Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 110 , Issue 4
Showing 1-10 articles out of 10 articles from the selected issue
Full Papers
  • Yukiko Mine, Kazuo Morikage, Seiko Oku, Takashi Yoshikawa, Isao Shimiz ...
    2009 Volume 110 Issue 4 Pages 415-423
    Published: 2009
    Released: August 11, 2009
    [Advance publication] Released: July 14, 2009
    JOURNALS FREE ACCESS
    Polyethylene glycol electrolyte lavage solution (PEG-ELS) is widely used for colon cleansing prior to colonoscopy and colonic surgery. It has recently been shown that coadministration of PEG-ELS and mosapride citrate hydrate (mosapride), a selective 5-HT4–receptor agonist, is clinically useful for barium enema examination as it allows adequate barium coating. However, there is no report showing that mosapride has beneficial effects on colon cleansing and its underlying mechanism in experimental animals. In the present study, we investigated the effects of mosapride on colonic transit and on the colon cleansing action of PEG-ELS in guinea pigs. Mosapride (10 – 20 mg/kg, i.g.) significantly enhanced colonic transit rate in guinea pigs. Although PEG-ELS alone showed adequate colon cleansing action, excess fluid remained in the colon. Coadministration of mosapride (20 mg/kg) and PEG-ELS, regardless of mosapride timing, reduced colonic content weight (dry residue and water amount) as compared to PEG-ELS alone. These findings suggest that mosapride enhances the colon cleansing action of PEG-ELS via an increase in colonic transit in guinea pigs, that is, it reduces not only fecal residue but also excessive fluid in the colonic lumen. It is therefore believed that coadministration of mosapride and PEG-ELS can allow better visualization in barium enema examination.
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  • Makoto Shuto, Kei Higuchi, Chie Sugiyama, Masanori Yoneyama, Nobuyuki ...
    2009 Volume 110 Issue 4 Pages 424-436
    Published: 2009
    Released: August 11, 2009
    [Advance publication] Released: July 14, 2009
    JOURNALS FREE ACCESS
    The organotin trimethyltin (TMT) is known to cause neuronal degeneration in the murine brain. Earlier studies indicate that TMT-induced neuronal degeneration is enhanced by adrenalectomy. However, no evaluation has been attempted to determine the mechanism underlying the enhancement of TMT neurotoxicity by adrenalectomy and its implications in neuronal degeneration. To assess the implications and determine the mechanism of adrenalectomy-elicited enhancement of TMT neurotoxicity, we examined neuronal degeneration and associated signaling pathways in adrenalectomized mice. Adrenalectomy dramatically enhanced the TMT-induced neuronal damage in certain brain regions including the dentate gyrus, olfactory bulb, and anterior olfactory nucleus, in addition to exacerbating the behavioral abnormalities. TMT-induced activation of caspase-3 and calpain was also enhanced by adrenalectomy. The above events elicited by TMT were almost entirely prevented by treatment with dexamethasone. In addition to the above events, adrenalectomy clearly enhanced the activation of c-Jun-N-terminal kinases and the formation of 4-hydroxynonenal in the dentate gyrus following TMT treatment. The dentate granule cell damage induced by TMT was exacerbated by mifepristone, a glucocorticoid-receptor antagonist. Taken together, our data suggest that endogenous and exogenous glucocorticoids prevent neurodegeneration induced by TMT in the central nervous system by attenuating intensive oxidative stress and associated signaling pathways.
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  • Kumiko Goto, Yoshihiko Chiba, Hiroyasu Sakai, Miwa Misawa
    2009 Volume 110 Issue 4 Pages 437-444
    Published: 2009
    Released: August 11, 2009
    [Advance publication] Released: July 14, 2009
    JOURNALS FREE ACCESS
    RhoA plays an important role in Ca2+ sensitization of bronchial smooth muscle in antigen-induced airway hyperresponsiveness (AHR). Tumor necrosis factor–α (TNF-α), a major proinflammatory cytokine, is capable of inducing AHR, but the mechanisms for this are still unknown. In the present study, the effect of TNF-α on RhoA protein expression was examined in cultured human bronchial smooth muscle cells (hBSMCs). To investigate the role of NF-κB in the TNF-α–induced upregulation of RhoA, the effects of an inhibitor of IκB kinase (IKK), BMS-345541, were also determined. Both immunoblot and immunocytochemical analyses revealed that incubation of the hBSMCs with TNF-α caused an activation of NF-κB (determined by a translocation of p65 proteins to nuclei): the peak response was observed when cells were incubated with 10 ng/mL of TNF-α for 30 min. An upregulation of RhoA protein was also observed at 12 – 24 h after the incubation with TNF-α (10 ng/mL). Both the activation of NF-κB and upregulation of RhoA were concentration-dependently inhibited by the co-incubation with BMS-345541. These results suggest that TNF-α–induced upregulation of RhoA might be mediated by an activation of NF-κB in hBSMCs.
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  • Saida Abdel Regal Aly, Murad Hossain, Mohiuddin Ahmed Bhuiyan, Takashi ...
    2009 Volume 110 Issue 4 Pages 445-450
    Published: 2009
    Released: August 11, 2009
    JOURNALS FREE ACCESS
    Naftidrofuryl is a peripheral vasodilator that has been clinically used in the treatment of intermittent claudication and dementia. It has 5-hydroxytryptamine 2 (5-HT2) antiserotonergic activity and selectively binds with the 5-HT2 receptor. The purpose of the present study is to assess the binding affinity and functional potency of naftidrofuryl to the 5-HT2A receptor, to find out the inverse agonist activity of this compound at a constitutively active mutant of 5-HT2A receptor, and finally to compare the findings with those of sarpogrelate. The investigation showed that the binding affinity (pKi) of naftidrofuryl was decreased 25- or 50-fold compared to sarpogrelate in the wild-type 5-HT2A receptor or Cys322Lys mutant receptor, respectively. Moreover, the functional potency (pKb) of naftidrofuryl was much lower compared to sarpogrelate at the 5-HT2A receptor. In addition, inverse agonist activity of naftidrofuryl was lower compared with sarpogrelate at the constitutively active mutant receptor. Thus, the data of the present study would be very important for the clarification of interaction sites of naftidrofuryl to 5-HT2A receptors and also may help to understand the mechanism of inverse agonist activity at the constitutively active mutant receptor.
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  • Ken-ichi Hamagami, Yusuke Sakurai, Norihito Shintani, Naoko Higuchi, K ...
    2009 Volume 110 Issue 4 Pages 451-458
    Published: 2009
    Released: August 11, 2009
    JOURNALS FREE ACCESS
    Development of human chronic pancreatitis is associated with intrapancreatic accumulation of pituitary adenylate cyclase–activating polypeptide (PACAP) accompanied with an altered inflammatory response (Michalski et al., Am J Physiol Gastrointest Liver Physiol. 2008;294:G50–G57). To investigate the role of pancreatic PACAP in the development of acute pancreatitis, we employed transgenic mice over-expressing PACAP in pancreatic β-cells (PACAP-Tg). In comparison to wild-type mice, PACAP-Tg mice exhibited more severe pathophysiological signs of the cerulein-induced pancreatitis at 12 h, as evidenced by higher serum amylase and lipase levels accompanied by the exacerbation of pancreatic edema, necrosis, and inflammation. Cerulein treatment increased mRNA expression of several proinflammatory cytokines (TNFα, IL-1β, and IL-6) at 12 h with similar magnitude both in wild-type and PACAP-Tg mice. In addition, the mRNA and protein levels of regenerating gene III β (RegIIIβ), a key factor in the pancreatic response to acute pancreatitis, were up-regulated at 24 h in wild-type mice upon cerulein administration, whereas they were attenuated in PACAP-Tg mice. These data indicate that over-expressed PACAP in pancreas enhances the cerulein-induced inflammatory response of both acinar cells, leading to aggravated acute pancreatitis, which was accompanied by a down-regulation of RegIIIβ, an anti-inflammatory factor.
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  • Shinji Takai, Denan Jin, Mariko Ohzu, Kazuhiko Tanaka, Mizuo Miyazaki
    2009 Volume 110 Issue 4 Pages 459-465
    Published: 2009
    Released: August 11, 2009
    [Advance publication] Released: August 01, 2009
    JOURNALS FREE ACCESS
    Angiotensin II may be involved in pancreatic disorganization, but the involvement of chymase has been unclear. In the present study, we examined whether chymase is involved in pancreatic disorganization in hamsters with streptozotocin (STZ)-induced diabetes. Hamsters were injected with streptozotocin (60 mg/kg), and non-injected hamsters served as controls. To investigate the effect of a chymase inhibitor, TY-51469 (30 mg/kg per day), hamsters in the STZ group were administered TY-51469 or placebo from 2 weeks after STZ injection, for 1 week. A significant increase in blood glucose level was observed at 1 week after STZ injection. This was maintained at 2 weeks, and a further significant increase was observed at 3 weeks. Until 2 weeks after STZ injection, all angiotensin II–related enzyme activities were unchanged, but at 3 weeks pancreatic chymase and total angiotensin II–forming activities, but not angiotensin-converting enzyme activity, were significantly increased. TY-51469 significantly attenuated blood glucose level along with reductions of chymase and total angiotensin II–forming activities and malondialdehyde level. Furthermore, there were significantly more pancreatic islets in the TY-51469 group than in the placebo group. In conclusion, chymase inhibition might protect against pancreatic islet disorganization.
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  • Hiromi Sato, Hiroki Iwata, Yasuyuki Takano, Ryota Yamada, Hiroko Okuza ...
    2009 Volume 110 Issue 4 Pages 466-475
    Published: 2009
    Released: August 11, 2009
    [Advance publication] Released: August 01, 2009
    JOURNALS FREE ACCESS
    The expression levels of connexin (Cx) proteins, which are gap junction (GJ) components, are often decreased in many cancers, and restoring their levels has been shown to have antitumor effects. Previously, dysfunctional gap junctional intercellular communication (GJIC) has been observed in several malignant mesotheliomas (MMs), and among the many Cx proteins, Cx43 is prominently expressed in nontumorigenic mesothelial tissues. Therefore, we investigated whether Cx43 upregulation has an antitumor effect on an MM cell line (H28 cell), especially with regard to drug resistance. After treatment with the chemotherapeutic agent cisplatin (CDDP), MM cell viability significantly decreased, and apoptosis induction was observed in Cx43-transfected clones. A specific GJIC inhibitor could not abrogate this effect. On the other hand, the Src protein is known to phosphorylate Cx43, which results in GJIC inhibition. This suggests that Src activity might also be regulated by the hyperexpression of Cx43. In fact, the Src protein level was decreased in Cx43-transfected clones. Moreover, Src inhibition reinforced CDDP cytotoxicity in parental H28 cells. These data suggest that Cx43 could improve the resistance to CDDP in a GJIC-independent manner, which may be partly mediated by the suppression of Src activity.
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  • Hirofumi Yokoyama, Yuji Nakamura, Hiroshi Iwasaki, Yukitoshi Nagayama, ...
    2009 Volume 110 Issue 4 Pages 476-482
    Published: 2009
    Released: August 11, 2009
    [Advance publication] Released: August 01, 2009
    JOURNALS FREE ACCESS
    Although acute treatment of pentamidine does not directly modify any ionic channel function in the heart at clinically relevant concentrations, its continuous exposure can prolong QT interval. Recent in vitro studies have indicated that hERG trafficking inhibition may play an important role in the onset of pentamidine-induced long QT syndrome. In this study, we examined acute in vivo electropharmacological effects of pentamidine using the halothane-anesthetized canine model (n = 5). The clinically relevant total dose of 4 mg/kg of pentamidine (namely, 1 mg/kg, i.v. over 10 min followed by 3 mg/kg, i.v. over 10 min with a pause of 20 min) decreased the mean blood pressure, ventricular contraction, preload to the left ventricle, and peripheral vascular resistance. Pentamidine also enhanced the atrioventricular conduction in parallel with its cardiohemodynamic actions, but it gradually prolonged both the ventricular repolarization period and effective refractory period, whereas no significant change was detected in the intraventricular conduction. Thus, acute administration of a clinically relevant dose of pentamidine can suppress cardiac function and vascular tone with reflex-mediated increase of sympathetic activity, whereas it may delay the repolarization process, suggesting that inhibition of potassium-channel trafficking might be induced more acutely in vivo than those previously expected in vitro.
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  • Tae Beom Seo, Kyungmin Baek, Ku-Birm Kwon, Sang-Ik Lee, Jong-Soon Lim, ...
    2009 Volume 110 Issue 4 Pages 483-492
    Published: 2009
    Released: August 11, 2009
    JOURNALS FREE ACCESS
    Shengmai-san (SMS) is a traditional Chinese medicine used to treat diverse symptoms including cardiovascular and neurological disorders. Here we investigated the effects of SMS on regenerative responses of spinal cord axons in rats that were given contusion injury at the lower thoracic level. The injury cavity was confined to a restricted area by SMS treatment, and the signals of glial scar protein chondroitin sulphate proteoglycan (CSPG) and inflammatory cell marker protein CD11β were heavily observed within the injury cavity in SMS-treated animals. Anterograde tracing of DiI-labeled corticospinal tract (CST) axons revealed increases in collateral arborization around and within the injury cavity and caudal elongation by SMS treatment. Furthermore, SMS treatment facilitated neurite elongation of dorsal root ganglion (DRG) sensory neurons that were co-cultured with non-neuronal cells prepared from injured spinal cord. Phospho-Erk1/2 was strongly induced in both spinal cord and motor cortical areas after spinal cord injury (SCI), and it was further unregulated in the motor cortex by SMS treatment. In contrast, upregulation of cell division cycle 2 (Cdc2) production by SMS treatment was limited to a local, SCI area. These data suggest that SMS may play an active role in regenerative responses and facilitate axonal regrowth after SCI.
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Short Communication
  • Yasuhiro Hama, Hiroshi Katsuki, Yasuhiko Izumi, Toshiaki Kume, Akinori ...
    2009 Volume 110 Issue 4 Pages 493-496
    Published: 2009
    Released: August 11, 2009
    [Advance publication] Released: August 01, 2009
    JOURNALS FREE ACCESS
    We have previously demonstrated an important role of influx of Cl rather than Ca2+ in acute excitotoxicity in adult rat retina. As p53 has been implicated in delayed apoptotic cell death, here we examined the appearance of p53 immunoreactivity in a rat eyecup preparation. Kainate induced p53 expression in a subpopulation of ganglion cells and other cells in the ganglion cell layer. Application of a calpain inhibitor, but not reduction of extracellular Cl, markedly inhibited kainate-induced p53 expression. The results suggest that, in contrast to acute excitotoxicity, delayed excitotoxicity in retinal neurons is mediated by Ca2+-dependent processes, including calpain activation.
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