Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 93 , Issue 2
Showing 1-15 articles out of 15 articles from the selected issue
Full Papers
  • Milind Parle, Dinesh Dhingra
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 129-135
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    Alzheimer’s disease is a progressive neurodegenerative disorder characterized by a gradual decline in memory. The occurrence of Alzheimer’s disease is commonplace among the Asian population, particularly among senior citizens. The present study was undertaken to assess the potential of ascorbic acid as a memory-enhancer. Swiss mice of either sex were employed in the present investigation. Elevated plus-maze and passive-avoidance apparatus served as the exteroceptive behavioral models, and diazepam-, scopolamine-, and aging-induced amnesia served as the interoceptive behavioral models. Ascorbic acid (60, 120 mg/kg) injected for 3 and 8 consecutive days improved learning and memory of aged mice as indicated by decreased transfer-latency and increased step-down latency. Furthermore, ascorbic acid provided protection to the young animals from scopolamine- and diazepam-induced impairment of memory. Ascorbic acid was found to be more potent than piracetam as reflected by the smaller dose, more pronounced effect, and quicker onset of action. Ascorbic acid has shown promise as a powerful memory-improving agent particularly effective in aged animals. Hence, ascorbic acid might prove to be a useful memory-restorative agent in the treatment of dementia seen in elderly individuals. The underlying mechanism of action of ascorbic acid may be attributed to its antioxidant property.
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  • Tak-Wah Wong, Katsuo Aizawa, Ilyar Sheyhedin, ChiMenGul Wushur, Harubu ...
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 136-142
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    Photodynamic therapy (PDT) is an evolving cancer treatment with promising results in treating malignant tumors by photoactivation of a photosensitizer with a specific wavelength. The second generation photosensitizer mono-L-aspartyl chlorin e6 (NPe6) was reported to have significant efficacy in killing cancer cells in vitro and in vivo. Though topical application might yield a higher local concentration and less systemic side effect, no data concerning topical absorption of NPe6 is available even though the drug has already been used in clinical trial for several years. To evaluate the possibility of topical delivery of NPe6 via an animal model, escalated concentrations of NPe6 were applied to BALB/c mouse skin for a different time periods after barrier disruption with tape stripping. Since NPe6 fluorescence intensity and drug concentration in tissue was well correlated, we evaluated drug penetration depth with frozen sections of treated and non-treated skin under a fluorescence microscope. An on-line fluorescence imaging system was used to monitor the NPe6 fluorescence kinetics in the skin. The fluorescence microscope confirmed successful topical delivery of NPe6 in mouse skin with or even without barrier disruption. Orange to red NPe6 fluorescence appeared at the epidermis, dermis, and even the muscular layer when using 10 mg/ml NPe6 application. The fluorescence intensity peaked at 1 h and revealed a dose-dependent response pattern. NPe6 treated versus non-treated skin showed a statistically significant difference by Student’s t-test (P<0.05). The results described here suggest that topical delivery of NPe6 is possible. It showed fast and deep penetration into mouse skin. This implies that NPe6 might be useful as a topical photosensitizer for PDT in treating skin cancers.
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  • Hiroaki Matsubayashi, Taku Amano, Takahiro Seki, Masashi Sasa, Norio S ...
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 143-148
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    The electrophysiological characteristics of nicotine-induced excitation of dopaminergic neurons in the rat substantia nigra was investigated using the whole-cell patch clamp technique under the voltage-clamp mode. Nicotine (0.01 – 100 μM) induced inward currents corresponding to nicotine-induced depolarization with an increase in firing in a dose-dependent manner. This current was inhibited by dihydro-β-erythroidine, a selective antagonist for the α4β2 type neuronal nicotinic receptor. Nicotine directly acts on postsynaptic α4β2 type nicotinic receptors and induces inward currents, resulting in excitation of dopaminergic neurons in the substantia nigra and subsequent enhancement of dopamine release in the corpus striatum.
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  • Raymundo Velasco, Xóchitl Trujillo, Clemente Vásquez, Mi ...
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 149-154
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    To evaluate the suitability of dimethyl sulfoxide (DMSO) as a solvent for muscle-contraction studies in the chicken, its effect on the slow muscle contracture induced by high-K+ solution was explored using the anterior latissimus dorsi (ALD) muscle from one-week-old chicks. Measurements were made of isometric tension and various characteristics of the contractures [peak tension, total tension (area under the curve), duration of contraction, drop in tension from peak to plateau, and resting tension], in the presence and absence of DMSO (20 mM). Exposure to DMSO led to a concentration-dependent reduction in resting tension of up to 9 ± 1.8% (n = 4) with respect to the control. The threshold concentration was 10 mM, and the maximum effect was reached between 20 and 30 mM. The drop in tension from peak to plateau was three times larger in the presence of DMSO (20 mM) than in its absence. At the same concentration, there was a 10 ± 2.3% increase in the time constant of activation. No significant changes were observed in peak tension or in total tension in the presence of 20 mM DMSO. As a consequence, this type of biological preparation is not suitable for research on muscle contractures involving drugs that must be dissolved in DMSO (at the DMSO concentrations tested here).
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  • Shu-Ming Tsai, Mao-Tsun Lin, Jhi-Joung Wang, Wu-Tein Huang
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 155-162
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    At first, we investigated whether both β-endorphin release level in the hypothalamus and body temperature can be altered after intracerebroventricular (i.c.v.) injection of either lipopolysaccharide (LPS), interleukin-1β (IL-1β), or prostaglandin E2 (PGE2) in rats. It was found that in the rat, i.c.v. administration of either LPS (0.5 μg in 10 μl), IL-1β (10 ng in 10 μl), or PGE2 (200 ng in 10 μl), in addition to producing fever, upregulated the immunoreactivity of β-endorphin in the preoptic anterior hypothalamus of rat brain. Secondarily, we assessed whether the fever induced by either LPS, IL-1β, or PGE2 can be altered by pretreatment with buprenorphine (an opioid receptor antagonist). The results revealed that i.c.v. administration of buprenorphine (1 – 10 μg in 10 μl) alone had an insignificant effect on the body temperature. However, the fever induced by i.c.v. injection of either LPS, IL-1β, or PGE2 was significantly attenuated by pretreatment with i.c.v. injection of buprenorphine 1 h before the pyrogen injection in rats. The results suggest that pyrogens enhance β-endorphin release in the hypothalamus and trigger fever which can be attenuated by buprenorphine, an opioid receptor antagonist.
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  • Koji Inomata, Hiroyuki Tanaka
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 163-170
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    We investigated the effect of benidipine, a calcium antagonist, against sodium azide (NaN3)-induced cell death in cultured neonatal rat cardiac myocytes with increase of LDH release, depletion of cellular ATP contents, and collapse of mitochondrial membrane potential (ΔΨ) as indicators. Cells were treated with 1 mmol/L NaN3 for 18 h. Benidipine concentration-dependently inhibited NaN3-induced cell death. The protective effect of benidipine was compared with those of amlodipine, nifedipine, candesartan, and captopril. Calcium antagonists exhibited a protective effect and the IC50 values of benidipine, amlodipine, and nifedipine were 0.65, 90, and 65 nmol/L, respectively. NaN3-induced cell death was inhibited completely with the calpain inhibitor. It was considered that the sustained elevation of [Ca2+]i might be implicated in NaN3-induced cell death. Benidipine, moreover, concentration-dependently preserved cellular ATP contents and maintained ΔΨ the extent of the control level. In conclusion, benidipine exhibited the protective effect at an approximately 100-fold lower concentration than those of amlodipine and nifedipine in the NaN3-induced cardiac cell death model. It was considered that both the inhibition of Ca2+ influx and the preservation of cellular ATP contents might play an important role in the protective effect of benidipine.
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  • Masahiko Kushida, Tadayoshi Takeuchi, Akikazu Fujita, Fumiaki Hata
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 171-179
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    Effects of various concentrations of ATP on Ca2+-induced contraction were studied in α-toxin-permeabilized preparations obtained from the rat femoral artery. The contractile magnitude was highest in the presence of 1 mM ATP and decreased with both increasing and decreasing the concentration, suggesting the presence of an optimum ATP concentration in inducing contraction. The magnitude of the contractions in various concentrations of ATP correlated with the extent of the phosphorylated myosin light chain (MLC). The rate of contractions in the presence of 1 mM ATP under an inhibition of MLC phosphatase was faster than in the presence of 4 mM ATP, suggesting that the increased phosphorylation of MLC at 1 mM ATP results from an increased activity of MLC kinase. On the other hand, MLC phosphatase activity appeared unchanged, because the rates of relaxations under the inhibition of MLC kinase were not different in the presence of either 1 or 4 mM ATP. The high sensitivity to 1 mM ATP was absent in the preparations that were permeabilized with β-escin or Triton X-100, suggesting the existence of an intracellular factor required for the increased activity of MLC kinase to ATP in the α-toxin-permeabilized preparations of the rat femoral artery.
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  • Shogo Matsuyama, Akira Matsumoto
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 180-187
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    Activation of nicotinic acetylcholine receptors (nAChRs) induces nocotinic long-term potentiation (LTPn) in vivo in the mouse dentate gyrus. We have found that α4β2 nAChRs activated by epibatidine induce LTPn, the full size of which requires the involvement of α4β2 and α7 nAChRs, in the intact mouse dentate gyrus using extracellular recording techniques. Intraperitoneal application of epibatidine, a potent α4β2 nAChR agonist, at 0.3 – 3.0 μg/kg induced a long-lasting increase similar to LTPn induced by choline, a selective α7 nAChR agonist, and at 10 μg/kg caused a transient increase followed by a depression. The LTPn induced by epibatidine at 3.0 μg/kg or choline at 30 mg/kg was significantly suppressed by pre-treatment but not post-treatment with mecamylamine (0.5 mg/kg, i.p.), a non-selective neuronal nicotinic antagonist. Post-application of nicotine at 3.0 mg/kg enhanced epibatidine-induced LTPn to the same level of nicotine-induced LTPn, but post-application of epibatidine had no effect on nicotine-induced LTPn. Epibatidine-induced LTPn was additionally increased by post-application of choline, and vice versa, reaching the same level of nicotine-induced LTPn. The present study revealed that epibatidine induced the LTPn via α4β2 nAChRs and that both α7 and α4β2 nAChRs were essential for full-sized LTPn, suggesting that both nAChRs play an important role in synaptic plasticity.
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  • Katsunori Iwasaki, Kenichi Mishima, Nobuaki Egashira, Izzettin Hatip A ...
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 188-196
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    We investigated the effects of nilvadipine and amlodipine on the cerebral ischemia-induced impairment of spatial memory in 8-arm radial maze performance and hippocampal CA1 apoptosis in rats. Single cerebral ischemia impaired memory without inducing apoptosis. In these rats, neither nilvadipine nor amlodipine at 3.2 mg/kg, i.p. improved the impaired memory. On the other hand, repeated cerebral ischemia (10 min ischemia × 2, 1 h interval) impaired spatial memory and induced hippocampal apoptosis 7 days after the final occlusion/reperfusion. Moreover, repeated ischemia increased the apoptotic cell number, an effect observed after 3 days and peaked after 7 days. However, mRNA expression of the apoptosis-related early oncogene bax and CPP 32 (caspase-3) was observed after 24 h. In these rats, nilvadipine, but not amlodipine, significantly improved memory, concomitantly decreased hippocampal apoptosis, and suppressed both bax and CPP 32 expression. These results suggest that nilvadipine improved the memory impairment in repeated ischemia by reducing bax and CPP 32 expression and suppressing the induction of apoptosis in the hippocampus. Nilvadipine may have a neuroprotective effect and could be a useful pharmacotherapeutic agent for cerebrovascular dementia.
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  • Fang Wang, Yu Cao, WanZhou Zhao, Hongyan Liu, Zhaodi Fu, Rui Han
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 197-203
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    An in vivo melanoma spontaneous metastases model was adopted to study the molecular mechanisms of the anti-metastatic effect of Taxol. The morphology of melanoma cells in the melanoma tissue lesions was examined by hematoxylin/eosin (H&E) staining and electron microscopy. The in situ programmed cell death was tested by TUNEL analysis. Vascular endothelial growth factor (VEGF) and E-cadherin expression were detected by immunohistochemistry. The metastases suppressor gene nm23 mRNA expression level was analyzed by in situ hybridization. The results showed that i.p. injection of Taxol at 5 mg/kg per day for three weeks significantly inhibited metastases formation in the pulmonary of mice. Taxol induced melanogenesis and apoptosis in the melanoma cells, inhibited angiogenesis in melanoma tissue lesions, and reduced the expression of VEGF. Conversely, Taxol increased the expression of E-cadherin and nm23. In conclusion, administration of Taxol in the early stage of melanoma metastases can significantly inhibit melanoma metastases. This effect was possibly related to apoptosis induction, tumor angiogenesis inhibition, and restoration of the metastasis suppression ability.
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  • Hideaki Noguchi, Kazuhiro Kitazumi, Megumi Mori, Yoji Shiobara, Toshih ...
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 204-209
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    Melatonin, a major hormone secreted by the pineal gland, is known to play an important role in regulation of the circadian rhythm. (N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (zaleplon) is a non-benzodiazepine hypnotic that acts via the benzodiazepine site of the GABAA receptor. In the present study, we investigated the effect of zaleplon on melatonin secretion in rabbits using RIA and compared the effect to triazolam and zopiclone. Zaleplon increased a dose-dependent concentration of melatonin in rabbit plasma collected at 30 min after intravenous administration at doses of 1 and 2 mg/kg. The zaleplon-induced increase in plasma melatonin level was not blocked by flumazenil, a benzodiazepine-receptor antagonist. In contrast, triazolam and zopiclone failed to affect the plasma melatonin level. We also investigated the effect of zaleplon on intracellular cAMP in rat pinealocytes. Consequently, zaleplon had no effect on the intracellular cAMP levels in rat pinealocytes. These results of the present studies suggest that zaleplon may promote melatonin secretion and the elevation of plasma levels of melatonin may suggest an influence of zaleplon on chronobiology.
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Short Communications
  • Eiji Masaki, Kazuhiro Shoji, Hirokazu Saito, Koji Yamazaki, Masahiro K ...
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 210-213
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    To examine effects of volatile anesthetics (VAs) on steroidogenesis, cell suspensions of isolated bovine adrenocortical cells were incubated with several steroidogenic agents in the presence or absence of halothane and sevoflurane. The adrenocortical cells were dispersed by trypsin digestion of bovine adrenal cortex. The cortisol level was measured fluorometrically. VAs inhibited adrenocorticotropic hormone-, acetylcholine-, angiotensin-II-, and KCl-stimulated steroidogenesis in a concentration-dependent manner with extracellular Ca2+. However, dibutyryl cyclic adenosine monophosphate-stimulated steroidogenesis was not inhibited by VAs. These results suggest that VAs inhibit steroidogenesis by blocking Ca2+-influx from the extracellular space without influencing the action of intracellular cyclic nucleotides.
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  • Young-Don Kwak, Hiroko Koike, Kiminobu Sugaya
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 214-217
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    RNA interference (RNAi), a process of sequence-specific gene suppression, has been known as a natural gene regulatory mechanism in a wide range of organisms. Recently, a small-interference RNA (siRNA) technology has been reported to produce post-transcriptional gene silencing in mammalian cells. In the present study, we constructed a human U6 promoter-driven mammalian expression vector to produce hairpin double-stranded RNA and transfected this into a human cell line. Using this siRNA system, we were able to knock down the gene expression of an enhanced green fluorescence protein. This result indicates that the plasmid vector-based siRNA system is a promising method to downregulate gene expression in human cells.
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  • Yeong-Ki Min, Seok-Hee Chung, Jong-Soo Lee, Sung-Soo Kim, Hyun-Dae Shi ...
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 218-221
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    Red ginseng has been used as an ergogenic aid for endurance exercise. In this study, the effect of aqueous extract of Red ginseng on the endurance in treadmill exercise and 5-hydroxytryptamine (serotonin) synthesis and tryptophan hydroxylase expression in the dorsal raphe of rats were studied. Rats receiving Red ginseng showed increased time to exhaustion for treadmill running, and Red ginseng treatment inhibited exercise-induced increases in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe. These results suggest that the suppressive effect of Red ginseng on serotonin level during exercise is a possible ergogenic mechanism of Red ginseng.
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  • Iwao Katsuyama, Tsutomu Arakawa
    Subject area: Infomation Science
    2003 Volume 93 Issue 2 Pages 222-224
    Published: 2003
    Released: October 22, 2003
    JOURNALS FREE ACCESS
    Patients suffering asthenopia are steadily increasing with an expanding use of visual display terminals such as computers. An attempt was made to develop an in vitro model for asthenopia. Ciliary muscle removed from eyeballs of a rabbit was stimulated with acethylcholine, resulting in contraction of the muscle. Repeated stimulations caused decreased contraction, which may be related to fatiguing of ciliary muscle and hence asthenopia. Treatment of the repeatedly stimulated muscle with cyanocobalamin restored contraction dose-dependently. Thus, the model developed in this study can be used to screen drug candidates for treating asthenopia.
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