Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 124 , Issue 4
Showing 1-13 articles out of 13 articles from the selected issue
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  • Nicoletta Galeotti, Mersedeh Farzad, Enrica Bianchi, Carla Ghelardini
    2014 Volume 124 Issue 4 Pages 409-417
    Published: April 20, 2014
    Released: April 17, 2014
    JOURNALS FREE ACCESS
    Our purpose was to combine the use of morphine with clinically available inhibitors of protein kinase C (PKC), finally potentiating morphine analgesia in humans. Thermal tests were performed in rodents and humans previously administered with acute or chronic morphine combined or not with increasing doses of the PKC-blocker St. John’s Wort (SJW) or its main component hypericin. Phosphorylation of the γ subunit of PKC enzyme was assayed by western blotting in the periaqueductal grey matter (PAG) from rodents co-administered with morphine and hypericin and was prevented in rodent PAG by SJW or hypericin co-administration with morphine, inducing a potentiation of morphine analgesia in thermal pain. The score of pain assessment in healthy volunteers were decreased by 40% when morphine was co-administered with SJW at a dose largely below those used to obtain an antidepressant or analgesic effect in both rodents and humans. The SJW/hypericin potentiating effect lasted in time and preserved morphine analgesia in tolerant mice. Our findings indicate that, in clinical practice, SJW could reduce the dose of morphine obtaining the same analgesic effect. Therefore, SJW and one of its main components, hypericin, appear ideal to potentiate morphine-induced analgesia.
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  • Guan Tao Du, Meng Hu, Zhen Lin Mei, Chao Wang, Guang Jun Liu, Mei Hu, ...
    2014 Volume 124 Issue 4 Pages 418-426
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: March 27, 2014
    JOURNALS FREE ACCESS
    Telmisartan, an angiotensin II type 1–receptor blocker (ARBs), has been reported to exert beneficial effects on the central nervous system (CNS). However, the effect of telmisartan on cognitive impairment associated with type 1 diabetes is not well known. Here, we examined the possibility that telmisartan could improve memory function in a type 1 diabetic mouse model, streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice subjected to the Morris Water Maze (MWM) task exhibited a significant decline of spatial learning and memory. Oral administration of telmisartan at two nonhypotensive doses (0.7 or 0.35 mg/kg) significantly improved memory deficits in STZ-induced diabetic mice. Telmisartan treatment markedly reduced Aβ42, APP, BACE1, RAGE, and NF-κB p65 of the hippocampus and cortex, but did not beneficially affect hyperglycemia and hypoinsulinemia in the STZ-induced diabetic mice compared with untreated diabetic mice. Taken together, our findings suggest that telmisartan ameliorates memory deficits in type 1 diabetic mice, at least partly because of attenuation of amyloidosis in the brain.
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  • Masato Katsuyama, Masakazu Ibi, Misaki Matsumoto, Kazumi Iwata, Yoichi ...
    2014 Volume 124 Issue 4 Pages 427-432
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: March 19, 2014
    JOURNALS FREE ACCESS
    Clioquinol was used extensively in the mid-1900s as an amebicide to treat indigestion and diarrhea. It was eventually withdrawn from the market because it was linked to subacute myelo-optic neuropathy (SMON) in Japan. However, the pathogenesis of SMON has not yet been elucidated in detail. As reported previously, we performed a global analysis on human neuroblastoma cells using DNA chips. The global analysis and quantitative PCR demonstrated that the mRNA level of VGF (nonacronymic), the precursor of neuropeptides involved in pain reactions, was significantly increased when SH-SY5Y and IMR-32 neuroblastoma cells were treated with clioquinol. Promoter analyses in SH-SY5Y cells revealed that a region responsive to clioquinol exists between −1381 and −1349 of the human VGF gene, which contains an activator protein (AP)-1 site–like sequence. The introduction of mutations at this site significantly reduced clioquinol-induced transcriptional activation. Clioquinol induced the expression of the AP-1 family transcription factors, c-Jun and c-Fos. Electrophoresis mobility shift assays demonstrated that c-Jun and c-Fos could bind to the AP-1 site at −1374/−1368 in SH-SY5Y cells treated with clioquinol. RNA interference against c-Fos significantly suppressed clioquinol-induced VGF mRNA expression. These results suggest that the clioquinol-induced expression of c-Fos mediates the induction of VGF expression.
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  • Nan Hu, Mengyue Hu, Ru Duan, Can Liu, Haifang Guo, Mian Zhang, Yunli Y ...
    2014 Volume 124 Issue 4 Pages 433-444
    Published: April 20, 2014
    Released: April 17, 2014
    JOURNALS FREE ACCESS
    Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contributing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concentration-dependently up-regulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N-4 cells. Data from western blotting and QT-PCR showed that induction of CYP3A4 activity was associated with up-regulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid–induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK-, PKC-, and NF-κB–dependent pathways, whereas that by palmitic acid was possibly associated with the PKC-dependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions.
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  • Yongheng Bai, Hong Lu, Liping Hu, Dan Hong, Linchao Ding, Bicheng Chen
    2014 Volume 124 Issue 4 Pages 445-456
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: March 27, 2014
    JOURNALS FREE ACCESS
    Aristolochic acid (AA) is known as a potent mutagen that induces significant cytotoxic and mutagenic effects on renal tubular epithelial cells. Clinically, the persistent injury of AA results in the infiltration of inflammatory cells, epithelial-to-mesenchymal transition (EMT), and renal tubulointerstitial fibrosis. There are no truly effective pharmaceuticals. In this study, we investigated the potential role of the extract of Sedum sarmentosum Bunge (SSB), a traditional Chinese herbal medicine, on rat tubuloepithelial (NRK-52E) cells after AA injury in vitro. Evidence revealed that AA induced mitochondrial-pathway–mediated cellular apoptosis, accompanied by cell proliferation in a feedback mechanism. Treatment with SSB also induced cells to enter early apoptosis, but inhibited cell proliferation. In cultured NRK-52E cells, AA induced the imbalance of MMP-2/TIMP-2 and promoted EMT and ECM accumulation. SSB treatment significantly alleviated AA-induced NRK-52E cells fibrosis-like appearance, inhibited the induction of EMT, and deposition of ECM. SSB also decreased the activity of the NF-κB signaling pathway, resulting in down-regulated expression of NF-κB–controlled chemokines and pro-inflammatory cytokines, including MCP-1, MIF, and M-CSF, which may regulate the macrophage-mediated inflammatory reaction during renal fibrosis in vivo. Therefore, these findings suggest that SSB exerts protective effects against AA-induced tubular epithelial cells injury through suppressing the synthesis of inflammatory factors, EMT, and ECM production.
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  • Daishu Mizuki, Zhao Qi, Ken Tanaka, Hironori Fujiwara, Tsutomu Ishikaw ...
    2014 Volume 124 Issue 4 Pages 457-467
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: March 19, 2014
    JOURNALS FREE ACCESS
    This study investigated the effects of alcoholic extract of Butea superba (BS) on cognitive deficits and depression-related behavior using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its actions. OBX mice were treated daily with BS (100 and 300 mg/kg, p.o.) or reference drugs, tacrine (2.5 mg/kg, i.p.) and imipramine (10 mg/kg, i.p.) from day 3 after OBX. OBX impaired non-spatial and spatial cognitive performances, which were elucidated by the novel object recognition test and modified Y maze test, respectively. These deficits were attenuated by tacrine and BS but not imipramine. OBX animals exhibited depression-like behavior in the tail suspension test in a manner reversible by imipramine and BS but not tacrine. OBX down-regulated phosphorylation of synaptic plasticity–related signaling proteins: NMDA receptor, AMPA receptor, calmodulin-dependent kinase II, and cyclic AMP-responsive element-binding protein. OBX also reduced choline acetyltransferase in the hippocampus. BS and tacrine reversed these neurochemical alterations. Moreover, BS inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BS ameliorates not only cognition dysfunction via normalizing synaptic plasticity–related signaling and facilitating central cholinergic systems but also depression-like behavior via a mechanism differing from that implicated in BS amelioration of cognitive function in OBX animals.
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  • Ling-ling Jia, Ze-yu Zhong, Feng Li, Zhao-li Ling, Yang Chen, Wei-man ...
    2014 Volume 124 Issue 4 Pages 468-479
    Published: April 20, 2014
    Released: April 17, 2014
    JOURNALS FREE ACCESS
    Clozapine (CLZ) was reported to be associated with hepatotoxicity. Glycyrrhetinic acid (GA) has a liver protective effect. Our preliminary experiments showed that GA aggravated rather than attenuated CLZ-induced hepatotoxicity in primary cultured rat hepatocytes. The study aimed to describe the enhancing effect of GA on CLZ-induced hepatotoxicity in vivo and in vitro. Data from primary cultured rat hepatocytes showed the decreased formation of metabolites demethylclozapine (nor-CLZ) and clozapine N-oxide (CLZ N-oxide) .The results in vivo showed that 7-day CLZ treatment led to marked accumulation of triglyceride (TG) and increase in γ-glutamyl transpeptidase (γ-GT) activity, liver weight, and serum AST in rats. Co-administration of GA enhanced the increases in hepatic TG, γ-GT, liver weight, and serum total cholesterol induced by CLZ. GA decreased plasma concentrations of nor-CLZ and CLZ N-oxide. Compared with control rats, hepatic microsomes of GA rats exhibited the decreased formations of nor-CLZ and CLZ N-oxide, accompanied by decreases in activities of CYP2C11 and CYP2C19 and increased activity of CYP1A2. QT-PCR analysis demonstrated that GA enhanced expression of CYP1A2, but suppressed expression of CYP2C11 and CYP2C13. All these results support the conclusion that GA aggravated CLZ-induced hepatotoxicity, which was partly via inhibiting CYP2C11 and CYP2C13 or inducing CYP1A2.
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  • Shin-ichi Uchida, Tomomi Tashiro, Mika Kawai-Uchida, Akihisa Mori, Pet ...
    2014 Volume 124 Issue 4 Pages 480-485
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: March 28, 2014
    JOURNALS FREE ACCESS
    The adenosine A2A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson’s disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most effective in potentiating motor function when combined with sub-maximal doses of l-DOPA. However, the effects of combining istradefylline with sub-optimal l-DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to l-DOPA. In these animals, single dose acute oral administration of istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of l-DOPA (2.5 mg/kg). The chronic co-administration of istradefylline (10 mg/kg) with l-DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that istradefylline can be used to potentiate the effects of sub-optimal doses of l-DOPA in the treatment of Parkinson’s disease without causing or worsening dyskinesia.
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  • Xuejiao Liu, Mingshan Niu, Xiaoyu Xu, Wei Cai, Lingyu Zeng, Xiuping Zh ...
    2014 Volume 124 Issue 4 Pages 486-493
    Published: April 20, 2014
    Released: April 17, 2014
    JOURNALS FREE ACCESS
    Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica, has been shown to exert anti-cancer and anti-proliferative activities in vitro as well as in animal tumor models. However, the mechanism underlying its anti-tumor action still remains unclear. CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors whose function is altered in cancer due to increased expression and overactive transport. We showed that CRM1 is a direct cellular target of plumbagin. The nuclei of cells incubated with plumbagin accumulated tumor-suppressor proteins and inhibited the interactions between CRM1 and these proteins. Particularly, we demonstrated that plumbagin could specifically react with the conserved Cys528 of CRM1 but not with a Cys528 mutant peptide through Mass spectrometric analysis. More importantly, cancer cells that are transfected with mutant CRM1 (C528S) are resistant to the inhibitory effects of plumbagin, demonstrating that the inhibition is through direct interaction with Cys528 of CRM1. The inhibition of nuclear traffic by plumbagin may account for its therapeutic properties in cancer and inflammatory diseases. Our findings could contribute to the development of a new class of CRM1 inhibitors.
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  • Yuji Nakamura, Junko Matsuo, Norimasa Miyamoto, Atsuko Ojima, Kentaro ...
    2014 Volume 124 Issue 4 Pages 494-501
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: April 02, 2014
    JOURNALS FREE ACCESS
    A prospective comparison study across 3 independent research laboratories of a pure IKr blocker E-4031 was conducted by using the same batch of human iPS cell–derived cardiomyocytes in order to verify the utility and reliability of our original standard protocol. Field potential waveforms were recorded with a multi-electrode array system to measure the inter-spike interval and field potential duration. The effects of E-4031 at concentrations of 1 to 100 nM were sequentially examined every 10 min. In each facility, E-4031 significantly prolonged the field potential duration corrected by Fridericia’s formula and caused early afterdepolarizations occasionally resulting in triggered activities, whereas it tended to decrease the rate of spontaneous contraction. These results were qualitatively and quantitatively consistent with previous non-clinical in vitro and in vivo studies as well as clinical reports. There were inter-facility differences in some absolute values of the results, which were not observed when the values were normalized as percentage change. Information described in this paper may serve as a guide when predicting the drug-induced repolarization delay and arrhythmias with this new technology of stem cells.
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  • Ryo Kitamura, Tsugunobu Andoh, Shizuka Mizoguchi, Yukako Saito, Hiroki ...
    2014 Volume 124 Issue 4 Pages 502-510
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: March 29, 2014
    JOURNALS FREE ACCESS
    Bortezomib, an inhibitor of proteasome holoenzyme, is used to treat relapsed and refractory multiple myeloma. Peripheral neuropathy is a treatment-limiting adverse effect of bortezomib and is very difficult to control. In this study, we examined the efficacy of gabapentin in inhibiting bortezomib-induced peripheral neuropathy. Single intravenous injections of bortezomib (0.03 – 0.3 mg/kg) dose-dependently induced mechanical allodynia with a peak effect 12 days after injection. Bortezomib (0.3 mg/kg) also caused mechanical hyperalgesia, but neither affected thermal nociception nor induced cold allodynia. Bortezomib increased the response of the saphenous nerve to weak punctate stimulation but not response to cool stimulation of the skin. When administered 12 days after bortezomib injection, oral and intracisternal gabapentin markedly inhibited mechanical allodynia. Intrathecal, but not intraplantar, gabapentin had a tendency to reduce mechanical allodynia. The antiallodynic activity of orally administered gabapentin was suppressed by noradrenaline, but not serotonin, depletion in the spinal cord. Bortezomib did not affect the expression levels of the calcium channel α2δ-1 subunit, a high-affinity binding site of gabapentin, in the plantar skin, spinal cord, medulla oblongata, and pons. These results suggest that gabapentin inhibits bortezomib-induced mechanical allodynia, most likely through the activation of the descending noradrenergic system.
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Short Communication
  • Keitaro Hayashi, Promsuk Jutabha, Takao Kamai, Hitoshi Endou, Naohiko ...
    2014 Volume 124 Issue 4 Pages 511-513
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: March 27, 2014
    JOURNALS FREE ACCESS
    Endothelial cell proliferation supporting angiogenesis requires sufficient nutrient supply because of facilitated intracellular metabolism. However, little is known about the mechanism for the promotion of nutrient incorporation in proliferating endothelial cells. Here we show that L-type amino acid transporter 1 (LAT1) is a major transporter of essential amino acids in human umbilical vein endothelial cells (HUVECs). Growing HUVECs express a certain level of LAT1. A LAT1-specific inhibitor suppressed leucine uptake, cell proliferation, and tube formation of HUVECs. Therefore, LAT1 acts to support effective uptake of amino acids, which is critical for the optimal function of HUVECs for angiogenesis.
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  • Meng Zhao, Saki Nakamura, Takahito Miyake, Kanako So, Hisashi Shirakaw ...
    2014 Volume 124 Issue 4 Pages 514-517
    Published: April 20, 2014
    Released: April 17, 2014
    [Advance publication] Released: March 27, 2014
    JOURNALS FREE ACCESS
    Oxaliplatin, a platinum-based chemotherapeutic agent, causes an acute peripheral neuropathy triggered by cold in almost all patients during or within hours after its infusion. We recently reported that a single administration of oxaliplatin induced cold hypersensitivity 2 h after the administration in mice. In this study, we examined whether standard analgesics relieve the oxaliplatin-induced acute cold hypersensitivity. Gabapentin, tramadol, mexiletine, and calcium gluconate significantly inhibited and morphine and milnacipran decreased the acute cold hypersensitivity, while diclofenac and amitriptyline had no effects. These results suggest that gabapentin, tramadol, mexiletine, and calcium gluconate are effective against oxaliplatin-induced acute peripheral neuropathy.
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