adult rat DG-derived neural precursor cells (ADP) via GSK-3β and β-catenin pathway. Following it, here we investigated the mechanism underlying the recovery effects of VPA on DEX-induced decrease of ADP proliferation. VPA is an inhibitor of histone deacetylase (HDAC). However, Trichostatin A, a HDAC inhibitor, had no effect on ADP proliferation. In contrast, SB415286, a specific GSK-3β inhibitor, recovered DEX-induced decrease of ADP proliferation. In addition, quercetin (Que), a β-catenin pathway inhibitor, abolished such a recovery effect of VPA. Moreover, nuclear β-catenin and the expression of cyclin D1 were altered by DEX, VPA and Que like the proliferation. Moreover, VPA increased the phosphorylation of Ser(9), which is known as the inhibitory phosphorylation site of GSK-3β. These suggest that HDAC is not involved in the recovery effect of VPA on ADP proliferation and that VPA recovers the inhibitory effects of DEX via increasing the phosphorylation of Ser(9) on GSK-3β and following up-regulation of β-catenin pathway. Therefore, GSK-3β and β-catenin pathway might play a role in the increasing effects of VPA on neurogenesis on adult DG., (© 2013 Published by Elsevier B.V.)
- Published
- 2014
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12. Anxiolytic-like effect of mirtazapine mediates its effect in the median raphe nucleus.
- Author
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An Y, Inoue T, Kitaichi Y, Izumi T, Nakagawa S, Song N, Chen C, Li X, Koyama T, and Kusumi I
- Subjects
- Amygdala anatomy & histology, Amygdala drug effects, Amygdala physiology, Animals, Behavior, Animal drug effects, Conditioning, Psychological, Fear psychology, Hippocampus anatomy & histology, Hippocampus drug effects, Hippocampus physiology, Male, Mianserin pharmacology, Mirtazapine, Motor Activity drug effects, Raphe Nuclei anatomy & histology, Raphe Nuclei physiology, Rats, Rats, Sprague-Dawley, Adrenergic alpha-Antagonists pharmacology, Anti-Anxiety Agents pharmacology, Fear physiology, Mianserin analogs & derivatives, Raphe Nuclei drug effects
- Abstract
Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), blocks the α2-adrenergic autoreceptors and heteroreceptors, which are responsible for controlling noradrenaline and 5-hydroxy-tryptamine (5-HT) release. Though preclinical and clinical studies have shown that mirtazapine exerts an anxiolytic action, its precise brain target sites remain unclear. In the present study, we investigated the brain area(s) in which mirtazapine exerts its anxiolytic-like effects on the expression of contextual conditioned freezing in rats. Mirtazapine (3 μg/site) was directly injected into three brain structures, the median raphe nucleus (MRN), hippocampus and amygdala. Freezing behavior tests were carried out 10 min after injections. Our results showed that the intra-MRN injection of mirtazapine reduced freezing significantly, whereas injections into the hippocampus or the amygdala did not. In addition, the intra-MRN injection of mirtazapine did not affect locomotor activity. These results suggest that the anxiolytic-like effect of mirtazapine might be mediated by its action on the MRN.
- Published
- 2013
13. Anti-inflammatory effect and selectivity profile of AS1940477, a novel and potent p38 mitogen-activated protein kinase inhibitor.
- Author
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Terajima M, Inoue T, Magari K, Yamazaki H, Higashi Y, and Mizuhara H
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Cell Line, Endotoxins toxicity, Female, Humans, Inflammation drug therapy, Inflammation metabolism, Interleukin-1beta metabolism, MAP Kinase Signaling System drug effects, Protein Kinase Inhibitors therapeutic use, Pyridazines therapeutic use, Pyrimidines therapeutic use, Rats, Substrate Specificity, Tumor Necrosis Factor-alpha metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Protein Kinase Inhibitors pharmacology, Pyridazines pharmacology, Pyrimidines pharmacology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
- Abstract
Given the key role p38 mitogen-activated protein kinase (MAPK) plays in inflammatory responses through the production of cytokines and inflammatory mediators, its inhibition is considered a promising therapeutic strategy for chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and chronic obstructive pulmonary disease. Here, we evaluated the anti-inflammatory effect and selectivity profile of the novel p38 MAPK inhibitor AS1940477. AS1940477 inhibited the enzymatic activity of recombinant p38α and β isoforms but showed no effect against other 100 protein kinases including p38γ and δ isoforms. We also confirmed the selectivity of AS1940477 in the intracellular signaling pathway. In human peripheral blood mononuclear cells, AS1940477 inhibited lipopolysaccharide (LPS)- or phytohemagglutinin A (PHA)-induced production of proinflammatory cytokines, including TNFα, IL-1β, and IL-6 at low concentrations (LPS/TNFα, IC(50)=0.45n M; PHA/TNFα, IC(50)=0.40 nM). In addition, equivalent concentrations of AS1940477 that inhibited cytokine production also inhibited TNFα- and IL-1 β-induced production of IL-6, PGE(2), and MMP-3 in human synovial stromal cells. AS1940477 was also found to potently inhibit TNF production in whole blood (IC(50)=12 nM) and effectively inhibited TNFα production induced by systemically administered LPS in rats at less than 0.1mg/kg (ED(50)=0.053 mg/kg) with an anti-inflammatory effect lasting for 20h after oral administration. Overall, this study demonstrated that AS1940477 is a novel and potent p38 MAPK inhibitor and may be useful as a promising anti-inflammatory agent for treating inflammatory disorders., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
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14. Effect of bFGF on neuronal damage induced by sequential treatment of amyloid β and excitatory amino acid in vitro and in vivo.
- Author
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Noshita T, Murayama N, Oka T, Ogino R, Nakamura S, and Inoue T
- Subjects
- Animals, Cerebral Cortex cytology, Dizocilpine Maleate pharmacology, Hippocampus cytology, Hippocampus drug effects, Hippocampus physiology, Ibotenic Acid toxicity, Learning drug effects, Male, Rats, Time Factors, Amyloid beta-Peptides toxicity, Fibroblast Growth Factor 2 pharmacology, Glutamic Acid toxicity, Neurons cytology, Neurons drug effects, Neuroprotective Agents pharmacology, Peptide Fragments toxicity
- Abstract
Effects of basic fibroblast growth factor (bFGF), a potent neurotrophin, on neuronal damage induced by sequential treatment of amyloid β (Aβ) peptide and excitatory amino acid were examined in vitro and in vivo. Treatment of rat primary cortical neurons with glutamate (10μM, 30μM) resulted in neuronal damage, and pretreatment of the neurons with Aβ(25-35) (1.0μM) at 48h before glutamate stimulation augmented the susceptibility of the cells to the glutamate-induced neurotoxicity. Application of bFGF (0.3, 1, 3ng/ml) and MK-801 (1, 3, 10, 30nM) to the culture at 24h before glutamate stimulation markedly decreased the neuronal damage elicited by Aβ(25-35) and glutamate. In a rat model of Alzheimer's disease, in which aggregated Aβ(1-40) (4μg/1μl) was injected into the hippocampus, followed by an injection of ibotenate (an NMDA receptor agonist, 0.3μg/0.5μl) into the same sites at 48h later, significant neuronal damage and learning deficit was induced. Administration of bFGF (25ng/1μl) into the hippocampus at 24h before ibotenate inhibited the neuronal damage and demonstrated a trend of attenuating spatial learning deficits. These results suggest that bFGF might be a useful agent for treatment of Alzheimer's disease in which Aβ peptide and glutamate would be involved as causative substances., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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15. Effects of piclozotan (SUN N4057), a partial serotonin 1A receptor agonist, on motor complications induced by repeated administration of levodopa in parkinsonian rats.
- Author
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Tani Y, Ogata A, Koyama M, and Inoue T
- Subjects
- Animals, Antiparkinson Agents pharmacokinetics, Antiparkinson Agents therapeutic use, Behavior, Animal drug effects, Benserazide toxicity, Corpus Striatum metabolism, Dopamine metabolism, Dopamine Agents toxicity, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Drug Partial Agonism, Dyskinesia, Drug-Induced blood, Hyperkinesis chemically induced, Hyperkinesis drug therapy, Levodopa pharmacokinetics, Levodopa therapeutic use, Male, Microdialysis, Motor Activity drug effects, Oxazepines blood, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT1A metabolism, Serotonin 5-HT1 Receptor Agonists blood, Antiparkinson Agents toxicity, Dyskinesia, Drug-Induced drug therapy, Levodopa toxicity, Oxazepines therapeutic use, Parkinson Disease drug therapy, Serotonin 5-HT1 Receptor Agonists therapeutic use
- Abstract
Serotonin 1A receptor agonists have attracted much interest recently as potential therapeutic agents for levodopa-induced motor complications, such as dyskinesia and motor fluctuations. The effects of piclozotan (SUN N4057) on a rat model of advanced Parkinson's disease were investigated. Parkinsonian rats, unilaterally 6-hydroxydopamine-lesioned rats, were administered levodopa for 8 to 9 weeks. Based on the results of rotational behavior and forelimb hyperkinesia in Week 5, the rats were allocated to three treatment groups (saline and two dosing rates of piclozotan set at 0.018 and 0.036 mg/kg/h). Piclozotan was administered via continuous subcutaneous infusion using an osmotic pump for 3 to 4 weeks. At Week 7 of repeated levodopa dosing, the effects of piclozotan on levodopa-induced behavior were evaluated. In addition, extracellular levels of levodopa-derived dopamine in the striatum were measured using microdialysis in Weeks 8 to 9 after completion of the respective behavioral studies. Chronic treatment with levodopa-induced forelimb hyperkinesia and shortened the duration of rotational behavior. Piclozotan (0.018 and 0.036 mg/kg/h, plasma concentrations 5.3±0.7 and 14.3±2.9 ng/ml) reduced levodopa-induced forelimb hyperkinesia by 55% and 69%, respectively, at 1h relative to the control. Piclozotan (0.036 mg/kg/h) significantly lengthened the duration of rotational behavior by 26% versus the control and attenuated the increase in striatal levodopa-derived extracellular dopamine levels. These findings suggest that piclozotan, a serotonin 1A agonist, can improve motor complications in patients with advanced Parkinson's disease., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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16. Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats.
- Author
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Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, and Koyama T
- Subjects
- Animals, Dopamine analysis, Dopamine metabolism, Dopamine pharmacology, Extracellular Space drug effects, Fluvoxamine metabolism, Male, Microdialysis, Norepinephrine analysis, Norepinephrine metabolism, Norepinephrine pharmacology, Paroxetine metabolism, Prefrontal Cortex drug effects, Rats, Rats, Sprague-Dawley, Serotonin analysis, Serotonin metabolism, Serotonin pharmacology, Selective Serotonin Reuptake Inhibitors metabolism, Sertraline metabolism, Corpus Striatum drug effects, Fluvoxamine pharmacology, Nucleus Accumbens drug effects, Paroxetine pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology, Sertraline pharmacology
- Abstract
Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for depression. Recent reports in the literature describe differences in antidepressant effects among SSRIs. Although each SSRI apparently has different pharmacological actions aside from serotonin reuptake inhibition, the relations between antidepressant effects and unique pharmacological properties in respective SSRIs remain unclear. This study was designed to compare abilities of three systemically administered SSRIs to increase the extracellular levels of serotonin, dopamine, and noradrenaline acutely in three brain regions of male Sprague-Dawley rats. We examined effects of sertraline, fluvoxamine, and paroxetine on extracellular serotonin, dopamine, and noradrenaline levels in the medial prefrontal cortex, nucleus accumbens and striatum of rats using in vivo microdialysis. Dialysate samples were collected in sample vials every 20 min for 460 min. Extracellular serotonin, dopamine, and noradrenaline levels were determined using high-performance liquid chromatography with electrochemical detection. All SSRI administrations increased extracellular serotonin levels in all regions. Only sertraline administration increased extracellular dopamine concentrations in the nucleus accumbens and striatum. All SSRI administrations increased extracellular noradrenaline levels in the nucleus accumbens, although fluvoxamine was less effective. These results suggest that neurochemical differences account for the differences in clinical antidepressant effects among SSRIs., (Copyright © 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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17. Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in beta-phenylethylamine.
- Author
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Kitaichi Y, Inoue T, Nakagawa S, Boku S, Izumi T, and Koyama T
- Subjects
- Animals, Antidepressive Agents administration & dosage, Antidepressive Agents pharmacology, Chromatography, High Pressure Liquid, Drug Therapy, Combination, Male, Monoamine Oxidase Inhibitors administration & dosage, Picolinic Acids pharmacology, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Prefrontal Cortex pathology, Rats, Rats, Sprague-Dawley, Serotonin metabolism, Extracellular Space metabolism, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology, Norepinephrine metabolism, Phenethylamines metabolism
- Abstract
Monoamine oxidase inhibitors (MAO inhibitors) have been widely used as antidepressants. However, it remains unclear whether a difference exists between non-selective MAO inhibitors and selective MAO-A inhibitors in terms of their antidepressant effects. Using in vivo microdialysis methods, we measured extracellular noradrenaline and serotonin levels following administration of Ro 41-1049, a reversible MAO-A inhibitor and/or lazabemide, a reversible MAO-B inhibitor in the medial prefrontal cortex (mPFC) of rats. We examined the effect of local infusion of beta-phenylethylamine to the mPFC of rats on extracellular noradrenaline and serotonin levels. Furthermore, the concentrations of beta-phenylethylamine in the tissue of the mPFC after combined treatment with Ro 41-1049 and lazabemide were measured. The Ro 41-1049 alone and the combined treatment significantly increased extracellular noradrenaline levels compared with vehicle and lazabemide alone. Furthermore, the combined treatment increased noradrenaline levels significantly more than Ro 41-1049 alone did. The Ro 41-1049 alone and the combined treatment significantly increased extracellular serotonin levels compared with vehicle and lazabemide alone, but no difference in serotonin levels was found between the combined treatment group and the Ro 41-1049 group. Local infusion of low-dose beta-phenylethylamine increased extracellular noradrenaline levels, but not that of serotonin. Only the combined treatment significantly increased beta-phenylethylamine levels in tissues of the mPFC. Our results suggest that the combined treatment with a MAO-A inhibitor and a MAO-B inhibitor strengthens antidepressant effects because the combined treatment increases extracellular noradrenaline levels more than a MAO-A inhibitor alone through increases in beta-phenylethylamine., (Copyright 2010 Elsevier B.V. All rights reserved.)
- Published
- 2010
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18. Effect of co-administration of the selective 5-HT1A receptor antagonist WAY 100,635 and selective 5-HT1B/1D receptor antagonist GR 127,935 on anxiolytic effect of citalopram in conditioned fear stress in the rat.
- Author
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Muraki I, Inoue T, and Koyama T
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- Animals, Behavior, Animal drug effects, Conditioning, Psychological, Data Interpretation, Statistical, Fear drug effects, Male, Motor Activity drug effects, Rats, Rats, Sprague-Dawley, Stress, Psychological drug therapy, Synaptic Transmission drug effects, Anti-Anxiety Agents pharmacology, Citalopram pharmacology, Fear psychology, Oxadiazoles pharmacology, Piperazines pharmacology, Pyridines pharmacology, Receptor, Serotonin, 5-HT1A drug effects, Receptor, Serotonin, 5-HT1B drug effects, Receptor, Serotonin, 5-HT1D drug effects, Serotonin Antagonists pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology, Stress, Psychological psychology
- Abstract
This study investigated the effect of co-administration of the selective 5-HT1A receptor antagonist WAY 100,635 and selective 5-HT(1B/1D) receptor antagonist GR 127,935 with a subactive dose of citalopram [selective serotonin (5-HT) reuptake inhibitor (SSRI)] on the expression of conditioned freezing, an index of fear. In the present study, acute administration of citalopram (s.c.) reduced freezing significantly at high doses (10, 30 and 100 mg/kg), while showing no significant effect at low doses (1 and 3 mg/kg). Co-administration of WAY 100,635 (0.15 mg/kg) with citalopram (3 mg/kg) reduced freezing markedly and significantly, as compared with either drug alone. However, the addition of GR 127,935 (4 mg/kg) did not potentiate the effects of citalopram (3 mg/kg) on freezing and did not enhance the effect of WAY 100,635 (0.15 mg/kg) with citalopram (3 mg/kg). Co-administration of WAY 100,635 (0.15 mg/kg) or GR 127,935 (4 mg/kg) gave no effect on high-dose citalopram (30 mg/kg)-induced inhibition of freezing behavior. These results suggest that co-administration of WAY 100,635 (0.15 mg/kg) strengthens the anxiolytic effect of citalopram (3 mg/kg) by facilitating central 5-HT neurotransmission. Since GR 127,935 (4 mg/kg) failed to accelerate the inhibition of freezing induced by citalopram (3 mg/kg) with WAY 100,635 (0.15 mg/kg) or citalopram (3 mg/kg) alone, it is suggested that blocking 5-HT1A receptors is more effective in facilitating the anxiolytic effect of citalopram than blocking 5-HT1B/1D receptors.
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- 2008
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19. Effect of co-administration of a serotonin-noradrenaline reuptake inhibitor and a dopamine agonist on extracellular monoamine concentrations in rats.
- Author
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Kitaichi Y, Inoue T, Izumi T, Nakagawa S, Tanaka T, Masui T, and Koyama T
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- Adrenergic Uptake Inhibitors administration & dosage, Animals, Antidepressive Agents administration & dosage, Cabergoline, Cyclopropanes administration & dosage, Dopamine metabolism, Dopamine Agonists administration & dosage, Drug Interactions, Ergolines administration & dosage, Injections, Intraperitoneal, Injections, Subcutaneous, Male, Microdialysis, Milnacipran, Norepinephrine metabolism, Prefrontal Cortex metabolism, Rats, Rats, Sprague-Dawley, Serotonin metabolism, Selective Serotonin Reuptake Inhibitors administration & dosage, Time Factors, Adrenergic Uptake Inhibitors pharmacology, Antidepressive Agents pharmacology, Biogenic Monoamines metabolism, Cyclopropanes pharmacology, Dopamine Agonists pharmacology, Ergolines pharmacology, Prefrontal Cortex drug effects, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
Recent studies have shown that dopamine agonists are useful for the treatment of not only Parkinson's disease, but also major depressive disorders. However, while these dopamine agonists provide a new treatment strategy for major depressive disorders, such as treatment-resistant cases, the antidepressant effect of dopamine agonists has yet to be investigated. To examine the mechanism of the antidepressive effect of dopamine agonists, we investigated the acute effect of the dopamine receptor agonist, cabergoline, and the serotonin-noradrenaline reuptake inhibitor, milnacipran, on extracellular noradrenaline, dopamine and serotonin concentrations in the rat medial prefrontal cortex. There was a greater increase in extracellular noradrenaline concentrations when acute milnacipran (30 mg/kg intraperitoneally) was administered after acute high-dose cabergoline (1 and 2 mg/kg subcutaneously) than when acute milnacipran was administered following acute vehicle or low-dose cabergoline (0.25 mg/kg subcutaneously). There were no significant differences noted in the dopamine or serotonin concentrations. These results suggest that the addition of cabergoline has the potential to strengthen the antidepressant effects of milnacipran and that the mechanism of action of the antidepressive effect of dopamine agonists might be due to enhancement of induced increases of extracellular noradrenaline.
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- 2008
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20. Usefulness of the dopamine system-stabilizer aripiprazole for reducing morphine-induced emesis.
- Author
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Shiokawa M, Narita M, Nakamura A, Kurokawa K, Inoue T, and Suzuki T
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- Animals, Aripiprazole, Ferrets, Male, Vomiting chemically induced, Analgesics, Opioid adverse effects, Antipsychotic Agents therapeutic use, Morphine adverse effects, Piperazines therapeutic use, Quinolones therapeutic use, Receptors, Dopamine D2 physiology, Vomiting drug therapy
- Abstract
In the management of pain, nausea and vomiting are some of the most distressing adverse effects induced by opioids. In the present study, we investigated the effect of the dopamine system-stabilizer aripiprazole on morphine-induced emesis. Morphine induced retching and vomiting in a dose-dependent manner in ferrets. The emetic effect of morphine was significantly suppressed by pretreatment with either the dopamine receptor antagonist haloperidol or aripiprazole. These results suggest that the co-administration of aripiprazole may be useful for reducing the severity of morphine-induced emesis.
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- 2007
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21. Involvement of chemical mediators in nasal allergic responses of HDC-KO mice.
- Author
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Rahman MA, Inoue T, Ishikawa T, Yatsuzuka R, Ohtsu H, and Kamei C
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- Animals, Behavior, Animal physiology, Chlorpheniramine pharmacology, Histamine H1 Antagonists pharmacology, Histidine Decarboxylase deficiency, Hydantoins pharmacology, Immunization, Immunoglobulin E analysis, Immunoglobulin E immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurokinin-1 Receptor Antagonists, Ovalbumin immunology, Piperidines pharmacology, Receptors, Immunologic antagonists & inhibitors, Receptors, Prostaglandin antagonists & inhibitors, Rhinitis, Allergic, Seasonal psychology, Sneezing physiology, Substance P pharmacology, Histidine Decarboxylase genetics, Histidine Decarboxylase physiology, Inflammation Mediators physiology, Rhinitis, Allergic, Seasonal physiopathology
- Abstract
The present study was undertaken to investigate the involvement of chemical mediators in nasal allergic responses using histidine decarboxylase knockout (HDC-KO) mice. An allergic rhinitis model was developed in HDC-KO and wild-type mice by the intraperitoneal injection of ovalbumin, aluminum hydroxide gel and pertussis toxin. Five days later, they were boosted by a subcutaneous injection of ovalbumin into the back. From day 18 after the first immunization to day 39, intranasal sensitization with ovalbumin was performed every day and the severity of allergic rhinitis was observed by measuring nasal allergic responses and total IgE levels. It was found that the intranasal administration of antigen caused a significant increase of nasal sneezing and rubbing from day 25 to day 39 both in sensitized HDC-KO and wild-type mice. In addition, a significant elevation of total IgE levels in serum was also found both in sensitized HDC-KO and wild-type mice from day 18 to day 39 after the first immunization. L-733,060, a tachykinin NK(1) receptor antagonist at a dose of 10 mg/kg (s.c.), resulted in the dose-dependent inhibition of nasal allergic responses induced by antigen in both HDC-KO and wild-type mice. In addition, both chlorpheniramine at doses of 3 and 10 mg/kg (p.o.) and BW A868C at doses of 0.3 and 1 mg/kg (i.v.) also showed a dose-related reduction of the nasal allergic responses induced by antigen in sensitized wild-type mice. On the other hand, they had no effects on the nasal signs induced by antigen in HDC-KO mice. From these results, it was revealed that substance P induces nasal allergic responses in the mouse model of chronic allergic rhinitis through the activation of tachykinin NK(1) receptors. Therefore, it can be concluded that not only histamine, but also substance P and prostaglandin D(2), participated in the nasal allergic responses induced by antigen in mice.
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- 2007
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22. Development of new atopic dermatitis models characterized by not only itching but also inflammatory skin in mice.
- Author
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Yatsuzuka R, Inoue T, Jiang S, Nakano Y, and Kamei C
- Subjects
- Animals, Dexamethasone therapeutic use, Female, Histamine H1 Antagonists therapeutic use, Immunoglobulin E blood, Mice, Mice, Inbred BALB C, Naloxone therapeutic use, Ovalbumin immunology, Skin pathology, Dermatitis, Atopic etiology, Disease Models, Animal, Pruritus etiology
- Abstract
The present study was performed to develop a new atopic dermatitis model characterized by not only itching but also inflammatory skin using BALB/c mice. From 18 days after the first systemic immunization, daily epicutaneous application of ovalbumin was performed for 2 weeks. Antigen challenge (ovalbumin) resulted in a significant increase of scratching behavior from day 23 to day 32. Moreover, skin symptoms such as erythema/hemorrhage, edema, excoriation/erosion and dryness/desquamation were also observed from day 19 to day 32. The frequency of scratching in the first stage (from day 24 to day 26 after the systemic first immunization) was decreased by chlorpheniramine and epinastine; however, in the last stage (from day 27 to day 30 after the systemic first immunization), both drugs showed no inhibition of scratching behavior. Therefore, an endogenous mediator other than histamine may be responsible for provoking the itching sensation in the last stage. Naloxone dose-dependently reduced the frequency of scratching in the last stage. Moreover, repeated local application of dexametasone significantly inhibited both scratching behavior and skin symptoms from day 24 to day 30. From these findings, it may be concluded that this model is essentially similar to atopic dermatitis in humans and could be used to elucidate the pathogenic mechanisms of atopic dermatitis and to develop appropriate new drugs for therapy.
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- 2007
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23. Effects of co-administration of antidepressants and monoamine oxidase inhibitors on 5-HT-related behavior in rats.
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Izumi T, Iwamoto N, Kitaichi Y, Kato A, Inoue T, and Koyama T
- Subjects
- 5-Hydroxytryptophan pharmacology, Animals, Cyclopropanes pharmacology, Drug Interactions, Imipramine pharmacology, Male, Mianserin pharmacology, Milnacipran, Rats, Rats, Sprague-Dawley, Antidepressive Agents pharmacology, Monoamine Oxidase Inhibitors pharmacology, Serotonin metabolism, Serotonin Syndrome chemically induced
- Abstract
5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur during co-administration of a monoamine oxidase (MAO) inhibitor and an antidepressant. We investigated the effects of acute administration of MAO inhibitors and subchronic administration of tricyclic and heterocyclic antidepressants, and a serotonin-noradrenaline reuptake inhibitor (SNRI) on 5-HT syndrome in rats treated with 5-hydroxytryptophan (5-HTP). The irreversible and non-selective MAO inhibitor pargyline, and the reversible and selective MAO-A inhibitor clorgyline, produced increases in 5-HT syndrome in the 5-HTP-treated rats, while subchronic co-administration of imipramine partly intensified and partly attenuated the syndrome, whereas milnacipran only attenuated the syndrome. Co-administration of mianserin partly intensified and partly attenuated the syndrome but the attenuating effect was dominant. Administration of the irreversible and selective MAO-B inhibitor selegiline did not produce any increase in 5-HT syndrome in the 5-HTP-treated rats, compared with the saline control. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with antidepressants. Furthermore, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor selegiline.
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- 2007
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24. Effects of TS-022, a newly developed prostanoid DP1 receptor agonist, on experimental pruritus, cutaneous barrier disruptions and atopic dermatitis in mice.
- Author
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Arai I, Takaoka A, Hashimoto Y, Honma Y, Koizumi C, Futaki N, Sugimoto M, Takahashi N, Inoue T, Nakanishi Y, Sakurai T, Tanami T, Yagi M, Ono N, and Nakaike S
- Subjects
- Animals, Concanavalin A immunology, Cytokines biosynthesis, Dermatitis, Atopic immunology, Dermatitis, Atopic metabolism, Dexamethasone pharmacology, Humans, Hydantoins pharmacology, Inflammation drug therapy, Inflammation immunology, Male, Mice, Platelet Aggregation drug effects, Prostaglandin D2 metabolism, Pruritus immunology, Pruritus metabolism, Skin immunology, Skin injuries, Tacrolimus pharmacology, Wound Healing drug effects, Acetates pharmacology, Antipruritics pharmacology, Cyclohexanes pharmacology, Dermatitis, Atopic drug therapy, Immunosuppressive Agents pharmacology, Pruritus drug therapy, Receptors, Immunologic agonists, Receptors, Prostaglandin agonists, Skin drug effects, Sulfhydryl Compounds pharmacology
- Abstract
TS-022, {4-[(1R, 2S, 3R, 5R)-5-Chloro-2-((S)-3-cyclohexyl-3-hydroxyprop-1-ynyl)-3-hydroxycyclopentyl] butylthio} acetic acid monohydrate, inhibits ADP-induced platelet aggregation, an effect significantly antagonized, as in the case of prostaglandin D(2) by the prostanoid DP(1) receptor antagonist (BW A868C). TS-022 is a prostanoid DP(1) receptor agonist, originally developed as a novel anti-pruritic drug for patients with atopic dermatitis. We examined the effects of TS-022 on experimental pruritus, cutaneous barrier disruption, and atopic dermatitis and in in vitro immune function tests. Topically applied TS-022 significantly suppressed scratching in skin-lesioned NC/Nga mice from a concentration of 2.5 nM, and this scratch-suppressive activity was significantly antagonized by BW A868C. Tacrolimus (FK-506) and dexamethasone, used as reference drugs for atopic dermatitis, also exhibited suppressive effects against scratching, but only at concentrations of 125 and 25,000 microM. TS-022 applied topically, once a day for 2 days, significantly accelerated repair of the cutaneous barrier disruption caused by mechanical scratching, from concentrations of 2.5 nM. This acceleration of repair of the disrupted cutaneous barrier by this drug was also significantly antagonized by BW A868C. FK-506 and dexamethasone showed no beneficial effects on the repair of the disrupted cutaneous barrier. Repeated topical application of 2.5 microM of TS-022 and 12.5 microM of FK-506 once a day for 6 weeks significantly improved the skin inflammation scores in the NC/Nga mice. In regard to the effects of TS-022 in vitro, the inhibitory activity of TS-022 against concanavalin A-induced cytokine production by splenocytes was marginal as compared with that of FK-506 or dexamethasone. These results suggest that the beneficial therapeutic effects of TS-022 in NC/Nga mice with atopic dermatitis are mediated by its suppressive effect on scratching and its effect of accelerating repair of the disrupted cutaneous barrier, both effects being attributable to its prostanoid DP(1) receptor agonistic activity.
- Published
- 2007
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25. Interactive effect of histamine and prostaglandin D2 on nasal allergic symptoms in rats.
- Author
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Rahman A, Inoue T, Ago J, Ishikawa T, and Kamei C
- Subjects
- Administration, Intranasal, Administration, Oral, Animals, Carbazoles administration & dosage, Carbazoles pharmacology, Chlorpheniramine administration & dosage, Chlorpheniramine pharmacology, Cyproheptadine administration & dosage, Cyproheptadine pharmacology, Dose-Response Relationship, Drug, Drug Synergism, Histamine immunology, Histamine Agents administration & dosage, Histamine Agents immunology, Histamine H1 Antagonists administration & dosage, Histamine H1 Antagonists pharmacology, Hydantoins administration & dosage, Hydantoins pharmacology, Injections, Intravenous, Nasal Mucosa immunology, Nasal Mucosa pathology, Prostaglandin D2 immunology, Rats, Rats, Wistar, Receptors, Immunologic antagonists & inhibitors, Receptors, Prostaglandin antagonists & inhibitors, Rhinitis chemically induced, Rhinitis prevention & control, Sneezing immunology, Sulfonamides administration & dosage, Sulfonamides pharmacology, Histamine administration & dosage, Nasal Mucosa drug effects, Prostaglandin D2 administration & dosage, Sneezing drug effects
- Abstract
This study was undertaken to investigate the interactive effect of histamine and prostaglandin D(2) in nasal allergic symptoms in rats. The intranasal application of histamine at doses lower than 10 mumol/site caused no sneezing or nasal rubbing. In addition, prostaglandin D(2) also showed no significant increase in these responses, even at a dose of 10 nmol/site. On the other hand, the simultaneous instillation of histamine and prostaglandin D(2) resulted in a 1000 times more potent effect in inducing nasal symptoms than the administration of histamine alone. Thus, prostaglandin D(2) enhanced the actions of histamine in inducing sneezing and nasal rubbing in a dose-dependent manner, and significant effects were observed at doses higher than 1 nmol/site. The responses induced by the simultaneous application of histamine and prostaglandin D(2) were inhibited by chlorpheniramine, cyproheptadine, BW A868C and ramatroban. Chlorpheniramine and cyproheptadine showed the dose-related inhibition of nasal symptoms induced by the combined administration of histamine (10 nmol) and prostaglandin D(2) (10 nmol), but the effect of cyproheptadine was relatively weak compared with chlorpheniramine. Moreover, BW A868C and ramatroban also showed the inhibition of nasal symptoms induced by the simultaneous administration of histamine and prostaglandin D(2) in a dose-dependent manner. BW A868C was more potent in inhibiting the nasal symptoms than ramatroban. These results clearly indicate that prostaglandin D(2) showed a synergistic effect on sneezing and nasal rubbing induced by histamine in rats, and its effect occurred through both prostaglandin D(2) and CRTH2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) receptors.
- Published
- 2007
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26. Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: a comparison with diazepam and buspirone.
- Author
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Harada K, Aota M, Inoue T, Matsuda R, Mihara T, Yamaji T, Ishibashi K, and Matsuoka N
- Subjects
- Animals, CHO Cells, Calcium metabolism, Calcium Signaling drug effects, Central Nervous System Depressants pharmacology, Cricetinae, Drug Interactions, Ethanol pharmacology, Exploratory Behavior drug effects, Feeding Behavior drug effects, Hexobarbital pharmacology, Hypnotics and Sedatives pharmacology, Interpersonal Relations, Male, Mesylates pharmacokinetics, Motor Activity drug effects, Neurotransmitter Transport Proteins metabolism, Piperazines, Postural Balance drug effects, Quinazolines pharmacokinetics, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Serotonin Antagonists pharmacokinetics, Sleep drug effects, Anti-Anxiety Agents, Buspirone pharmacology, Diazepam pharmacology, Mesylates pharmacology, Quinazolines pharmacology, Receptor, Serotonin, 5-HT2C drug effects, Serotonin Antagonists pharmacology
- Abstract
Hyperfunction of brain 5-hydroxytryptamine(2C) (5-HT(2C)) receptor is suggested to be involved in anxiety as evidenced by the fact that a putative 5-HT(2C) receptor agonist 1-(m-chlorophenyl)-piperazine (m-CPP) causes anxiety in humans. We have recently identified FR260010 (N-[3-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6-dihydrobenzo[h]quinazolin-4-amine dimethanesulfonate) as novel 5-HT(2C) receptor antagonist from diaryl amine derivatives, and here characterized in vitro and in vivo profiles of the compound. FR260010 showed high affinity for human 5-HT(2C) receptor (K(i): 1.10 nM) and high selectivity over 5-hydroxytryptamine(2A) (5-HT(2A)) receptor (K(i): 386 nM) and many other transmitter receptors. FR260010 showed antagonist activity at human 5-HT(2C) receptor in an intracellular calcium assay and showed no detectable intrinsic activity. The compound dose-dependently inhibited the hypolocomotion (ID(50): 1.89 mg/kg, p.o.) and hypophagia (ID(50): 2.84 mg/kg, p.o.) in rats induced by m-CPP, putative indices of brain 5-HT(2C) receptor antagonist activity. We then compared the effects of FR260010 with those of two other anxiolytics belonging to different classes, diazepam and buspirone, in anxiety models in rats and mice and adverse effect tests in mice. FR260010 (0.1-3.2 mg/kg, p.o.) and diazepam (1-10 mg/kg, p.o.) decreased behavioral indices of anxiety in all models, whereas buspirone (0.32-10 mg/kg, p.o.) did not significantly affect them in any models. In adverse effect tests, FR260010 and buspirone showed modest effects, whereas diazepam showed significant effects in all tests. These results suggest that FR260010 is a novel, potent, orally active and brain penetrable antagonist of 5-HT(2C) receptor, and may have therapeutic potential for treatment of anxiety, with more desirable profiles than benzodiazepines or 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonists.
- Published
- 2006
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27. E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, is a novel, selective and competitive dipeptidyl peptidase-IV inhibitor.
- Author
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Yasuda N, Nagakura T, Inoue T, Yamazaki K, Katsutani N, Takenaka O, Clark R, Matsuura F, Emori E, Yoshikawa S, Kira K, Ikuta H, Okada T, Saeki T, Asano O, and Tanaka I
- Subjects
- Animals, Blood Glucose analysis, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases blood, Dogs, Female, Glucagon-Like Peptide 1 blood, Humans, Hypoglycemic Agents pharmacokinetics, Hypoglycemic Agents toxicity, Imidazoles pharmacokinetics, Imidazoles toxicity, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells pathology, Male, Mice, No-Observed-Adverse-Effect Level, Protease Inhibitors pharmacokinetics, Protease Inhibitors toxicity, Pyridazines pharmacokinetics, Pyridazines toxicity, Rats, Rats, Sprague-Dawley, Rats, Wistar, Rats, Zucker, Recombinant Proteins metabolism, Tosyl Compounds pharmacokinetics, Tosyl Compounds toxicity, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases antagonists & inhibitors, Hypoglycemic Agents pharmacology, Imidazoles pharmacology, Protease Inhibitors pharmacology, Pyridazines pharmacology, Tosyl Compounds pharmacology
- Abstract
Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate, which is a novel imidazopyridazinone-derived DPP-IV inhibitor. E3024 inhibited recombinant human and mouse DPP-IV with IC50 values of approximately 100 nM. E3024 inhibited DPP-IV in human, mouse, rat and canine plasma with IC50 values of 140 to 400 nM. In contrast, E3024 did not inhibit DPP-8 or DPP-9 activity. Kinetic analysis indicated that E3024 is a competitive DPP-IV inhibitor. In Zucker fa/fa rats, E3024 (1 mg/kg) reduced glucose excursion after glucose load, with increases in plasma insulin and active glucagon-like peptide-1 levels. In fasted rats, this compound did not cause hypoglycemia. In a rat 4-week toxicological study, no notable changes were found at doses up to 750 mg/kg. The present preclinical studies indicate that E3024 is a novel selective DPP-IV inhibitor with anti-diabetic effects and a good safety profile.
- Published
- 2006
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28. Effect of combined treatment with noradrenaline and serotonin reuptake inhibitors on conditioned freezing.
- Author
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Inoue T, Nakagawa S, Izumi T, Kitaichi Y, and Koyama T
- Subjects
- Analysis of Variance, Animals, Antidepressive Agents pharmacology, Behavior, Animal drug effects, Conditioning, Psychological, Dose-Response Relationship, Drug, Drug Synergism, Fear psychology, Male, Norepinephrine metabolism, Rats, Rats, Sprague-Dawley, Reboxetine, Citalopram pharmacology, Fear drug effects, Morpholines pharmacology, Norepinephrine antagonists & inhibitors, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
To clarify the therapeutic interaction between serotonin and noradrenaline reuptake inhibition on fear, this study examined the acute and subchronic effects of combined treatment with the selective serotonin reuptake inhibitor citalopram and the selective noradrenaline reuptake inhibitor reboxetine on the expression of conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks). After fear conditioning was achieved with footshocks, the drugs were administered to rats and freezing behavior, as an index of fear, was observed in the shock chamber. Acute and subchronic treatment with citalopram was reproducibly anxiolytic against conditioned freezing. Acute reboxetine worsened conditioned freezing and reversed the acute anxiolytic effects of citalopram, but this anxiogenic effect of noradrenaline reuptake inhibition was not observed after subchronic treatment. These results suggest that adding noradrenaline reuptake inhibitors to serotonin reuptake inhibitors adversely affects fear, at least with acute treatment.
- Published
- 2006
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29. Target brain sites of the anxiolytic effect of citalopram, a selective serotonin reuptake inhibitor.
- Author
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Izumi T, Inoue T, Kitaichi Y, Nakagawa S, and Koyama T
- Subjects
- Amygdala metabolism, Animals, Anti-Anxiety Agents therapeutic use, Anxiety drug therapy, Anxiety metabolism, Citalopram therapeutic use, Conditioning, Psychological drug effects, Disease Models, Animal, Electric Stimulation, Fear, Male, Motor Activity drug effects, Motor Cortex drug effects, Motor Cortex metabolism, Proto-Oncogene Proteins c-fos metabolism, Rats, Rats, Sprague-Dawley, Selective Serotonin Reuptake Inhibitors therapeutic use, Somatosensory Cortex drug effects, Somatosensory Cortex metabolism, Amygdala drug effects, Anti-Anxiety Agents pharmacology, Citalopram pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
The purpose of the present study was to elucidate the brain regions in which citalopram, a selective serotonin reuptake inhibitor (SSRI), exerts its anxiolytic effects in conditioned fear stress (CFS) in rats, an animal model of anxiety. The effect of citalopram on CFS-induced c-Fos expression was investigated using immunohistochemistry. Systemic administration of citalopram attenuated contextual CFS-induced c-Fos expression in the secondary motor cortex, primary somatosensory cortex, and basolateral nucleus of the amygdala. Among these regions the basolateral nucleus of the amygdala is a likely candidate region in which citalopram exerts its anxiolytic effect.
- Published
- 2006
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30. Effects of co-administration of a selective serotonin reuptake inhibitor and monoamine oxidase inhibitors on 5-HT-related behavior in rats.
- Author
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Izumi T, Iwamoto N, Kitaichi Y, Kato A, Inoue T, and Koyama T
- Subjects
- Analysis of Variance, Animals, Brain drug effects, Brain enzymology, Clorgyline toxicity, Dose-Response Relationship, Drug, Drug Synergism, Fluvoxamine toxicity, Male, Motor Activity drug effects, Pargyline toxicity, Rats, Rats, Sprague-Dawley, Selegiline toxicity, Serotonin, Serotonin Syndrome metabolism, Behavior, Animal drug effects, Monoamine Oxidase Inhibitors toxicity, Serotonin Syndrome etiology, Selective Serotonin Reuptake Inhibitors toxicity
- Abstract
5-hydroxytryptamine (5-HT) syndrome is a dangerous condition of 5-HT excess that can occur in the case of co-administration of a monoamine oxidase (MAO) inhibitor and a serotonin reuptake inhibitor (SSRI). The goal of the present study was to investigate the effects of acute administration of MAO inhibitors and subchronic administration of fluvoxamine on 5-HT-related behaviors (head shaking and 5-HT syndrome) in rats treated with 5-hydroxytryptophan (5-HTP). Administration of the non-selective MAO inhibitor, pargyline, and the selective MAO-A inhibitor, clorgyline, resulted in 5-HT syndrome in 5-HTP-treated rats, and subchronic co-administration of fluvoxamine intensified the syndrome. However, administration of the selective MAO-B inhibitor, selegiline, did not induce 5-HT syndrome with or without subchronic fluvoxamine co-administration. These data suggest that non-selective MAO and selective MAO-A inhibitors can induce 5-HT syndrome in humans when co-administered with SSRI. Further, the risk of 5-HT syndrome may be lower with the selective MAO-B inhibitor, selegiline.
- Published
- 2006
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31. Effect of co-administration of subchronic lithium pretreatment and acute MAO inhibitors on extracellular monoamine levels and the expression of contextual conditioned fear in rats.
- Author
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Kitaichi Y, Inoue T, Nakagawa S, Izumi T, and Koyama T
- Subjects
- Animals, Antidepressive Agents therapeutic use, Anxiety metabolism, Behavior, Animal drug effects, Clorgyline pharmacology, Clorgyline therapeutic use, Dopamine metabolism, Dose-Response Relationship, Drug, Drug Combinations, Fear, Lithium Carbonate therapeutic use, Male, Models, Animal, Monoamine Oxidase Inhibitors therapeutic use, Motor Activity drug effects, Norepinephrine metabolism, Picolinic Acids pharmacology, Picolinic Acids therapeutic use, Prefrontal Cortex metabolism, Rats, Rats, Sprague-Dawley, Serotonin metabolism, Antidepressive Agents pharmacology, Anxiety drug therapy, Lithium Carbonate pharmacology, Monoamine Oxidase Inhibitors pharmacology, Prefrontal Cortex drug effects
- Abstract
We investigated the effects of clorgyline [a selective MAO (monoamine oxidase inhibitor)-A inhibitor] and lazabemide (a selective MAO-B inhibitor) on extracellular serotonin, dopamine and noradrenaline concentrations in the medial prefrontal cortex after 1-week treatment with subchronic 0.2% or 0.05% Li2CO3 (p.o.) and the effects on expression of contextual conditioned fear, previously reported to be reduced by facilitation of serotonin neurotransmission. As compared to normal diet controls, the subchronic 0.2% Li2CO3 group showed significantly higher levels of extracellular serotonin, but not noradrenaline. No changes were observed in the 0.05% Li2CO3 group. Acute clorgyline (10 mg/kg) treatments combined with subchronic 0.2% Li2CO3 treatments showed significant increases in extracellular serotonin concentrations, but not in dopamine or noradrenaline, as compared with clorgyline treatment alone. There was an additive effect with combined treatment of subchronic 0.2% Li2CO3 and acute clorgyline on the reduction of conditioned freezing, an index of conditioned fear, and this was not observed with subchronic 0.05% Li2CO3. These behavioral data indicate the functional significance of increased extracellular serotonin concentrations due to combined use of a MAO-A inhibitor with subchronic lithium. Effects of lazabemide (10 mg/kg) on extracellular monoamine concentrations and conditioned fear were slight or negligible, and were not affected by subchronic lithium treatment. The present study suggests that lithium augmentation of the antidepressant effect of MAO inhibitors is mediated by additional increases in the extracellular serotonin concentrations induced by MAO-A inhibition and suggests that the anxiolytic action of MAO inhibitors may be enhanced by lithium.
- Published
- 2006
- Full Text
- View/download PDF
32. Role of substance P in allergic nasal symptoms in rats.
- Author
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Rahman MA, Inoue T, and Kamei C
- Subjects
- Animals, Antigens immunology, Cyproheptadine pharmacology, Dibenzazepines pharmacology, Dibenzoxepins pharmacology, Dose-Response Relationship, Drug, Electroencephalography drug effects, Histamine H1 Antagonists pharmacology, Hypersensitivity immunology, Hypersensitivity prevention & control, Imidazoles pharmacology, Male, Neurokinin-1 Receptor Antagonists, Olopatadine Hydrochloride, Rats, Rats, Wistar, Tryptophan analogs & derivatives, Tryptophan pharmacology, Hypersensitivity physiopathology, Sneezing drug effects, Substance P toxicity
- Abstract
The present study was undertaken to investigate the pathological role of substance P in allergic nasal symptoms in rats. The topical application of substance P caused an increase in the incidence of sneezing and nasal rubbing in a dose-dependent fashion, and at a dose of 30 nM/site it showed a significant effect. L-732,138, a tachykinin NK(1) receptor antagonist, at doses of 3 and 10 mg/kg showed a significant inhibition of the nasal signs induced by exogenous substance P in rats. In addition, L-732,138 also showed a significant inhibition of nasal behavior induced by antigen in actively sensitized rats at the same dose. On the other hand, histamine H(1) receptor antagonists, such as cyproheptadine, epinastine and olopatadine had no effect on the nasal behaviors induced by exogenous substance P, even at higher doses, indicating that exogenous substance P does not cause the degranulation of mucosal mast cells in the rat. Moreover, all the histamine H(1) receptor antagonists showed the dose-dependent inhibition of the nasal signs induced by antigen in actively sensitized rats, which revealed that the inhibition of these drugs was exhibited through the antagonistic effect on histamine H(1) receptors. Therefore, from these results, it is reasonable to conclude that substance P released from the nasal mucosa through the activation of tachykinin NK(1) receptors during the antigen antibody reaction plays an important role in allergic nasal symptoms.
- Published
- 2006
- Full Text
- View/download PDF
33. 5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala.
- Author
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Li X, Inoue T, Abekawa T, Weng S, Nakagawa S, Izumi T, and Koyama T
- Subjects
- Amygdala anatomy & histology, Amygdala physiology, Animals, Behavior, Animal drug effects, Fear psychology, Hippocampus anatomy & histology, Hippocampus physiology, Male, Microinjections, Motor Activity drug effects, Piperazines administration & dosage, Prefrontal Cortex physiology, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT1A physiology, Serotonin Receptor Agonists administration & dosage, Serotonin Receptor Agonists pharmacology, Synapses drug effects, Synapses physiology, Amygdala drug effects, Conditioning, Psychological drug effects, Fear drug effects, Hippocampus drug effects, Piperazines pharmacology, Serotonin 5-HT1 Receptor Agonists
- Abstract
Evidence from preclinical and clinical studies has shown that 5-HT(1A) receptor agonists have anxiolytic actions. The anxiolytic actions of 5-HT(1A) receptor agonists have been tested by our previous studies using fear conditioning. However, little is known about the brain regions of anxiolytic actions of 5-HT(1A) receptor agonists in this paradigm. In the present study, we investigated the effects of bilateral microinjections of flesinoxan, a selective 5-HT(1A) receptor agonist, into the hippocampus, amygdala and medial prefrontal cortex on the expression of contextual conditioned freezing and the defecation induced by conditioned fear stress in rats. These results reveal that both intrahippocampal and intraamygdala injections of flesinoxan decreased the expression of conditioned freezing, while injections into the medial prefrontal cortex did not. In addition, intraamygdala injection of flesinoxan attenuated the increased defecation induced by conditioned fear, but injections into the hippocampus and medial prefrontal cortex failed. These results suggest that flesinoxan exerts its anxiolytic actions in the fear conditioning through stimulations of the postsynaptic 5-HT(1A) receptors in the hippocampus and amygdala.
- Published
- 2006
- Full Text
- View/download PDF
34. FK962, a novel enhancer of somatostatin release, exerts cognitive-enhancing actions in rats.
- Author
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Tokita K, Inoue T, Yamazaki S, Wang F, Yamaji T, Matsuoka N, and Mutoh S
- Subjects
- Aging, Amnesia chemically induced, Amnesia physiopathology, Amnesia prevention & control, Animals, Animals, Newborn, Avoidance Learning drug effects, Basal Nucleus of Meynert drug effects, Basal Nucleus of Meynert physiopathology, Benzamides chemistry, Calcium metabolism, Dose-Response Relationship, Drug, Hippocampus cytology, Hippocampus drug effects, Hippocampus metabolism, Male, Maze Learning drug effects, Membrane Potentials drug effects, Neurons drug effects, Neurons metabolism, Neurons physiology, Nootropic Agents chemistry, Patch-Clamp Techniques, Piperazines chemistry, Piperidines chemistry, Potassium pharmacology, Rats, Rats, Inbred F344, Scopolamine administration & dosage, Somatostatin pharmacology, Benzamides pharmacology, Nootropic Agents pharmacology, Piperazines pharmacology, Piperidines pharmacology, Somatostatin metabolism
- Abstract
FK962 (N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide) is a derivative of FK960 (N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate), with putative anti-dementia properties. Here, we wanted to determine whether FK962 retained the ability of the parent compound to both facilitate somatostatinergic nerve activity in hippocampal neurons and to ameliorate cognitive dysfunction in rat models. FK962 (10(-9) - 10(- 6) M) significantly enhanced high K+-evoked somatostatin release from rat hippocampal slices. FK962 also significantly reduced somatostatin-induced inhibition of Ca2+ channels at 10(-9) - 10(-7) M in single rat hippocampal neurons using whole-cell patch-clamp. Furthermore, administration of FK962 (0.032-3.2 mg/kg, i.p.) significantly ameliorated memory deficits in passive avoidance task in animal models: scopolamine-treated rats, nucleus basalis magnocellularis-lesioned rats and aged rats. FK962 (0.01- 1) mg/kg, i.p.) significantly improved spatial memory deficits induced by nucleus basalis magnocellularis-lesion in water maze task. These results suggest that FK962 ameliorates cognitive impairment in rats via activation of the somatostatinergic nervous system in the hippocampus, indicating that FK962 could be a potent cognitive enhancer and therefore might be of therapeutic value for cognitive disorders such as Alzheimer's disease.
- Published
- 2005
- Full Text
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35. Subchronic milnacipran treatment increases basal extracellular noradrenaline concentrations in the medial prefrontal cortex of rats.
- Author
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Kitaichi Y, Inoue T, Izumi T, Nakagawa S, Kato A, and Koyama T
- Subjects
- Administration, Oral, Animals, Antidepressive Agents, Second-Generation administration & dosage, Cyclopropanes administration & dosage, Dopamine metabolism, Male, Microdialysis, Milnacipran, Prefrontal Cortex metabolism, Rats, Rats, Sprague-Dawley, Serotonin metabolism, Synaptic Transmission drug effects, Antidepressive Agents, Second-Generation pharmacology, Cyclopropanes pharmacology, Norepinephrine metabolism, Prefrontal Cortex drug effects
- Abstract
In this study, we investigated the acute effects of milnacipran, a serotonin-noradrenaline reuptake inhibitor, following subchronic treatment with milnacipran (30 mg/kg periorally for 7 days) on extracellular noradrenaline, dopamine and serotonin concentrations in the medial prefrontal cortex. Subchronic administration of milnacipran produced significantly higher basal levels of extracellular noradrenaline. Acute milnacipran administration following subchronic milnacipran treatment for 7 days produced a greater increase in extracellular noradrenaline than a single dose of milnacipran alone. The present results suggest that subchronic milnacipran treatment enhances noradrenergic neural transmission beyond that achieved with acute administration of milnacipran alone, but has no effect on serotonergic or dopaminergic neural transmission.
- Published
- 2005
- Full Text
- View/download PDF
36. Effect of a dopamine D1/5 receptor antagonist on haloperidol-induced inhibition of the acquisition of conditioned fear.
- Author
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Inoue T, Izumi T, Li XB, Kitaichi Y, Nakagawa S, and Koyama T
- Subjects
- Analysis of Variance, Animals, Anxiety psychology, Behavior, Animal drug effects, Benzazepines pharmacology, Dopamine Antagonists pharmacology, Dose-Response Relationship, Drug, Fear psychology, Lithium Carbonate pharmacology, Male, Quinolines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D1 physiology, Receptors, Dopamine D5, Serotonin Antagonists pharmacology, Conditioning, Psychological drug effects, Fear drug effects, Haloperidol pharmacology, Receptors, Dopamine D1 antagonists & inhibitors
- Abstract
This study examined the effects of combined treatment with the typical antipsychotic drug haloperidol and dopamine D1/5 receptor antagonist SCH 23390 on the acquisition of contextual conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks), compared with those of various antipsychotic adjuvants, which may increase the effects of antipsychotic drugs. Rats were treated subcutaneously with haloperidol (3 mg/kg) combined with SCH 23390 (0.03 mg/kg) and were given fear conditioning by 5 min footshocks in shock chambers 30 min after the injection. One week after the footshocks, the rats were tested in the same shock chamber without shocks and freezing behavior was observed as an index of fear and anxiety. Haloperidol significantly inhibited the acquisition of conditioned freezing. SCH 23390 combined with haloperidol inhibited the acquisition of conditioned freezing more than either drug alone did. These results suggest that combined dopamine D2-like receptor antagonism and dopamine D1-like receptor antagonism is a promising and effective strategy to increase antipsychotic effects.
- Published
- 2005
- Full Text
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37. Effect of milnacipran on extracellular monoamine concentrations in the medial prefrontal cortex of rats pre-treated with lithium.
- Author
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Kitaichi Y, Inoue T, Nakagawa S, Izumi T, and Koyama T
- Subjects
- Animals, Antidepressive Agents pharmacology, Dopamine metabolism, Dose-Response Relationship, Drug, Extracellular Space drug effects, Extracellular Space metabolism, Injections, Intraperitoneal, Male, Microdialysis, Milnacipran, Norepinephrine metabolism, Prefrontal Cortex metabolism, Rats, Rats, Sprague-Dawley, Serotonin metabolism, Time Factors, Biogenic Monoamines metabolism, Cyclopropanes pharmacology, Lithium Compounds pharmacology, Prefrontal Cortex drug effects
- Abstract
Antidepressants are effective in most patients with depression, but sometimes have sub-optimal effects. Thus, there is a need to use more powerful antidepressants when dealing with treatment-resistant cases. Lithium carbonate is widely used for this purpose. We investigated the acute effects of milnacipran, a serotonin-noradrenaline reuptake inhibitor, on extracellular serotonin, dopamine and noradrenaline concentrations, in the rat medial prefrontal cortex. The effects of milnacipran were examined in rats following 7 days of treatment with lithium, and in untreated controls. The lithium group had significantly greater basal levels of extracellular serotonin than the control group. Milnacipran (3 mg/kg) combined with lithium treatment caused a greater increase in extracellular noradrenaline and dopamine levels than milnacipran alone. Milnacipran (3 and 30 mg/kg) combined with lithium treatment also caused a greater increase in extracellular serotonin levels than milnacipran alone. Thus, lithium might augment the antidepressant effects of serotonin-noradrenaline reuptake inhibitors by augmenting serotonin release.
- Published
- 2005
- Full Text
- View/download PDF
38. Pharmacological and pharmacokinetic study of olmesartan medoxomil in animal diabetic retinopathy models.
- Author
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Nakamura H, Inoue T, Arakawa N, Shimizu Y, Yoshigae Y, Fujimori I, Shimakawa E, Toyoshi T, and Yokoyama T
- Subjects
- Angiotensin II Type 1 Receptor Blockers pharmacokinetics, Animals, Area Under Curve, Benzimidazoles pharmacokinetics, Benzimidazoles pharmacology, Biphenyl Compounds pharmacokinetics, Biphenyl Compounds pharmacology, Blood Glucose metabolism, Blood Pressure drug effects, Body Weight drug effects, Diabetes Mellitus, Experimental complications, Diabetes Mellitus, Experimental physiopathology, Diabetic Retinopathy blood, Diabetic Retinopathy physiopathology, Disease Models, Animal, Dose-Response Relationship, Drug, Electroretinography, Glycated Hemoglobin metabolism, Heart Rate drug effects, Hypertension complications, Hypertension physiopathology, Hypoxia physiopathology, Imidazoles pharmacokinetics, Male, Olmesartan Medoxomil, Oxygen pharmacology, Rats, Rats, Inbred SHR, Retinal Neovascularization metabolism, Retinal Neovascularization physiopathology, Retinal Neovascularization prevention & control, Tetrazoles pharmacokinetics, Angiotensin II Type 1 Receptor Blockers pharmacology, Diabetic Retinopathy prevention & control, Imidazoles pharmacology, Tetrazoles pharmacology
- Abstract
A close relationship between the renin-angiotensin system and the pathophysiology of diabetic retinopathy has been suggested, several angiotensin II type 1 receptor (angiotensin AT1 receptor) antagonists being effective in animal models. Therefore, we examined the efficacy of an angiotensin AT1 receptor antagonist, olmesartan medoxomil (CS-866), in animal retinopathy models. In diabetic stroke-prone spontaneously hypertensive (SHRSP) rats, 4-week treatment with CS-866 prevented the elongation of oscillatory potential peaks dose-dependently which almost normalized at 3 mg/kg/day. Next, in oxygen-induced retinopathy mice, CS-866 at 1 mg/kg significantly prevented the retinal neovascularization. In these animal models, plasma concentrations of CS-866 were comparable to the in vitro IC50 value of the angiotensin AT1 receptor. In summary, our data demonstrated that CS-866 was effective in early and late stage retinopathy models through the inhibition of the angiotensin AT1 receptor. These findings suggest the possibility of CS-866 as a therapeutic agent for diabetic retinopathy.
- Published
- 2005
- Full Text
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39. Prostanoid DP1 receptor agonist inhibits the pruritic activity in NC/Nga mice with atopic dermatitis.
- Author
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Arai I, Takano N, Hashimoto Y, Futaki N, Sugimoto M, Takahashi N, Inoue T, and Nakaike S
- Subjects
- 6-Ketoprostaglandin F1 alpha metabolism, Alprostadil pharmacology, Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Arachidonic Acid pharmacology, Behavior, Animal drug effects, Dinoprost metabolism, Dinoprostone metabolism, Dinoprostone pharmacology, Dose-Response Relationship, Drug, Epoprostenol pharmacology, Histamine administration & dosage, Indomethacin pharmacology, Male, Mice, Mice, Inbred ICR, Mice, Inbred Strains, Prostaglandin D2 metabolism, Prostaglandin D2 pharmacology, Prostaglandins metabolism, Pruritus etiology, Skin drug effects, Skin metabolism, Skin pathology, Time Factors, Dermatitis, Atopic complications, Prostaglandin D2 analogs & derivatives, Prostaglandins pharmacology, Pruritus prevention & control, Receptors, Prostaglandin agonists
- Abstract
NC/Nga mice have similar pathological and behavioral features of human atopic dermatitis and are used as a model of the disease. Under conventional circumstances, spontaneous and persistent scratching is frequent and can lead to the onset of skin inflammation. We examined the effects of several prostanoids and their related compounds on the scratching behavior of NC/Nga mice. Among them, topically applied prostaglandin D2, prostaglandin E1, prostaglandin E2 and prostaglandin I2 significantly suppressed the scratching, the order of inhibitory activities being prostaglandin D2>>prostaglandin I2>prostaglandin E1=prostaglandin E2. Prostaglandin D2 metabolite, prostaglandin J2 also significantly suppressed the scratching but not so 13,14-dihydro-15-keto-prostaglandin D2, and 15-deoxy-Delta12,14-prostaglandin J2. The order of the inhibitory activities of these prostaglandin D2 metabolites depended on affinity of the prostanoid DP1 receptor but not on the DP2 receptor (chemoattractant receptor-homologous molecule expressed on T helper2 cells, CRTH2) and PPAR-gamma receptors. Likewise, topically applied arachidonic acid significantly suppressed the scratching while indomethacin enhanced it. Pretreatment of arachidonic acid increased the skin prostaglandins (prostaglandin D2, prostaglandin E2, prostaglandin F2alpha and 6-keto-prostaglandin F1alpha) contents, but indomethacin decreased the prostaglandin D2 and prostaglandin E2 contents. On the other hand, prostaglandin D2 and indomethacin had no apparent effects on histamine-induced scratching of ICR mice. These results suggested that prostaglandin D2 plays a physiological role in inhibiting pruritus of NC/Nga mice via their specific prostanoid DP1 receptors, and that prostaglandin D2 and/or a prostanoid DP1 receptor agonist may have therapeutic effects for cases of consecutive skin inflammation.
- Published
- 2004
- Full Text
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40. Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala.
- Author
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Inoue T, Li XB, Abekawa T, Kitaichi Y, Izumi T, Nakagawa S, and Koyama T
- Subjects
- Amygdala drug effects, Animals, Behavior, Animal drug effects, Citalopram administration & dosage, Fear psychology, Male, Mediodorsal Thalamic Nucleus physiology, Microinjections, Motor Activity drug effects, Prefrontal Cortex physiology, Rats, Rats, Sprague-Dawley, Selective Serotonin Reuptake Inhibitors administration & dosage, Amygdala physiology, Citalopram pharmacology, Conditioning, Operant drug effects, Fear drug effects, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
Selective serotonin reuptake inhibitors are first-line treatment for most anxiety disorders, but their mechanism of anxiolytic action has not been clarified. Selective serotonin reuptake inhibitors are anxiolytic in conditioned fear stress (re-exposure to an environment paired previously with inescapable electric footshocks). To clarify the brain regions where selective serotonin reuptake inhibitors act, we examined the effect of microinjection of the selective serotonin reuptake inhibitor, citalopram, into the amygdala, medial prefrontal cortex and mediodorsal nucleus of the thalamus on freezing behavior, an index of fear, induced by conditioned fear stress. Bilateral injection of citalopram into the amygdala before testing reduced freezing significantly, while bilateral injection into the medial prefrontal cortex or mediodorsal nucleus of the thalamus did not. These results suggest that the anxiolytic effect of a selective serotonin reuptake inhibitor in conditioned fear is mediated by its effect in the amygdala, and support the hypothesis of serotonin function in anxiety by which facilitation of serotonin neurotransmission decreases anxiety.
- Published
- 2004
- Full Text
- View/download PDF
41. Effect of co-administration of lithium and reboxetine on extracellular monoamine concentrations in rats.
- Author
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Kitaichi Y, Inoue T, Nakagawa S, Izumi T, and Koyama T
- Subjects
- Administration, Oral, Animals, Dopamine chemistry, Dopamine metabolism, Drug Administration Schedule, Drug Synergism, Drug Therapy, Combination, Extracellular Space metabolism, Injections, Intraperitoneal, Lithium Carbonate administration & dosage, Male, Morpholines administration & dosage, Norepinephrine chemistry, Norepinephrine metabolism, Prefrontal Cortex chemistry, Prefrontal Cortex drug effects, Rats, Rats, Sprague-Dawley, Reboxetine, Serotonin chemistry, Serotonin metabolism, Extracellular Space chemistry, Extracellular Space drug effects, Lithium Carbonate pharmacokinetics, Morpholines pharmacokinetics
- Abstract
We investigated the effect of reboxetine, a selective noradrenaline reuptake inhibitor, 7 days after treatment with subchronic lithium on extracellular noradrenaline, dopamine and serotonin (5-HT) concentrations in the medial prefrontal cortex. Acute treatment with reboxetine significantly increased extracellular concentrations of noradrenaline and dopamine, but did not alter 5-HT concentrations. Subchronic lithium increased basal levels of extracellular 5-HT, but not noradrenaline or dopamine. Co-administration of reboxetine and lithium treatment increased the extracellular concentrations of noradrenaline, dopamine and 5-HT, though reboxetine alone increased the extracellular levels of noradrenaline and dopamine only. Thus, combined lithium and reboxetine produces an additive effect neurochemically rather than their interaction.
- Published
- 2004
- Full Text
- View/download PDF
42. The combination of metformin and a dipeptidyl peptidase IV inhibitor prevents 5-fluorouracil-induced reduction of small intestine weight.
- Author
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Yamazaki K, Yasuda N, Inoue T, Nagakura T, Kira K, Saeki T, and Tanaka I
- Subjects
- Animals, Biguanides pharmacology, Enteroendocrine Cells drug effects, Enteroendocrine Cells physiology, Glucagon-Like Peptide 1, Glucagon-Like Peptide 2, Male, Mice, Mice, Inbred BALB C, Organ Size drug effects, Peptides metabolism, Pyrroles pharmacology, Rats, Rats, Inbred F344, Valine pharmacology, Antimetabolites antagonists & inhibitors, Antimetabolites toxicity, Dipeptidyl Peptidase 4 physiology, Fluorouracil antagonists & inhibitors, Fluorouracil toxicity, Hypoglycemic Agents pharmacology, Intestine, Small drug effects, Metformin pharmacology, Protease Inhibitors pharmacology
- Abstract
Glucagon-like peptide 2 (GLP-2), which has intestinotrophic effects, is secreted from L-cells in the intestine in response to nutrient ingestion and is degraded by dipeptidyl peptidase IV (DPPIV). In this report, we show that biguanides promote GLP-2 release. Plasma GLP-2 levels were significantly increased by 1.4- to 1.6-fold in fasted F344 rats 1 h after oral meformin (300 mg/kg), phenformin (30 and 100 mg/kg) and buformin (100 mg/kg) treatment. In addition, metformin administration (300 mg/kg, p.o.) significantly elevated plasma GLP-2 in fasted CD-1 mice by about 2.0-fold 1 and 3 h after the treatment. Metformin and/or valine-pyrrolidide, a DPPIV inhibitor, was orally given (300 and 30 mg/kg, respectively, p.o., b.i.d., 3 days) to BALB/c mice treated with 5-fluorouracil (5-FU; 60 mg/kg, s.i.d.), which induces gastrointestinal damage leading to a reduction of small intestine wet weight. Metformin and valine-pyrrolidide co-administration prevented the 5-FU-induced reduction of wet weight of the small intestine, whereas metformin or valine-pyrrolidide alone had no effect. These results suggest that GLP-2 is co-secreted with GLP-1 flollowing biguanide stimulation, and that the combination of metformin with a DPPIV inhibitor might a useful oral treatment for gastrointestinal damage, based on GLP-2 actions.
- Published
- 2004
- Full Text
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43. Functional characterization of the adenosine receptor contributing to glycogenolysis and gluconeogenesis in rat hepatocytes.
- Author
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Yasuda N, Inoue T, Horizoe T, Nagata K, Minami H, Kawata T, Hoshino Y, Harada H, Yoshikawa S, Asano O, Nagaoka J, Murakami M, Abe S, Kobayashi S, and Tanaka I
- Subjects
- Animals, Dose-Response Relationship, Drug, Gluconeogenesis drug effects, Hepatocytes drug effects, Male, Purinergic P1 Receptor Agonists, Purinergic P1 Receptor Antagonists, Rats, Rats, Wistar, Gluconeogenesis physiology, Glycogen metabolism, Hepatocytes metabolism, Receptors, Purinergic P1 metabolism
- Abstract
The adenosine receptor subtype mediating glucose production by glycogenolysis and gluconeogenesis was studied in primary cultured rat hepatocytes. Adenosine and adenosine agonists caused cyclic AMP accumulation in rat hepatocytes. The order of potency was 5'-N-ethylcarboxamidoadenosine (NECA)>R(-)-N(6)-(2-phenylisopropyl)adenosine (RPIA)>adenosine>2-[p-(carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). Furthermore, adenosine agonists stimulated glycogenolysis and gluconeogenesis. The order of potency was NECA>RPIA>CGS21680. The rank order of potency is typical for adenosine A(2B) receptors. Glycogenolysis stimulated by NECA was fully inhibited by nonselective adenosine antagonists, 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943). However, the adenosine A(2A) receptor-selective antagonist, 8-(3-chlorostyryl)caffeine (CSC), and the adenosine A(1) receptor-selective antagonist, (+)-(R)-[(E)-3-(2-phenylpyrazolo[1,5-alpha]pyridin-3-yl)acryloyl]-2-piperidine ethanol (FK453), had a low inhibitory potency. A strong correlation was found between the inhibitory effect of adenosine antagonists on NECA-induced glucose production and that on intracellular cyclic AMP generation in rat hepatocytes. Our results suggest that adenosine stimulates cyclic AMP formation and regulates glycogenolysis and gluconeogenesis, most likely through the adenosine A(2B) receptor subtype in rat hepatocytes.
- Published
- 2003
- Full Text
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44. Long-lasting change in 5-HT2A receptor-mediated behavior in rats after a single footshock.
- Author
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Izumi T, Suzuki K, Inoue T, Li XB, Maki Y, Muraki I, Kitaichi Y, Hashimoto S, and Koyama T
- Subjects
- Amphetamines pharmacology, Animals, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Electric Stimulation methods, Male, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT2A, Serotonin Receptor Agonists pharmacology, Time, Behavior, Animal physiology, Receptors, Serotonin metabolism, Stress, Physiological metabolism
- Abstract
To investigate the long-term functional change in the 5-HT(2A) receptor after acute stress, we examined the effect of single footshock on head shake behavior induced by the 5-HT(2A) receptor agent (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) in rats. Head shakes were evoked in a dose-dependent manner by 0.1-10 mg/kg of DOI, and the maximal response was attenuated by a single footshock given 24 h before. This suggests that there is a decrease in the number of functionally effective 5-HT(2A) receptors. The single footshock-induced reduction in head shakes evoked by DOI was observed immediately and 24 h after footshock, and lasted until 1 and 2 weeks after footshock. Because there were no changes in the [3H]ketanserin binding of the frontal cortex 1 week after footshock, decreases in head shakes were not due to the down-regulation of 5-HT(2A) receptors evoked by footshock.
- Published
- 2002
- Full Text
- View/download PDF
45. Effect of chronic treatment with the protein kinase C inhibitor staurosporine on the acquisition and expression of contextual fear conditioning.
- Author
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Li XB, Inoue T, and Koyama T
- Subjects
- Animals, Conditioning, Psychological physiology, Dose-Response Relationship, Drug, Fear physiology, Male, Pain Measurement drug effects, Protein Kinase C metabolism, Rats, Rats, Sprague-Dawley, Carrier Proteins administration & dosage, Conditioning, Psychological drug effects, Fear drug effects, Intracellular Signaling Peptides and Proteins, Protein Kinase C antagonists & inhibitors, Staurosporine administration & dosage
- Abstract
The present study investigated the effects of acute and chronic administration of the protein kinase C inhibitor, staurosporine, on the acquisition and expression of conditioned freezing behavior, an index of anxiety induced by conditioned fear stress. Results revealed that acute staurosporine (0.01 and 0.1 mg/kg, i.p.) did not affect either acquisition or expression of conditioned freezing. Chronic staurosporine administration (0.01 or 0.1 mg/kg, i.p., for 14 days) significantly reduced the acquisition of conditioned freezing at a dose of 0.1 mg/kg, but failed to affect the expression of conditioned freezing at any dose. These results suggest the involvement of protein kinase C in synaptic and cellular plasticity underlying emotional learning and memory.
- Published
- 2002
- Full Text
- View/download PDF
46. Effect of E3040, an inhibitor of 5-lipoxygenase and thromboxane synthase, on rat bowel damage induced by lipopolysaccharide.
- Author
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Oketani K, Inoue T, and Murakami M
- Subjects
- Animals, Benzothiazoles, Dinoprostone metabolism, Dose-Response Relationship, Drug, Eicosanoids metabolism, Gastrointestinal Agents pharmacology, Injections, Intravenous, Intestinal Mucosa drug effects, Intestinal Mucosa pathology, Intestine, Large metabolism, Intestine, Large pathology, Leukotriene B4 metabolism, Lipopolysaccharides immunology, Male, Prednisolone pharmacology, Rats, Rats, Inbred F344, Sulfasalazine pharmacology, Thromboxane B2 metabolism, Time Factors, Intestine, Large drug effects, Lipopolysaccharides administration & dosage, Lipoxygenase Inhibitors pharmacology, Pyridines pharmacology, Thiazoles pharmacology, Thromboxane-A Synthase antagonists & inhibitors
- Abstract
Intravenous administration of lipopolysaccharide to rats that had been immunized with lipopolysaccharide induced hemorrhagic damage in the large intestine. We investigated the role of 5-lipoxygenase and thromboxane synthase products in the damage of the large intestine induced by lipopolysaccharide. In the large intestine of lipopolysaccharide-immunized rats, intravenous injection of lipopolysaccharide increased the vascular permeability, production of leukotriene B(4), leukotriene C(4)/D(4), thromboxane B(2) and prostaglandin E(2), and also increased the activity of myeloperoxidase, a marker enzyme of neutrophils. Oral administration of E3040 (6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole), a novel dual inhibitor of 5-lipoxygenase and thromboxane synthase, at 30 and 100 mg/kg inhibited the increase in vascular permeability induced by lipopolysaccharide in the large intestine. E3040 inhibited the production of leukotriene B(4) and thromboxane B(2) and tended to increase the production of prostaglandin E(2) in the large intestine. Sulfasalazine (500 mg/kg) and prednisolone (10 mg/kg), drugs used for the treatment of inflammatory bowel disease, had no significant effect on eicosanoid production and vascular permeability. These results indicate that E3040 inhibits the production of both leukotriene B(4) and thromboxane B(2) and prevents lipopolysaccharide-induced damage in the large intestine of lipopolysaccharide-immunized rats.
- Published
- 2001
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47. Effect of chronic administration of flesinoxan and fluvoxamine on freezing behavior induced by conditioned fear.
- Author
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Li XB, Inoue T, Hashimoto S, and Koyama T
- Subjects
- Analysis of Variance, Animals, Conditioning, Psychological physiology, Dose-Response Relationship, Drug, Male, Motor Activity drug effects, Rats, Rats, Sprague-Dawley, Behavior, Animal drug effects, Fear psychology, Fluvoxamine pharmacology, Piperazines pharmacology, Serotonin Receptor Agonists pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
The present study investigated the acute effects of flesinoxan (a selective 5-HT(1A) receptor agonist), fluvoxamine (a selective serotonin reuptake inhibitor) and their co-administration on the expression of conditioned freezing, and index of anxiety in rats. This study also examined the acute effects of fluvoxamine and flesinoxan following chronic flesinoxan or chronic fluvoxamine on the expression of conditioned freezing. Acute administration of flesinoxan (s.c.; 0.1-3 mg/kg) reduced freezing dose dependently, and fluvoxamine (i.p.) at a high dose (60 mg/kg) reduced freezing significantly. Acute co-administration of fluvoxamine (30 mg/kg) and flesinoxan (0.3 mg/kg) showed an additive inhibitory effect on freezing. Chronic flesinoxan treatment (0.3 mg/kg, for 13 days) did not affect the inhibitory effect of acute flesinoxan treatment, but enhanced that of acute fluvoxamine (30 mg/kg) on conditioned freezing. Chronic fluvoxamine treatment (30 mg/kg, for 13 days) enhanced the inhibitory effect of acute fluvoxamine (30 mg/kg) and the inhibitory effect of acute flesinoxan (0.3 mg/kg) on conditioned freezing. These results suggest that co-administration of a selective serotonin reuptake inhibitor and a 5-HT(1A) receptor agonist is useful for the treatment of anxiety disorders.
- Published
- 2001
- Full Text
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48. In vitro effects of E3040, a dual inhibitor of 5-lipoxygenase and thromboxane A(2) synthetase, on eicosanoid production.
- Author
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Oketani K, Nagakura N, Harada K, and Inoue T
- Subjects
- Animals, Arachidonate 5-Lipoxygenase metabolism, Benzothiazoles, Dinoprostone metabolism, Dose-Response Relationship, Drug, Humans, Hydroxyurea analogs & derivatives, Hydroxyurea pharmacology, Indomethacin pharmacology, Leukocytes cytology, Leukocytes metabolism, Leukotriene B4 metabolism, Male, Mesalamine pharmacology, Methacrylates pharmacology, Neutrophils cytology, Neutrophils drug effects, Neutrophils metabolism, Peritoneal Cavity cytology, Prostaglandin-Endoperoxide Synthases drug effects, Prostaglandin-Endoperoxide Synthases metabolism, Rats, Rats, Inbred F344, Sheep, Sulfasalazine pharmacology, Thromboxane B2 metabolism, Thromboxane-A Synthase metabolism, Eicosanoids metabolism, Leukocytes drug effects, Lipoxygenase Inhibitors pharmacology, Pyridines pharmacology, Thiazoles pharmacology, Thromboxane-A Synthase antagonists & inhibitors
- Abstract
In vitro pharmacological profiles of E3040, 6-hydroxy-5, 7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl) benzothiazole were investigated. Against the 5-lipoxygenase activity of rat basophilic leukemia cells, E3040 and zileuton (a 5-lipoxygenase inhibitor) had an IC(50) of 0.23 and 0.93 microM, respectively. Against the thromboxane A(2) synthetase activity of human platelets, E3040 had an IC(50) of 0.01 microM, which was comparable to that of OKY-1581 (sodium (E)-3-[4-(3-pyridylmethyl) phenyl]-2-methylacrylate, a thromboxane A(2) synthetase inhibitor). Against cyclooxygenase activity of sheep seminal vesicles, E3040 showed no inhibition (IC(50), >300 microM). Sulfasalazine and 5-aminosalicylic acid, therapeutic drugs for inflammatory bowel disease, inhibited 5-lipoxygenase activity with an IC(50) of 293 and 970 microM, respectively. Sulfasalazine inhibited thromboxane A(2) synthetase activity with an IC(50) of 20 microM. In rat peritoneal leukocytes, E3040 inhibited leukotriene B(4) and thromboxane B(2) production with an IC(50) of 0.17 and 0.24 microM, respectively. E3040 inhibited leukotriene B(4) production in human neutrophils and thromboxane B(2) production in human platelets (IC(50) of 0.21 and 0.09 microM, respectively). These results indicated that E3040 potently inhibited 5-lipoxygenase and thromboxane A(2) synthetase and blocked leukotriene B(4) and thromboxane B(2) production in rat peritoneal and human blood cells.
- Published
- 2001
- Full Text
- View/download PDF
49. Monoamine oxidase inhibitors reduce conditioned fear stress-induced freezing behavior in rats.
- Author
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Maki Y, Inoue T, Izumi T, Muraki I, Ito K, Kitaichi Y, Li X, and Koyama T
- Subjects
- Animals, Drug Therapy, Combination, Fear, Male, Microdialysis, Motor Activity drug effects, Rats, Rats, Sprague-Dawley, Anti-Anxiety Agents pharmacology, Behavior, Animal drug effects, Monoamine Oxidase Inhibitors pharmacology
- Abstract
The present study examined the acute anxiolytic effects of monoamine oxidase inhibitors on freezing behavior, a putative index of anxiety induced by conditioned fear stress. The selective serotonin 1A receptor agonist tandospirone (0.1-10 mg/kg) inhibited freezing dose dependently. The irreversible, non-selective monoamine oxidase inhibitors tranylcypromine (3 and 15 mg/kg) and phenelzine (30 and 80 mg/kg) reduced freezing significantly. Clorgyline (10 mg/kg, irreversible selective monoamine oxidase A inhibitor), N-(2-aminoethyl)-5-(m-fluorophenyl)-4-thiazole carboxamide (Ro 41-1049) (30 mg/kg, reversible selective monoamine oxidase A inhibitor), selegiline (3 mg/kg, irreversible selective monoamine oxidase B inhibitor) and lazabemide (10 mg/kg, reversible selective monoamine oxidase B inhibitor) had no effect on freezing behavior. However, combined administration of clorgyline (10 mg/kg) and selegiline (3 mg/kg) reduced freezing significantly, as well as combined administration of clorgyline (10 mg/kg) and lazabemide (10 mg/kg), Ro 41-1049 (30 mg/kg) and selegiline (3 mg/kg), or Ro 41-1049 (30 mg/kg) and lazabemide (10 mg/kg). These effects of monoamine oxidase inhibitors on freezing were not due to non-specific motor effects. These results suggest that acute inhibition of both monoamine oxidase A and B reduced anxiety or fear, while inhibition of monoamine oxidase A or B alone failed to reduce anxiety or fear.
- Published
- 2000
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- View/download PDF
50. Effect of subchronic lithium carbonate treatment on anxiolytic-like effect of citalopram and MKC-242 in conditioned fear stress in the rat.
- Author
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Muraki I, Inoue T, Hashimoto S, Izumi T, Ito K, Ohmori T, and Koyama T
- Subjects
- Animals, Conditioning, Psychological drug effects, Drug Therapy, Combination, Male, Motor Activity drug effects, Rats, Rats, Sprague-Dawley, Antidepressive Agents administration & dosage, Citalopram pharmacology, Dioxanes pharmacology, Dioxoles pharmacology, Fear drug effects, Lithium Carbonate administration & dosage, Serotonin Receptor Agonists pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
We investigated the effect of citalopram [selective serotonin (5-HT) reuptake inhibitor] and MKC-242 (5-[3-¿(2S)-(1, 4-Benzodioxan-2-ylmethyl) amino¿propoxy]-1, 3-benzo-dioxol hydrochloride; a selective 5-HT(1A) receptor agonist) on the expression of conditioned freezing, an index of anxiety, following treatment with subchronic lithium carbonate (LiCO(3)). Male Sprague-Dawley rats were used in these experiments. Acute administration of citalopram (subcutaneously, s.c.) reduced freezing significantly at a high dose (30 mg/kg), while showing no effect at lower doses (3 and 10 mg/kg). Acute administration of MKC-242 (s.c.; 0.1-10 mg/kg) dose dependently reduced freezing. Subchronic LiCO(3) treatment (1 week; 0.05% or 0.2% LiCO(3) in diet; p.o.) showed no effect on freezing behavior. Acute treatment with both citalopram (3 and 30 mg/kg) and MKC-242 (1 mg/kg) after subchronic treatment with the higher, but not the lower concentration of LiCO(3) (1 week), reduced freezing markedly and significantly, as compared with either drug alone. These results suggest that subchronic LiCO(3) treatment enhanced the anxiolytic-like effects of these serotonergic drugs by facilitating central 5-HT neurotransmission at clinically therapeutic plasma lithium levels.
- Published
- 1999
- Full Text
- View/download PDF
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