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Pharmacology & Pharmacy 2016年第5期7卷 193-199页

作者： Kazuki Ohuchi Kazuhiro Tsuruma Masamitsu Shimazawa Junji Nakamura hideaki hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Asahi Kasei Pharma Corporation Tokyo Japan

The expression of cytosolic phospholipase A2 (cPLA2) expression is up-regulated in animal model of ALS and in patients with familial amyotrophic lateral sclerosis (fALS). Inhibition of cyclooxygenase 2 (COX2), which is a downstream enzyme of cPLA2, ameliorates the impairment of motor function in the ALS model mice. Therefore, the arachidonic acid cascade, including the cPLA2-COX2 pathway, is an important therapeutic target of ALS. The current study was designed to investigate the potential of AK106-001616, an inhibitor of cPLA2, in protection of motor neuron cell death induced by mutant superoxide dismutase (SOD1G93A). AK106-001616 (1 - 10 μM) protected NSC34 cells (mouse motor neuron like cells) against SOD1G93A-induced motor neuron cell death. Furthermore, aspirin, an inhibitor of COX1/2, reduced the SOD1G93A-induced motor neuron cell death at a concentration that inhibited COX2. Celecoxib, a selective COX2 inhibitor, also reduced the SOD1G93A-induced motor neuron cell death. These results suggest that the arachidonic acid cascade is important for SOD1G93A-induced motor neuron cell death and AK106-001616 has a potent neuroprotective effect against it. AK106-001616 may be a useful therapeutic agent against SOD1G93A-induced ALS.

关键词： AK106-001616 Amyotrophic Lateral Sclerosis cPLA2 NSC34 SOD1G93A

The Effects of Blue LED Light on Behavior and Retinal Function in Maternal and Offspring Mice

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Journal of Behavioral and Brain Science 2017年第8期7卷 348-359页

作者： Megumi Horibe Yuta Yoshino Shinichi Domoto Maho Nakamura Masamitsu Shimazawa hideaki hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan

In the present study, we investigated whether blue light emission diode (LED) light exposure affects the maternal behavior of mice. The brain function of the offspring mice, including short-term memory, locomotor activity, anxiety-like behavior, and depression-like behavior, was evaluated. Pregnant mice at day 11 were housed in the apparatus for exposure to blue LED light during the daytime. Nesting behavior and the survival of pups were observed until weaning. After weaning, the offspring mice were bred in normal light conditions until 12 weeks old, and then the Y-maze test, open field test, and tail suspension test were performed. Retinal functions were evaluated by electroretinogram and histological analysis. Blue LED light exposure during the daytime induced retinal damage, but did not affect behavior related to maternal care in maternal mice. In the offspring mice, blue LED light exposure during the daytime did not affect the retina or brain functions. These findings suggest that blue LED light during the daytime might not be a risk factor for disruption of the mother-infant relationship or offspring brain development in mice.

关键词： Blue LED Light Maternal Behavior Daytime Retina Brain

Crocetin Prevents Amyloid β1-42-Induced Cell Death in Murine Hippocampal Cells

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Pharmacology & Pharmacy 2014年第1期5卷 37-42页

作者： Yuta Yoshino Mitsue Ishisaka Naofumi Umigai Masamitsu Shimazawa Kazuhiro Tsuruma hideaki hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Riken Vitamin Co. Ltd. Tokyo Japan.

Crocetin is an aglycon of carotenoid extracted by saffron stigmas (Crocus sativus L.) and known to have a potent anti-oxidative effect. Amyliod β (Aβ), hallmark of Alzheimer’s disease, is reported to have neurotoxicity partly via oxidative stress. In this study, we investigated the effect of crocetin on hippocampal HT22 cell death induced by Aβ1-42. Furthermore, to clarify the mechanism underlying the protective effects of crocetin against Aβ1-42- induced cell death, we measured reactive oxygen species (ROS) production by CM-H2DCFDA kit assay. Crocetin at 1 -10 μM protected HT22 cells against Aβ1-42-induced neuronal cell death and decreased ROS production increased by Aβ1-42. These results that crocetin has the potent neuroprotective effect against Aβ1-42-induced cytotoxicity in hippocampal cells by attenuating oxidative stress, suggest that crocetin may provide a useful therapeutic strategy against Aβ-related disorders.

关键词： Alzheimer’s Disease Amyloid β1-42 Crocetin HT22 Oxidative Stress

Increased Seizure Susceptibility in a Mouse with Diacylglycerol Kinase βDeficiency

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Neuroscience & Medicine 2013年第2期4卷 117-122页

作者： Mitsue Ishisaka Kazuhiro Tsuruma Masamitsu Shimazawa Yasuhito Shirai Naoaki Saito hideaki hara Biosignal Research Center Kobe University Kobe Japan. Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Graduate School of Agriculture Kobe Japan

Diacylglycerol kinase (DGK) is an enzyme that converts diacylglycerol to phosphatidic acid. Several DGK isoforms have been implicated in the pathogenesis of seizure, but the role of DGKβ in seizure is unknown. In the present study, we investigated the involvement of DGKβ in seizure using DGKβ knockout (KO) mice. Seizures were more severe in DGKβ KO mice than in wild-type (WT) mice after pentylenetetrazol (PTZ) treatment and after kainic acid treatment, but there were no differences in latency to seizure. The expression levels of DGKβ in the hippocampal CA1, CA3, or DG areas did not differ between PTZ (60 mg/kg) treatment and saline treatment. There were fewer parvalbumin-positive interneurons in the hippocampal CA3 area in DGKβ KO mice than in control WT mice, which might partly account for the increased seizure susceptibility displayed by DGKβ KO mice. These results suggest that DGKβ may play a pivotal role in the development of the relevant interneurons, and that on inherent deficiency of DGKβ increases the animal’s sensitivity to seizure-inducing stimuli.

关键词： Diacylglycerol Kinase Seizure Parvalbumin

The Effects of Rufinamide on in VitroSpinal Muscular Atrophy Model

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Pharmacology & Pharmacy 2019年第4期10卷 159-168页

作者： Shiori Ando Arisu Sato Michinori Funato Kazuki Ohuchi Satoshi Inagaki Shinsuke Nakamura Masamitsu Shimazawa Hideo Kaneko hideaki hideaki hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Department of Clinical Research National Hospital Organization Nagara Medical Center Gifu Japan

Spinal muscular atrophy (SMA) is devastating genetic disease characterized by progressive loss of motor neuron and skeletal muscle weakness. SMA is the most common lethal genetic disease in infancy. SMA is caused by deletion or mutation of SMN1 gene and subsequent lack of SMN protein. Our purpose in this study was to evaluate the therapeutic potential of rufinamide, an antiepileptic drug. In this study, SMA patient-derived fibroblasts and differentiated spinal motor neurons (MNs) using SMA patient-derived iPSCs were used as in vitro SMA model. SMN mRNA was significantly increased by addition of rufinamide in type III SMA patient-derived fibroblasts. Furthermore, rufinamide stimulated neurite elongation in type III SMA patient derived-iPSCs-MNs. In contrast of the result using type III SMA patient-derived fibroblasts, the expression level of SMN mRNA was not changed after rufinamide treatment in type I SMA patient-derived fibroblasts, and rufinamide did not affect neurite outgrowth in type I SMA patients derived-iPSCs-MNs. These findings indicate that rufinamide may be one of the potential candidate drugs for mild type of SMA.

关键词： Spinal Muscular Atrophy Rufinamide iPSCs

Establishment and Effects of Ginger and Kikyoto of a Haloperidol-Induced Dysphagia Model in Guinea Pigs

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Pharmacology & Pharmacy 2016年第2期7卷 97-105页

作者： Takahiro Mizoguchi Mitsue Ishisaka Yui Kobatake Hiroaki Kamishina Yasuhiko Nishioka Tsukasa Kirimoto Masamitsu Shimazawa hideaki hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Department of Veterinary Medicine Faculty of Applied Biological Sciences Gifu University Gifu Japan Taiho Pharmaceutical Co. Ltd. Tokushima Japan

Dysphagia induces aspiration and causes aspiration pneumonia. There is no treatment for dysphagia fundamentally. Haloperidol reportedly induces dysphagia. In the present study, we established a haloperidol-induced dysphagia model in guinea pigs, and evaluated the effects of ginger, kikyoto, and a mixture of ginger and kikyoto on swallowing. Swallowing ability was evaluated using behavioral tests, computed tomography (CT), and videofluoroscopic examination of swallowing. To investigate the effect of ginger and kikyoto on swallowing, ginger, kikyoto, or a mixture of ginger and kikyoto was administered orally to guinea pigs with haloperidol-induced dysphagia. Effects of these compounds were evaluated with behavioral tests. Chronic administration of haloperidol reduced the number of swallows, as evaluated by the behavioral test and videofluoroscopic examination of swallowing. In our model, these compounds improved swallowing dysfunction. Our results suggest that this model might be useful in revealing the pathogenesis of dysphagia and evaluating compounds that might improve swallowing.

关键词： Dysphagia Guinea Pig Videofluoroscopic Examination of Swallowing Haloperidol Ginger

Comparison of Efficacy and Safety Evaluation of Latanoprost Formulations with and without Benzalkonium Chloride

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Pharmacology & Pharmacy 2013年第4期4卷 377-384页

作者： Hiroyoshi Kasai Yumiko Aoyama Takashi Kurasawa Tomoyo Imamura Kazuhiro Tsuruma hideaki hara Haruhisa Hirata Tetsuya Yamamoto Department of Ophthalmology Gifu University Graduate School of Medicine Gifu Japan Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Research and Development Wakamoto Pharmaceutical Co. Ltd. Tokyo Japan Sagami Research Laboratories Wakamoto Pharmaceutical Co. Ltd. Kanagawa Japan

Background: This study investigated the safety (cytotoxicity in vitro) and pharmacological effects (ocular hypotensive effects and aqueous humor concentrations in normotensive monkeys in vivo) of latanoprost formulations with benzalkonium chloride (latanoprost with BAK) and without BAK (NP). Methods: A bioequivalence study of latanoprost with BAK and NP was also conducted on human healthy volunteers. Cytotoxicity and the protective effect against H2O2 stress in vitro were evaluated using human corneal epithelial cells. The ocular hypotensive effects in normotensive monkeys were measured by pneumatonometer and the aqueous humor concentrations of latanoprost free acid were determined by liquid chromatography/mass spectrum (LC/MS) methods. The bioequivalence study of latanoprost with BAK and NP was carried out as a single eye drop, two-sequence, crossover randomized study. Results: Cytotoxicity tests in vitro revealed that NP was less toxic than latanoprost with BAK and significantly inhibited H2O2 induced cell damage while latanoprost with BAK did not. The hypotensive efficacy and the latanoprost free acid concentrations in aqueous humor of each formulation were not significantly different in monkeys. In the bioequivalence study, NP was bioequivalent to latanoprost with BAK. NP was safer than latanoprost with BAK with respect the results obtained in the in vitro cytotoxicity test. There was no difference observed between latanoprost with BAK and NP in the IOP lowering effect in monkeys and healthy volunteers. Conclusion: Taken together, these results indicate that NP is as effective as latanoprost with BAK, and is more likely to maintain ocular surface health than latanoprost with BAK.

关键词： Latanoprost NP Benzalkonium Benzalkonium-Free Bioequivalence

Restraint-Induced Expression of Endoplasmic Reticulum Stress-Related Genes in the Mouse Brain

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Pharmacology & Pharmacy 2011年第1期2卷 10-16页

作者： Mitsue Ishisaka Takashi Kudo Masamitsu Shimazawa Kenichi Kakefuda Atsushi Oyagi Kana Hyakkoku Kazuhiro Tsuruma hideaki hara 不详

Depression is a significant public health concern but its pathology remains unclear. Previously, increases in an endoplasmic reticulum (ER) stress-related protein were reported in the temporal cortex of subjects with major depressive disorder who had died by suicide. This finding suggests an association between depression and ER stress. The present study was designed to investigate whether acute stress could affect the ER stress response. Mice were immobilized for a period of 6 hr and then expression of ER stress response-related genes was measured by real-time PCR. We also used enzyme-linked immunosorbent assay for concomitant measurement of the plasma corticosterone levels in the mice. The effect of corticosterone on ER stress proteins was further investigated by treating mice with corticosterone for 2 weeks and then measuring ER protein expression by Western blotting. After a 6 hr restraint stress, mRNA levels of ER stress-related genes, such as the 78-kilodalton glucose regulated protein (GRP78), the 94-kilodalton glucose regulated protein (GRP94), and calreticulin, were increased in the cortex, hippocampus, and striatum of mouse brain. Blood plasma corticosterone level was also increased. In the corticosterone-treated mouse model, the expression of GRP78 and GRP94 was significantly increased in the hippocampus. These results suggest that acute stress may affect ER function and that ER stress may be involved in the pathogenesis of restraint stress, including the development of depression.

关键词： Corticosterone Depression Endoplasmic Reticulum Stress Restraint Stress

Identification of the Stress Which Causes Optineurin Aggregation

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Neuroscience & Medicine 2019年第2期10卷 150-161页

作者： Satoshi Inagaki Michinori Funato Junko Seki Chizuru Kawase Kazuki Ohuchi Shiori Ando Shinsuke Nakamura Masamitsu Shimazawa Hideo Kaneko hideaki hara Molecular Pharmacology Department of Biofunctional Evaluation Gifu Pharmaceutical University Gifu Japan Department of Clinical Research National Hospital Organization Nagara Medical Center Gifu Japan

Glaucoma is a common neurodegenerative disease that can cause blindness and occurs worldwide. Currently, lowering intraocular pressure is the only therapy available to protect retinal ganglion cells (RGCs). However, this therapy does not prevent RGC death in all patients. Therefore, new therapeutic approaches for glaucoma are urgently required, and neuroprotection of RGCs is a focus for many researchers. Optineurin (OPTN) is one of the normal tension glaucoma (NTG) relative genes, while mutant OPTN can form a characteristic aggregation, causing RGC death. Hence, elucidation of the mechanism of OPTN aggregation might provide a clue to help understand RGC death. To examine whether non-mutant OPTN could also aggregate, we pharmacologically induced some glaucoma-related stresses, such as endoplasmic reticulum (ER) stress, glutamate toxicity, activation of TNF-α signaling, mitochondrial dysfunction, and autophagic flux impairment. Our results showed that ER stress, TNF-α signaling, and autophagic flux are involved in OPTN aggregation. Furthermore, our data indicated that increased ER stress, activation of TNF-α signaling, and impaired autophagic flux induce OPTN aggregation, suggesting that OPTN aggregation might be an important therapeutic target not only for familial NTG with mutated OPTN but also for patients with glaucoma more generally.

关键词： Glaucoma Induced Pluripotent Stem Cells Retinal Ganglion Cells Optineurin Protein Aggregation

Mineral sulphide-lime reactions and effect of CaO/C mole ratio during carbothermic reduction of complex mineral sulphides

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International Journal of Minerals,Metallurgy and Materials 2014年第1期21卷 1-11页

作者： Yotamu Stephen Rainford hara Institute for Materials Research(IMR) School of ProcessEnvironmental and Materials Engineering(SPEME)University of Leeds

Mineral sulphide （MS）-lime （CaO） ion exchange reactions （MS ＋ CaO = MO ＋ CaS） and the effect of CaO/C mole ratio during carbothermic reduction （MS ＋ CaO ＋ C = M ＋ CaS ＋ CO（g）） were investigated for complex froth flotation mineral sulphide concentrates. Phases in the partially and fully reacted samples were characterised by X-ray diffraction （XRD） and scanning electron microscopy （SEM）. The primary phases during mineral sulphide-lime ion exchange reactions are Fe304, CaSO4 Cu2S, and CaS. A complex liquid phase of Ca2CuFeO3S forms during mineral sulphide-lime exchange reactions above 1173 K. The formation mechanisms of Ca2CuFeO3S liquid phase are determined by characterising the partially reacted samples. The reduction rate and extent of mineral sulphides in the presence of CaO and C increase with the increase in CaO/C ratio. The metallic phases are surrounded by the CaS rich phase at CaO/C 〉 1, but the metallic phases and CaS are found as separate phases at CaO/C 〈 1. Experimental results show that the stoichiometric ratio of carbon should be slightly higher than that of CaO. The reactions between CaO and gangue minerals （SiO2 and A1203） are only observed at CaO/C 〉 1 and the reacted samples are excessively sintered.

关键词： sulphide minerals ion exchange carbothermic reduction lime