Koji Takeuchi

Kyoto Pharmaceutical University, Kioto, Kyōto, Japan

Are you Koji Takeuchi?

Claim your profile

Publications (481)2761.92 Total impact

  • Source
    Koji Takeuchi · Hisayuki Uneyama

    Preview · Article · Jul 2015 · YAKUGAKU ZASSHI
  • Source
    Kikuko Amagase · Eiji Nakamura · Shinichi Kato · Koji Takeuchi
    [Show abstract] [Hide abstract]
    ABSTRACT: Monosodium glutamate (MSG) is known to provide the umami taste in the food. We have recently reported that glutamate has the potential to protect the small intestine against non-steroidal anti-inflammatory drugs (NSAIDs)-induced lesions in rats. In this paper, we examined this protective effect using sodium loxoprofen, one of the NSAIDs frequently used in Asian countries, to determine whether MSG accelerates the healing of loxoprofen-induced small intestinal lesions in rats. Loxoprofen at 60 mg/kg caused hemorrhagic lesions in the small intestine, mainly in the jejunum and ileum. These lesions spontaneously healed within 7 days, but this healing process was delayed by repeated administration of loxoprofen at low doses (10, 30 mg/kg) for 5 d after lesion induction. The healing-impairment action of loxoprofen was accompanied by the down-regulation of vascular endothelium-derived growth factor (VEGF) expression and an angiogenic response. The impaired healing caused by loxoprofen was significantly restored by co-treatment with a diet containing 5% MSG for 5 d, accompanied by the enhancement of VEGF expression and angiogenesis. We suggest that daily intake of MSG not only protects the small intestine against NSAIDs-induced damage but also exerts healing-promoting effects on these lesions.
    Full-text · Article · Jun 2015 · YAKUGAKU ZASSHI
  • [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the roles of muscarinic (M) acetylcholine receptor subtype in the cholinergic stimulation of duodenal HCO3(-) secretion using knockout (KO) mice. Wild-type and M1-M5 KO C57BL/6J mice were used. The duodenal mucosa was mounted on an Ussing chamber, and HCO3(-) secretion was measured at pH 7.0 using a pH-stat method in vitro. Carbachol (CCh) or other agents were added to the serosal side. CCh dose-dependently stimulated HCO3(-) secretion in wild-type mice, and this effect was completely inhibited in the presence of atropine. The HCO3(-) response to CCh in wild-type mice was also inhibited by pirenzepine (M1 antagonist), 4DAMP (M3 antagonist), and tropicamide (M4 antagonist), but not by methoctramine (M2 antagonist). CCh stimulated HCO3(-) secretion in M2 and M5 KO animals as effectively as in WT mice; however, this stimulatory effect was significantly attenuated in M1, M3, and M4 KO mice. The decrease observed in the CCh-stimulated HCO3(-) response in M4 KO mice was reversed by the co-application of CYN154806, a somatostatin receptor type 2 (SST2) antagonist. Octreotide (a somatostatin analogue) decreased the basal and CCh-stimulated secretion of HCO3(-) in wild-type mice. The co-localized expression of somatostatin and M4 receptors was confirmed immunohistologically in the duodenum. We concluded that the duodenal HCO3(-) response to CCh was directly mediated by M1/M3 receptors and indirectly modified by M4 receptors. The activation of M4 receptors was assumed to inhibit the release of somatostatin from D cells and potentiate the HCO3(-) response by removing the negative influence of somatostatin via the activation of SST2 receptors.
    No preview · Article · Jun 2015 · Journal of physiology and pharmacology: an official journal of the Polish Physiological Society
  • [Show abstract] [Hide abstract]
    ABSTRACT: We herein reviewed the mechanism underlying the gastric hyperemic response following barrier disruption, with a focus on cyclooxygenase (COX) isozymes, prostaglandin (PG) E2, and capsaicin-sensitive afferent neurons. Mucosal damage was induced by exposing the stomach to 20 mM taurocholate (TC) with 50 mM HCl. The TC treatment disrupted surface epithelial cells, and then increased acid back-diffusion and mucosal blood flow (GMBF) in the stomachs of rats or wild-type mice. This hyperemic response in the rat stomach was inhibited by indomethacin without affecting acid back-diffusion, which resulted in the aggravation of lesions. The effect of indomethacin was mimicked by loxoprofen and the selective COX-1 inhibitor, SC-560, but not by the selective COX-2 inhibitor, celecoxib. The GMBF responses induced by TC were similarly observed in the stomachs of wild-type mice and EP3 receptor knockout mice, but not in mice lacking the EP1 receptor or pretreated with an EP1 antagonist. The increase in the GMBF response associated with acid back-diffusion after the TC treatment was also inhibited by the chemical ablation of capsaicin-sensitive afferent neurons, but not capsazepine, a TRPV1 antagonist. Thus, endogenous PGE2 produced by COX-1 plays a role in the gastric hyperemic response following barrier disruption of the stomach by interacting with capsaicin-sensitive afferent neurons, mainly through EP1 receptors, and facilitating the GMBF response to acid back-diffusion. These findings have also contributed to a deeper understanding of mucosal defensive mechanisms following barrier disruption and the development of new strategies for the treatment of gastrointestinal diseases.
    No preview · Article · May 2015 · Current pharmaceutical design

  • No preview · Article · Apr 2015 · Gastroenterology
  • Koji Takeuchi · Hiroshi Satoh
    [Show abstract] [Hide abstract]
    ABSTRACT: NSAID-induced enteropathy has been the focus of recent basic and clinical research subsequent to the development of the capsule endoscope and double-balloon endoscope. We review the possible pathogenic mechanisms underlying NSAID-induced enteropathy and discuss the role of the inhibition of COX-1/COX-2 and the influences of food as well as various prophylactic treatments on these lesions. Studies were performed in experimental animals. Multiple factors, such as intestinal hypermotility, decreased mucus secretion, enterobacteria, and upregulation of iNOS/NO expression, are involved in the pathogenesis of NSAID-induced enteropathy, in addition to the decreased production of PGs due to the inhibition of COX. Enterobacterial invasion is the most important pathogenic event, and intestinal hypermotility, which was associated with this event, is essential for the development of these lesions. NSAIDs also upregulate the expression of COX-2, and the inhibition of both COX-1 and COX-2 is required for the intestinal ulcerogenic properties of NSAIDs to manifest. NSAID-induced enteropathy is prevented by PGE2, atropine, ampicillin, and aminoguanidine as well as soluble dietary fiber, and exacerbated by antisecretory drugs such as proton pump inhibitors. These findings on the pathogenesis of NSAID-induced enteropathy will be useful for the future development of intestinal-sparing alternatives to standard NSAIDs. © 2015 S. Karger AG, Basel.
    No preview · Article · Mar 2015 · Digestion
  • [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the roles of cyclooxygenase (COX) isozymes and prostaglandins (PGs) and their receptors in mucosal defense against cold-restraint stress (CRS)-induced gastric lesions. Male C57BL/6 wild-type (WT) mice and those lacking COX-1 or COX-2 as well as those lacking EP1, EP3, or IP receptors were used after 18 h fasting. Animals were restrained in Bollman cages and kept in a cold room at 10°C for 90 min. CRS induced multiple hemorrhagic lesions in WT mouse stomachs. The severity of these lesions was significantly worsened by pretreatment with the nonselective COX inhibitors (indomethacin, loxoprofen) or selective COX-1 inhibitor (SC-560), while neither of the selective COX-2 inhibitors (rofecoxib and celecoxib) had any effect. These lesions were also aggravated in animals lacking COX-1, but not COX-2. The expression of COX-2 mRNA was not detected in the stomach after CRS, while COX-1 expression was observed under normal and stressed conditions. The gastric ulcerogenic response to CRS was similar between EP1 or EP3 knockout mice and WT mice, but was markedly worsened in animals lacking IP receptors. Pretreating WT mice with iloprost (the PGI2 analog) significantly prevented CRS-induced gastric lesions in the presence of indomethacin. PGE2 also reduced the severity of these lesions, and the effect was mimicked by the EP4 agonist, AE1-329. These results suggest that endogenous PGs derived from COX-1 play a crucial role in gastric mucosal defense during CRS, and this action is mainly mediated by PGI2 /IP receptors and partly by PGE2 /EP4 receptors. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
    No preview · Article · Dec 2014 · Journal of Gastroenterology and Hepatology
  • Koji Takeuchi
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostaglandin E2 not only prevents NSAID-generated small intestinal lesions, but also promotes their healing. The protective effects of prostaglandin E2 are mediated by the activation of EP4 receptors and functionally associated with the stimulation of mucus/fluid secretions and inhibition of intestinal hypermotility, resulting in the suppression of enterobacterial invasion and iNOS up-regulation, which consequently prevents intestinal lesions. Prostaglandin E2 also promotes the healing of intestinal damage by stimulating angiogenesis through the up-regulation of VEGF expression via the activation of EP4 receptors. These findings have contributed to a further understanding of the mechanisms responsible for ‘protective’ and ‘healing-promoting’ effects of prostaglandin E2 and the development of new strategies for the prophylactic treatment of NSAID-induced enteropathy.
    No preview · Article · Dec 2014 · Current Opinion in Pharmacology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined the prophylactic effect of rebamipide on gastric bleeding induced by the perfusion of aspirin (acetylsalicylic acid [ASA]) plus clopidogrel under the stimulation of acid secretion in rats. Under urethane anesthesia, acid secretion was stimulated by the i.v. infusion of histamine (8 mg/kg/h), and the stomach was perfused with 25 mmol/L ASA at a rate of 0.4 mL/min. Gastric bleeding was evaluated as the concentration of hemoglobin in the perfusate. Clopidogrel (30 mg/kg) was given p.o. 24 h before the perfusion. Rebamipide (3-30 mg/kg) or other antiulcer drugs were given i.d. before the ASA perfusion. Slight gastric bleeding or damage was observed with the perfusion of ASA under the stimulation of acid secretion, whereas these responses were significantly increased in the presence of clopidogrel. Both omeprazole and famotidine inhibited acid secretion and prevented these responses to ASA plus clopidogrel. Rebamipide had no effect on acid secretion, but dose-dependently prevented gastric bleeding in response to ASA plus clopidogrel, with the degree of inhibition being almost equivalent to that of the antisecretory drugs, and the same effects were obtained with the gastroprotective drugs, irsogladine and teprenone. These agents also reduced the severity of gastric lesions, although the effects were less than those of the antisecretory drugs. These results suggest that the antiplatelet drug, clopidogrel, increases gastric bleeding induced by ASA under the stimulation of acid secretion, and the gastroprotective drug, rebamipide, is effective in preventing the gastric bleeding induced under such conditions, similar to antisecretory drugs. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
    Preview · Article · Dec 2014 · Journal of Gastroenterology and Hepatology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hydrogen sulfide (H2S) is known to be an important gaseous mediator that affects various functions under physiological and pathological conditions. We examined the effects of NaHS, a H2S donor, on HCO3(-) secretion in rat stomachs and investigated the mechanism involved in this response. Under urethane anesthesia, rat stomachs were mounted on an ex vivo chamber and perfused with saline. Acid secretion had been inhibited by omeprazole. The secretion of HCO3(-) was measured at pH 7.0 using a pH-stat method and by the addition of 10 mM HCl. NaHS (0.5-10 mM) was perfused in the stomach for 5 min. Indomethacin or L-NAME was administered s.c. before NaHS treatment, while glibenclamide (a KATP channel blocker), ONO-8711 (an EP1 antagonist), or propargylglycine (a cystathionine γ-lyase inhibitor) was given i.p. before. The mucosal perfusion of NaHS dose-dependently increased the secretion of HCO3(-), and this effect was significantly attenuated by indomethacin, L-NAME, and sensory deafferentation, but not by glibenclamide or ONO-8711. The luminal output of nitric oxide, but not the mucosal production of prostaglandin E2, was increased by the perfusion of NaHS. Mucosal acidification stimulated HCO3(-) secretion, and this response was inhibited by sensory deafferentation, indomethacin, L-NAME, and ONO-8711, but not by propargylglycine. These results suggested that H2S increased HCO3(-) secretion in the stomach, and this effect was mediated by capsaicin-sensitive afferent neurons and dependent on nitric oxide and prostaglandins, but not ATP-sensitive K(+) channels. Further study is needed to define the role of endogenous H2S in the mechanism underlying acid-induced gastric HCO3(-) secretion. Copyright © 2014 Elsevier Inc. All rights reserved.
    No preview · Article · Nov 2014 · Nitric Oxide
  • Koji Takeuchi · Jian-Ying Wang

    No preview · Article · Oct 2014 · Current Opinion in Pharmacology
  • Koji Takeuchi · Shinichi Takayama · Chitose Izuhara
    [Show abstract] [Hide abstract]
    ABSTRACT: Aims: The present study compared the effects of frequently used anti-platelet drugs, such as clopidogrel, ticlopidine, and cilostazol, on the gastric bleeding and ulcerogenic responses induced by intraluminal perfusion with 25 mM aspirin acidified with 25 mM HCl (acidified ASA) in rats. Main methods: The stomach was perfused with acidified ASA at a rate of 0.4 mI/min for 60 min under urethane anesthesia, and gastric bleeding was measured as the concentration of hemoglobin in the luminal perfusate, which was collected every 15 min. Clopidogrel (10-100 mg/kg), ticlopidine (10-300 mg/kg), or cilostazol (3-30 mg/kg) was given p.o. 24 h or 90 min before the perfusion of acidified ASA, respectively. Key findings: Perfusion of the stomach with acidified ASA alone led to slight bleeding and lesions in the stomach. The pretreatment with clopidogrel, even though it did not cause bleeding or damage by itself, dose-dependently increased the gastric bleeding and ulcerogenic responses induced by acidified ASA. Ticlopidine also aggravated the severity of damage by increasing gastric bleeding, and the effects of ticlopidine at 300 mg/kg were equivalent to those of clopidogrel at 100 mg/kg. In contrast, cilostazol dose-dependently decreased gastric bleeding and damage in response to acidified ASA. Significance: These results demonstrated that clopidogrel and ticlopidine, P2Y(12) receptor inhibitors, increased gastric bleeding and ulcerogenic responses to acidified ASA, to the same extent, while cilostazol, a phosphodiesterase III inhibitor, suppressed these responses. Therefore, cilostazol may be safely used in dual anti-platelet therapy combined with ASA, without increasing the risk of gastric bleeding.
    No preview · Article · Aug 2014 · Life Sciences
  • Koji Takeuchi · Eitaro Aihara

    No preview · Chapter · Jul 2014
  • Koji Takeuchi · Shinichi Takayama · Chitose Izuhara
    [Show abstract] [Hide abstract]
    ABSTRACT: Aims: The present study compared the effects of frequently used anti-platelet drugs, such as clopidogrel, ticlopidine, and cilostazol, on the gastric bleeding and ulcerogenic responses induced by intraluminal perfusion with 25 mM aspirin acidified with 25 mM HCl (acidified ASA) in rats. Main methods: The stomach was perfused with acidified ASA at a rate of 0.4 ml/min for 60 min under urethane anesthesia, and gastric bleeding was measured as the concentration of hemoglobin in the luminal perfusate, which was collected every 15 min. Clopidogrel (10-100mg/kg), ticlopidine (10-300 mg/kg), or cilostazol (3-30 mg/kg) was given p.o. 24h or 90 min before the perfusion of acidified ASA, respectively. Key findings: Perfusion of the stomach with acidified ASA alone led to slight bleeding and lesions in the stomach. The pretreatment with clopidogrel, even though it did not cause bleeding or damage by itself, dose-dependently increased the gastric bleeding and ulcerogenic responses induced by acidified ASA. Ticlopidine also aggravated the severity of damage by increasing gastric bleeding, and the effects of ticlopidine at 300 mg/kg were equivalent to those of clopidogrel at 100mg/kg. In contrast, cilostazol dose-dependently decreased gastric bleeding and damage in response to acidified ASA. Significance: These results demonstrated that clopidogrel and ticlopidine, P2Y12 receptor inhibitors, increased gastric bleeding and ulcerogenic responses to acidified ASA, to the same extent, while cilostazol, a phosphodiesterase III inhibitor, suppressed these responses. Therefore, cilostazol may be safely used in dual anti-platelet therapy combined with ASA, without increasing the risk of gastric bleeding.
    No preview · Article · Jun 2014 · Life Sciences

  • No preview · Article · May 2014 · Gastroenterology
  • Koji Takeuchi · Fumitake Ise · Eitaro Aihara · Shusaku Hayashi
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined the effect of H2S on duodenal HCO3- secretion in rats and investigated the mechanism involved in this response. Animals were fasted overnight and anesthetized with urethane. A duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH stat-method. The loop was perfused at a rate of 0.2 mL/min with NaHS (H2S donor) for 5 min or 10 mM HCl for 10 min. Indomethacin or l-NAME was given s.c. 30 min or 3 h, respectively, before NaHS or acidification, while glibenclamide (KATP channel blocker) or propargylglycine (cystathionine-g-lyase inhibitor) was given i.p. 30 min before. Mucosal perfusion with NaHS dose-dependently increased the HCO3- secretion, and this effect was significantly attenuated by indomethacin and l-NAME as well as sensory deafferentation, but not by glibenclamide. Mucosal PGE2 and NO production were both increased by NaHS perfusion. Mucosal acidification stimulated HCO3- secretion concomitant with increase in PGE2 and NO production, and these responses were mitigated by propargylglycine. The duodenal damage induced by acid (100 mM HCl for 4 h) was aggravated by pretreatment with propargylglycine. These results suggest that H2S increases HCO3- secretion in the duodenum, and this action is partly mediated by PG and NO as well as by capsaicin-sensitive afferent neurons. It is assumed that endogenous H2S is involved in the regulatory mechanism of acid-induced HCO3- secretion and mucosal protection in the duodenum.
    No preview · Conference Paper · May 2014
  • Hisayuki Uneyama · Koji Takeuchi · Yvette F. Tache

    No preview · Article · May 2014 · Current Pharmaceutical Design
  • Koji Takeuchi · Kikuko Amagase · Hiroshi Satoh

    No preview · Article · May 2014 · Gastroenterology

  • No preview · Article · May 2014 · Gastroenterology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lubiprostone, a bicyclic fatty acid derived from prostaglandin E1, has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of ClC-2/CFTR chloride channels. We examined the effects of lubiprostone on indomethacin-induced enteropathy and investigated the functional mechanisms involved, including its relationship with the EP4 receptor subtype. Male SD rats were administered indomethacin (10 mg/kg) p.o. and killed 24 h later to examine the hemorrhagic lesions that developed in the small intestine. Lubiprostone (0.01-1mg/kg) was administered p.o. in a single injection 30 min before the indomethacin treatment. Indomethacin markedly damaged the small intestine, accompanied by intestinal hypermotility, a decrease in mucus and fluid secretion, and an increase in enterobacterial invasion as well as the up-regulation of iNOS and TNFα mRNAs. Lubiprostone significantly reduced the severity of these lesions, with the concomitant suppression of the functional changes. The effects of lubiprostone on the intestinal lesions and functional alterations were significantly abrogated by the co-administration of AE3-208, a selective EP4 antagonist, but not by CFTR(inh)-172, a CFTR inhibitor. These results suggested that lubiprostone may prevent indomethacin-induced enteropathy via an EP4 receptor-dependent mechanism. This effect may be functionally associated with the inhibition of intestinal hypermotility and increase in mucus/fluid secretion, resulting in the suppression of bacterial invasion and iNOS/TNFα expression, which are major pathogenic events in enteropathy. The direct activation of CFTR/ClC-2 chloride channels is unlikely to have contributed to the protective effects of lubiprostone.
    Preview · Article · Apr 2014 · Journal of Pharmacology and Experimental Therapeutics

Publication Stats

7k Citations
2,761.92 Total Impact Points

Institutions

  • 1987-2015
    • Kyoto Pharmaceutical University
      • Laboratory of Pharmacology and Experimental Therapeutics
      Kioto, Kyōto, Japan
  • 2001-2002
    • Osaka City University
      • Department of Gastroenterology
      Ōsaka, Ōsaka, Japan
  • 2000-2001
    • Kyoto University
      Kioto, Kyōto, Japan
  • 1977
    • Bunkyo University
      Edo, Tōkyō, Japan
  • 1974-1977
    • The University of Tokyo
      • Department of Pharmaceutical Sciences
      白山, Tōkyō, Japan