Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 91 , Issue 4
Showing 1-10 articles out of 10 articles from the selected issue
Current Perspectives
  • Kiyofumi Yamada, Toshitaka Nabeshima
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 267-270
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    Activity-dependent changes in synaptic strength are considered mechanisms underlying learning and memory. Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity such as long-term potentiation. Recent experimental evidence supports the role of BDNF in memory processes: Memory acquisition and consolidation are associated with an increase in BDNF mRNA expression and the activation of its receptor TrkB. Genetic as well as pharmacologic deprivation of BDNF or TrkB impairs learning and memory. In a positively motivated radial arm maze test, activation of the TrkB/phosphatidylinositol-3 kinase (PI3-K) signaling pathway in the hippocampus is associated with consolidation of spatial memory through an activation of translational processes. In a negatively motivated passive avoidance test, mitogen-activated protein kinase (MAPK) is activated during acquisition of fear memory. Furthermore, recent findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory. A Src-family tyrosine kinase, Fyn plays a role in this interaction by linking TrkB with NR2B. These findings suggest that BDNF/TrkB signaling in the hippocampus plays a crucial role in learning and memory.
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  • Ryuji Inoue, Toyohisa Hanano, Juan Shi, Yasuo Mori, Yushi Ito
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 271-276
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    In both excitable and non-excitable cells, many chemical and physical stimuli elicit continuous Ca2+ influx through yet poorly understood pathways distinct from voltage-gated Ca2+ channels, leading to activation and modulation of various cellular functions. The molecular entities of these pathways have long been enigmatic, but important clues have been obtained from recent investigations on the Drosophila transient receptor potential (TRP) protein and its mammalian homologues. TRP proteins function as non-voltage-gated Ca2+ channels that are constitutively active or gated by a multitude of stimuli including light, pheromones, lipids, temperature, acid, osmolarity, and oxidative stress; and thus they may play divergent roles in cell pathophysiology. This short paper briefly overviews the current knowledge about these channels with a main focus on their possible linkage with in vivo function.
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Full Papers
  • Tadayoshi Takeuchi, Akikazu Fujita, Masahiko Kushida, Fumiaki Hata
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 277-284
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    Since it was suggested in our previous study that ATP newly synthesized from ADP and phosphocreatine (PCr) by creatine kinase had an important role in Ca2+-induced phasic contraction in α-toxin permeabilized smooth muscle of rat proximal colon, we studied the role of newly synthesized ATP on myosin ATPase activity, by assessing a rate of force development as an index of myosin ATPase activity. The α-toxin-permeabilized preparations were thiophosphorylated by treatment with ATPγS. After the thiophosphorylation, the contraction induced by ATP plus PCr in the absence of Ca2+ reached the maximum at 30 s. When PCr was omitted from the bathing solution, the initial rate of the contraction was significantly slower, while the level of myosin light chain thiophosphorylation remained unchanged. An inhibitor of creatine kinase slowed the initial contractile rate to a rate similar to that induced by ATP alone. ADPβS had no effect on ATP plus PCr-induced contraction, suggesting that accumulation of ADP does not affect the initial rate of the contraction. PCr alone did not contract the thiophosphorylated-preparations. However, in the presence of ADP, PCr induced contraction at the initial rate which was slower than that induced by ATP plus PCr. These results indicate that newly synthesized ATP together with preexisting ATP is utilized as a substrate for myosin ATPase.
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  • Masayo Okaji, Hideaki Sakai, Eiko Sakai, Mitsue Shibata, Fumio Hashimo ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 285-294
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    Osteoclastic bone resorption has recently been implicated in the tooth formation and eruption in alveolar bone. Cathepsin K (CK) is a cysteine proteinase expressed predominantly in osteoclasts and is believed to play a critical role in degradation of bone matrix proteins. Here we present evidence that the alveolar bone resorption is essential for the tooth formation and that eruption proceeds normally in CK-deficient (CK−/−) mice. Radiographic and histological analyses revealed that the alveolar bone from these animals had no significant abnormalities during the tooth development between 5 and 28 days after birth. The tooth crown was normally erupted through the alveolar bone layer at 28 days after birth. The number of tartrate-resistant acid phosphatase-positive multinuclear cells in the alveolar bone around the tooth germ was apparently increased in 5-day-old CK−/− mice compared with age-matched littermates. More important, however, the immunohistochemical localization of matrix metalloproteinase-9 (MMP-9) was clearly increased in the CK−/− osteoclasts. In contrast, no significant difference in the immunoreactivity for cathepsin D was observed between the CK−/− osteoclasts and the wild-type ones. These results indicate that CK−/− osteoclasts are fully differentiated and are capable of degrading the organic phase of alveolar bone during the tooth formation and eruption, which may result from the compensatory action by MMP-9 increasingly expressed in the osteoclasts.
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  • Rudolf Gesztelyi, Judit Zsuga, Ágnes Cseppentõ, Á ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 295-304
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    Chronic thyroxine treatment reduces the susceptibility of atrial myocardium to adenosine. While the possible role of membrane adenosine receptors in this action is supported by several studies, the involvement of intracellular adenosine mechanisms has not been defined. The present experiments were carried out in electrically driven euthyroid and hyperthyroid guinea pig atrial myocardium. The extracellular and intracellular actions of adenosine were analyzed pharmacologically by the use of specific blockers of membrane adenosine transport and intracellular adenosine deaminase (ADA). The involvement of phosphoprotein phosphatase, phospholamban, and sarcoplasmic reticulum Ca2+ ATPase (SERCA) in the adenosine-induced responses was also studied. The major findings were as follows: i) pD2- and Emax-values for adenosine-induced decrease of mechanical activity were significantly reduced after an 8-day thyroxine treatment in atrial tissues; ii) in atria of thyroxine-treated animals, membrane purine transport inhibitors (dipyridamole, NBTI) induced similar leftward shifts in concentration-response curves for adenosine in both euthyroid and hyperthyroid atrial myocardium without altering the depressed Emax values; iii) the leftward displacement evoked by inhibitors of intracellularly located ADA (coformycin, EHNA) was more striking in hyperthyroid than euthyroid myocardia. ADA inhibitors induced a complete reversal of the maximum adenosine actions; iv) inhibition by cantharidin of phosphoprotein phosphatases (after inhibition of ADA) reduced the adenosine-induced responses. This inhibition was stronger in hyperthyroid atria; v) pharmacological elimination of sarcoplasmic reticulum Ca2+ ATPase by cyclopiazonic acid did not alter the cardiac responses to adenosine and this was independent of thyroid status. It is suggested that distinct modulation of the extra- and intracellular adenosine actions is present in eu- and hyperthyroid hearts. In the latter, a predominance of intracellular adenosine mechanisms can be proposed.
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  • Yasuko Karasawa, Hiroko Komiyama, Shigeru Yoshida, Noriko Hino, Yasuhi ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 305-312
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    We investigated the effect of TTC-909, a drug preparation of the stable prostaglandin I2 analogue clinprost (isocarbacyclin methylester; methyl 5-{(1S,5S,6R,7R)-7-hydroxy-6-[(E)-(S)-3-hydroxy-1-octenyl] bicyclo[3.3.0]oct-2-en-3-yl} pentanoate) incorporated into lipid microspheres, on cerebral infarction 7 days after permanent occlusion of the middle cerebral artery (MCA) in stroke prone spontaneously hypertensive rats (SHRSP). Under the anesthesia, the MCA was permanently occluded above the rhinal fissure. In schedule 1, vehicle or TTC-909 was injected i.v. once daily over 7 days starting immediately after MCA occlusion. In schedule 2, vehicle or TTC-909 was infused for 3 h starting immediately after MCA occlusion. In schedule 3, vehicle or TTC-909 was infused for 3 h starting immediately after MCA occlusion followed by bolus injection once daily over 6 days. Seven days later, the infarct volume was estimated following hematoxylin and eosin staining. Cerebral infarction produced by permanent occlusion of MCA was limited to the cerebral cortex. While this volume was reduced significantly in case of schedule 3, the infarct volume was not reduced significantly in schedules 1 and 2. Ozagrel, a thromboxane A2 synthetase inhibitor, had no effect on the infarct volume in schedule 3. These results suggest that cerebral infarction can be developed progressively not only during the first few hours but also after a permanent occlusion of MCA in SHRSP. TTC-909 inhibited cerebral infarction, maybe by improving cerebral blood flow and by protecting against neuronal damage.
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  • Atsushi Takahashi, Kenji Onodera, Junzo Kamei, Shinobu Sakurada, Hisas ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 313-318
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    We investigated the effects of chronic administration of zonisamide, an antiepileptic agent, on bone metabolism in growing rats. Administration of zonisamide at a dose of 80 mg/kg per day, s.c. for 5 weeks significantly decreased bone mineral density (BMD) at the tibial metaphysis and the diaphysis. The percent rate of decrease in BMD at the tibial metaphysis and the tibial diaphysis was 9.2% and 5.0%, respectively. There was no significant difference between these groups in the growth of the rats. Treatment with zonisamide at a dose of 80 mg/kg increased serum pyridinoline level, a marker of bone resorption, while it does not affect the serum intact osteocalcin level, a marker of bone formation. Combined administration of alfacalcidol, an active vitamin D3 metabolite, at a dose of 0.1 μg/kg per day with zonisamide prevented a decrease in BMD and showed an increase of serum pyridinoline levels. These results suggest that zonisamide may cause bone loss by accelerating bone resorption rather than inhibiting bone formation. Moreover, the bone loss induced by zonisamide could be prevented by combining zonisamide with alfacalcidol.
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  • Daisuke Chino, Yukiyoshi Fujita, Kunio Ishii, Koichi Nakayama
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 319-329
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    Effects of DX-9065a ((+)-2S-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride pentahydrate), a dibasic propanoic acid and an inhibitor of factor Xa, were compared with those of argatroban, a low molecular weight thrombin inhibitor, on the ellagic acid-induced plantar skin thrombosis in the rats treated with tetrodotoxin and Nω-nitro-L-arginine. Plantar skin blood flow was measured with laser Doppler flow meters, and skin temperature of the hindlimb was monitored simultaneously. In order to induce thrombus in plantar skin vasculature, ellagic acid (300 μg, i.a.) was injected into a branch of femoral artery. The formation of thrombus in femoral and plantar vessels was assessed by light microscopy. Ellagic acid decreased plantar skin blood flow and skin temperature. Intravenous injections of DX-9065a (3 mg/kg) and argatroban (1 – 3 mg/kg) significantly inhibited the ellagic acid-induced disturbance of plantar skin blood flow and lowering skin temperature without affecting bleeding time. The oral administration of DX-9065a (30 – 100 mg/kg) significantly prevented the decrease in skin temperature induced by ellagic acid, but it partially inhibited the disturbance of plantar skin blood flow. DX-9065a and argatroban also prolonged prothrombin time in a dose-dependent manner. These results suggest that DX-9065a effectively prevented thrombosis produced by ellagic acid in the skin circulation without a risk of bleeding.
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Short Communications
  • Kazuyuki Takata, Yoshihisa Kitamura, Masaaki Umeki, Daiju Tsuchiya, Ju ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 330-333
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    In Alzheimer’s disease, fibrillar amyloid-β (Aβ) peptides form senile plaques associated with microglia. However, the relationship between Aβ peptides and microglia is not fully understood. In this study, the incubation of Aβ1-40 (Aβ40) produced small oligomers, while incubation with Aβ1-42 (Aβ42) caused large molecular aggregates. Microglial production of nitrite, interleukin-6 and tumor necrosis factor-α was induced by Aβ40, but not Aβ42. This production was significantly reduced by 15-deoxy-Δ12,14 prostaglandin J2, and it was completely suppressed by β-sheet breaker peptide, Leu-Pro-Phe-Phe-Asp. These results suggest that small oligomers, rather than large molecular aggregates, mediate microglial activation induced by Aβ peptides.
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  • Masahito Hitosugi, Munehiro Niwa, Tomoyoshi Takahashi, Akira Kurosu, H ...
    Subject area: Infomation Science
    2003 Volume 91 Issue 4 Pages 334-336
    Published: 2003
    Released: April 21, 2003
    JOURNALS FREE ACCESS
    We examined the effects on whole blood viscosity and coagulation time of various dosages of the synthetic low-molecular protease inhibitors gabexate mesilate and nafamostat mesilate with an oscillation-type viscometer. When either agent was added, blood viscosity decreased dose-dependently along a sigmoid-like curve. Furthermore, coagulation time was shorter with gabexate mesilate than with nafamostat mesilate owing to the differences of half-life in human blood. Thrombin generation, which results from the activation of coagulation factors, is inhibited by synthetic protease inhibitors and subsequently decreases blood viscosity dose-dependently.
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