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笠原二郎

徳島大学

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2024年11月13日更新

職名: 准教授
電話: 088-633-7278
電子メール: awajiro@tokushima-u.ac.jp
学歴: 1994/3: 九州大学理学部生物学科卒業
1996/3: 九州大学大学院理学研究科生物学専攻修士課程修了
1997/3: 九州大学大学院医学系研究科分子生命科学系専攻中退
学位: 博士(理学) (九州大学) (2000年1月)
職歴・経歴: 1996/4: 日本学術振興会DC1特別研究員
1997/4: 熊本大学医学部助手
2001/4: 日本学術振興会海外特別研究員 (Center for Learning and Memory, Massachusetts Institute of Technology)
2002/10: 東北大学大学院薬学研究科助手
2004/4: 東北大学大学院薬学研究科講師
2009/12: 徳島大学大学院ヘルスバイオサイエンス研究部(薬科学教育部)准教授

専門分野・研究分野: 薬学 (Pharmacy)

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2024年11月13日更新

専門分野・研究分野: 薬学 (Pharmacy)
担当経験のある授業科目: 医療における人間学 (学部)
医薬品安全性学特論 (大学院)
実務実習事前学習 (学部)
専攻公開ゼミナール (大学院)
演習 (学部)
演習3 (学部)
生体内シグナル概論 (学部)
生物化学実習 (学部)
育薬共通演習 (大学院)
臨床病態学特論 (大学院)
薬学演習 (大学院)
薬学課題研究 (大学院)
薬物治療学3(神経) (学部)
薬科学演習1 (大学院)
薬科学特別研究 (大学院)
遺伝子生化学 (学部)
指導経験: 研究者総覧に該当データはありませんでした。

研究者総覧で最新データを確認する

2024年11月13日更新

専門分野・研究分野: 薬学 (Pharmacy)

研究テーマ: 研究者総覧に該当データはありませんでした。

著書

Jiro Kasahara, ME Choudhury, Noriko Nishikawa, Akie Tanabe, Ryosuke Tsuji, Yu Zhou, Masatoshi Ogawa, Hironori Yokoyama, Junya Tanaka and Masahiro Nomoto :
Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal models of Parkinson's disease.,
Academic Press, Jun. 2017. Jiro Kasahara, Mohammed Emamussalehin Choudhury, Hironori Yokoyama, Naoto Kadoguchi and Masahiro Nomoto :
Animal Models for the Study of Human Disease (Edited by Conn PM), --- Part VII: The Brain, Stroke, and Neuromuscular, Chapter 26: Neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Animal Models for Parkinson's Disease ---,
Academic Press, Jul. 2013.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/B978-0-12-415894-8.00026-9
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-84902032640

(DOI: 10.1016/B978-0-12-415894-8.00026-9, Elsevier: Scopus)

論文

Yukuto Ogawa, Sohei Tsugita, Yuka Torii, Hiten Iwamoto, Tsukasa Sato, Jiro Kasahara, Masaki Takeuchi, Tomohiko Kuwabara, Masamitsu Iiyama, Toshio Takayanagi and Hitoshi Mizuguchi :
Microdialysis-integrated HPLC system with dual-electrode detection using track-etched membrane electrodes for in vivo monitoring of dopamine dynamics,
Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, Vol.1247, 124318, 2024.

(要約): A capillary high-performance liquid chromatography (HPLC) system equipped with a dual-electrode detector utilizing track-etched membrane electrodes (TEMEs) was combined with a microdialysis sampling setup. The electrochemical detector benefits from the high electrolysis efficiency of TEMEs, allowing for calibration-free coulometric detection and simplifying data analysis to determine the dopamine recovery through a dialysis probe. Additionally, this system was used for in vivo monitoring of dopamine in the right striatum of a mouse brain. Temporal changes in dopamine levels, including an exponential decay immediately after the dialysis probe insertion and an excess release of dopamine induced by a high concentration of potassium ions, confirmed the system's proper operation. Furthermore, subsequent measurements following the intraperitoneal injection of mirtazapine showed no increase in dopamine levels in the right dorsal striatum. The dual-electrode system displayed characteristic dopamine detection behavior, with anodic and cathodic peak pairs indicative of reversible electrochemical reactions. This capability facilitated the identification of the dopamine peak within the complex chromatogram of the mouse brain dialysate. The consistency between dopamine collection efficiency from standard solutions and dialysate indicated the absence of interfering electroactive substances overlapping with the dopamine peak in the chromatogram. This integrated analysis system successfully tracked temporal fluctuations in dopamine concentration within the mouse brain.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jchromb.2024.124318
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39299150; ● Summary page in Scopus @ Elsevier: 2-s2.0-85204058127

(DOI: 10.1016/j.jchromb.2024.124318, PubMed: 39299150, Elsevier: Scopus) Masatoshi Ogawa, Yu Zhou, Ryosuke Tsuji, Jiro Kasahara and Satoshi Goto :
Intrastriatal Memantine Infusion Dampens Levodopa-Induced Dyskinesia and Motor Deficits in a Mouse Model of Hemiparkinsonism,
Frontiers in Neurology, No.10, 1258, 2019.

(要約): Although the administration of dopamine precursor levodopa remains as the mainstay for the treatment of Parkinson's disease, long-term exposure to levodopa often causes a disabling complication, referred to as levodopa-induced dyskinesias. Therefore, the development of new therapeutic interventions to dampen levodopa-induced dyskinesias and parkinsonian motor deficits is needed in the treatment of Parkinson's disease. Intracerebral brain infusion has the merit of being able to specifically deliver any drug into any brain part. By using an intracerebral infusion system equipped with implantable, programmable, and refillable pumps, we show herein that continuous intrastriatal administration of memantine (MMT), which is a non-competitive N-methyl-D-aspartate receptor antagonist, attenuates levodopa-induced dyskinesias and parkinsonian signs in 6-hydroxydopamine-lesioned hemiparkinsonian mice that received daily levodopa treatment. Corroborating the general thought that overactivation of the striatal N-methyl-D-aspartate receptor function might generate levodopa-induced dyskinesias and parkinsonism, our results suggest that a continuous intrastriatal MMT infusion can be beneficial for the management of Parkinson's disease with levodopa-induced dyskinesias. Our study also provides indications for the prototypic use of pharmacological deep-brain modulation through intracerebral infusion systems for treating medically intractable movement disorders.
(キーワード): intracerebral brain infusion / levodopa-induced dyskinesia / memantine / N-methyl-D-aspartate receptor / Parkinson's disease
(徳島大学機関リポジトリ): ● Metadata: 114098
(出版サイトへのリンク): ● Publication site (DOI): 10.3389/fneur.2019.01258
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1050001339320658176; ● Summary page in Scopus @ Elsevier: 2-s2.0-85077276016

(徳島大学機関リポジトリ: 114098, DOI: 10.3389/fneur.2019.01258, CiNii: 1050001339320658176, Elsevier: Scopus) Kazuhisa Miyake, Ayuko Sakane, Ikuko Sagawa, Yoko Tomida, Jiro Kasahara and Takuya Sasaki :
Actin Cytoskeletal Reorganization Function of JRAB/MICAL-L2 Is Fine-tuned by Intramolecular Interaction between First LIM Zinc Finger and C-terminal Coiled-coil Domains,
Scientific Reports, Vol.9, No.1, 12794, 2019.

(要約): JRAB/MICAL-L2 is an effector protein of Rab13, a member of the Rab family of small GTPase. JRAB/MICAL-L2 consists of a calponin homology domain, a LIM domain, and a coiled-coil domain. JRAB/MICAL-L2 engages in intramolecular interaction between the N-terminal LIM domain and the C-terminal coiled-coil domain, and changes its conformation from closed to open under the effect of Rab13. Open-form JRAB/MICAL-L2 induces the formation of peripheral ruffles via an interaction between its calponin homology domain and filamin. Here, we report that the LIM domain, independent of the C-terminus, is also necessary for the function of open-form JRAB/MICAL-L2. In mechanistic terms, two zinc finger domains within the LIM domain bind the first and second molecules of actin at the minus end, potentially inhibiting the depolymerization of actin filaments (F-actin). The first zinc finger domain also contributes to the intramolecular interaction of JRAB/MICAL-L2. Moreover, the residues of the first zinc finger domain that are responsible for the intramolecular interaction are also involved in the association with F-actin. Together, our findings show that the function of open-form JRAB/MICAL-L2 mediated by the LIM domain is fine-tuned by the intramolecular interaction between the first zinc finger domain and the C-terminal domain.
(キーワード): 3T3 Cells / Actins / Animals / Cytoskeleton / Hydrogen Deuterium Exchange-Mass Spectrometry / Mice / Microfilament Proteins / Models, Molecular / Mutation / Protein Domains / 構造活性相関 (structureactivity relationship) / Zinc Fingers
(徳島大学機関リポジトリ): ● Metadata: 114610
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41598-019-49232-8
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31488862; ● Summary page in Scopus @ Elsevier: 2-s2.0-85071764631

(徳島大学機関リポジトリ: 114610, DOI: 10.1038/s41598-019-49232-8, PubMed: 31488862, Elsevier: Scopus) Masatoshi Ogawa, Zhou Yu, Ryosuke Tsuji, Satoshi Goto and Jiro Kasahara :
Video-based assessmens of the hind limb stepping in a mouse model of hemi-parkinsonism.,
Neuroscience Research, Vol.154, 56-59, 2019.

(要約): Unilateral injection of 6-hydroxydopamine (6-OHDA) is commonly used to generate a rodent model of Parkinson's disease (PD). Although motor deficits of the lower extremities represent one of the major clinical symptoms in PD patients, validated tests for assessing motor impairments of the hind limb in 6-OHDA mice are currently unavailable. We here report the video-based assessments of the asymmetric use of hind limbs in 6-OHDA mice. A significantly decreased number of spontaneous hind limb stepping was observed in the contralateral-to-lesioned side, and was dose dependently reversed by levodopa, suggesting that it could be utilized for screening PD therapeutics.
(徳島大学機関リポジトリ): ● Metadata: 114103
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.neures.2019.05.002
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31103423; ● Summary page in Scopus @ Elsevier: 2-s2.0-85066110619

(徳島大学機関リポジトリ: 114103, DOI: 10.1016/j.neures.2019.05.002, PubMed: 31103423, Elsevier: Scopus) Yu Zhou, Yukio Yamamura, Masatoshi Ogawa, Ryosuke Tsuji, Koichiro Tsuchiya, Jiro Kasahara and Satoshi Goto :
c-Abl inhibition exerts symptomatic antiparkinsonian effects through a striatal postsynaptic mechanism.,
Frontiers in Pharmacology, Vol.9, 1311, 2018.

(要約): Parkinson's disease (PD) is caused by a progressive degeneration of nigral dopaminergic cells leading to striatal dopamine deficiency. From the perspective of antiparkinsonian drug mechanisms, pharmacologic treatment of PD can be divided into symptomatic and disease-modifying (neuroprotective) therapies. An increase in the level and activity of the Abelson non-receptor tyrosine kinase (c-Abl) has been identified in both human and mouse brains under PD conditions. In the last decade, it has been observed that the inhibition of c-Abl activity holds promise for protection against the degeneration of nigral dopaminergic cells in PD and thereby exerts antiparkinsonian effects. Accordingly, c-Abl inhibitors have been applied clinically as a disease-modifying therapeutic strategy for PD treatment. Moreover, in a series of studies, including that presented here, experimental evidence suggests that in a mouse model of parkinsonism induced by -methyl-4-phenyl-1,2,3,6-tetrahydropyridine, c-Abl inhibition exerts an immediate effect improving motor impairments by normalizing altered activity in striatal postsynaptic signaling pathways mediated by Cdk5 (cyclin-dependent kinase 5) and DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa). Based on this, we suggest that c-Abl inhibitors represent an ideal antiparkinsonian agent that has both disease-modifying and symptomatic effects. Future research is required to carefully evaluate the therapeutic efficacy and clinical challenges associated with applying c-Abl inhibitors to the treatment of PD.
(徳島大学機関リポジトリ): ● Metadata: 114097
(出版サイトへのリンク): ● Publication site (DOI): 10.3389/fphar.2018.01311
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30505273; ● Search Scopus @ Elsevier (PMID): 30505273; ● Search Scopus @ Elsevier (DOI): 10.3389/fphar.2018.01311

(徳島大学機関リポジトリ: 114097, DOI: 10.3389/fphar.2018.01311, PubMed: 30505273) Jiro Kasahara, Hiroto Uchida, Kenta Tezuka and Nanae Oka :
Postischemic anhedonia associated with neurodegenerative changes in the hippocampal dentate gyrus of rats,
Neural Plasticity, Vol.2016, No.2016, 5054275, 2016.

(徳島大学機関リポジトリ): ● Metadata: 114096
(出版サイトへのリンク): ● Publication site (DOI): 10.1155/2016/5054275
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27057366; ● Summary page in Scopus @ Elsevier: 2-s2.0-84962770150

(徳島大学機関リポジトリ: 114096, DOI: 10.1155/2016/5054275, PubMed: 27057366, Elsevier: Scopus) Satomi Kikuta, Yukiyo Nakamura, Yukio Yamamura, Atsushi Tamura, Noriyasu Homma, Yuchio Yanagawa, Hajime Tamura, Jiro Kasahara and Makoto Osanai :
Quantitative activation-induced manganese-enhanced MRI reveals severity of Parkinsons disease in mice,
Scientific Reports, Vol.5, No.12800, 2015.

(要約): We demonstrate that activation-induced manganese-enhanced magnetic resonance imaging with quantitative determination of the longitudinal relaxation time (qAIM-MRI) reveals the severity of Parkinson's disease (PD) in mice. We first show that manganese ion-accumulation depends on neuronal activity. A highly active region was then observed by qAIM-MRI in the caudate-putamen in PD-model mice that was significantly correlated to the severity of PD, suggesting its involvement in the expression of PD symptoms.
(徳島大学機関リポジトリ): ● Metadata: 114971
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/srep12800
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26255701; ● Summary page in Scopus @ Elsevier: 2-s2.0-84938920842

(徳島大学機関リポジトリ: 114971, DOI: 10.1038/srep12800, PubMed: 26255701, Elsevier: Scopus) Naoto Kadoguchi, Shinji Okabe, Yukio Yamamura, Misaki Shono, Fukano T, Akie Tanabe, Hironori Yokoyama and Jiro Kasahara :
Mirtazapine has a therapeutic potency in 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease,
BMC Neuroscience, Vol.15, No.79, 2014.

(要約): Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), shows multiple pharmacological actions such as inhibiting presynaptic α2 noradrenaline receptor (NAR) and selectively activating 5-hydroxytriptamine (5-HT) 1A receptor (5-HT1AR). Mirtazapine was also reported to increase dopamine release in the cortical neurons with 5-HT dependent manner. To examine whether mirtazapine has a therapeutic potency in Parkinson's disease (PD), we examined this compound in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model of PD. Male C57BL/6 mice were subjected to MPTP treatment to establish a PD model. Mirtazapine was administered once a day for 3 days after MPTP treatment. MPTP-induced motor dysfunction, assessed by beam-walking and rota-rod tests, was significantly improved by administration of mirtazapine. Biochemical examinations by high performance liquid chromatography and western blot analysis suggested mirtazapine facilitated utilization of dopamine by increasing turnover and protein expression of transporters, without affecting on neurodegenerative process by MPTP. These therapeutic effects of mirtazapine were reduced by administration of WAY100635, an inhibitor for 5HT1AR, or of clonidine, a selective agonist for α2-NAR, or of prazosin, an inhibitor for α1-NAR, respectively. Our results showed mirtazapine had a therapeutic potency against PD in a mouse model. Because PD patients sometimes show depression together, it will be a useful drug for a future PD treatment.
(キーワード): Animals / Antidepressive Agents, Tricyclic / Brain / Disease Models, Animal / Feasibility Studies / MPTP Poisoning / Male / Mianserin / Mice / Mice, Inbred C57BL / Treatment Outcome
(徳島大学機関リポジトリ): ● Metadata: 114769
(出版サイトへのリンク): ● Publication site (DOI): 10.1186/1471-2202-15-79
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24965042; ● Search Scopus @ Elsevier (PMID): 24965042; ● Search Scopus @ Elsevier (DOI): 10.1186/1471-2202-15-79

(徳島大学機関リポジトリ: 114769, DOI: 10.1186/1471-2202-15-79, PubMed: 24965042) Akie Tanabe, Yukio Yamamura, Jiro Kasahara, Ryoma Morigaki, Ryuji Kaji and Satoshi Goto :
A novel tyrosine kinase inhibitor AMN107 (nilotinib) normalizes striatal motor behaviors in a mouse model of Parkinson's disease.,
Frontiers in Cellular Neuroscience, Vol.8, No.50, 2014.

(要約): Abnormal motor behaviors in Parkinson's disease (PD) result from striatal dysfunction due to an imbalance between dopamine and glutamate transmissions that are integrated by dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). c-Abelson tyrosine kinase (c-Abl) phosphorylates cyclin-dependent kinase 5 (Cdk5) at Tyr15 to increase the activity of Cdk5, which reduces the efficacy of dopaminergic signaling by phosphorylating DARPP-32 at Thr75 in the striatum. Here, we report that in the mouse striatum, a novel c-Abl inhibitor, nilotinib (AMN107), inhibits phosphorylation of both Cdk5 at Tyr15 and DARPP-32 at Thr75, which is negatively regulated by dopamine receptor activation through a D2 receptor-mediated mechanism. Like a D2-agonist, nilotinib synergizes with a D1-agonist for inducing striatal c-Fos expression. Moreover, systemic administration of nilotinib normalizes striatal motor behaviors in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These findings suggest that nilotinib could possibly serve as a new and alternative agent for treating PD motor symptoms.
(徳島大学機関リポジトリ): ● Metadata: 114464
(出版サイトへのリンク): ● Publication site (DOI): 10.3389/fncel.2014.00050
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24600352; ● Summary page in Scopus @ Elsevier: 2-s2.0-84894260952

(徳島大学機関リポジトリ: 114464, DOI: 10.3389/fncel.2014.00050, PubMed: 24600352, Elsevier: Scopus) Yukio Yamamura, Ryoma Morigaki, Jiro Kasahara, Hironori Yokoyama, Akie Tanabe, Shinya Ohkita, Hidetaka Koizumi, Shinji Nagahiro, Ryuji Kaji and Satoshi Goto :
Dopamine signaling negatively regulates striatal phosphorylation of Cdk5 at tyrosine 15 in mice,
Frontiers in Cellular Neuroscience, Vol.7, No.12, 1-10, 2013.

(要約): Striatal functions depend on the activity balance between the dopamine and glutamate neurotransmissions. Glutamate inputs activate cyclin-dependent kinase 5 (Cdk5), which inhibits postsynaptic dopamine signaling by phosphorylating DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) at Thr75 in the striatum. c-Abelson tyrosine kinase (c-Abl) is known to phosphorylate Cdk5 at Tyr15 (Tyr15-Cdk5) and thereby facilitates the Cdk5 activity. We here report that Cdk5 with Tyr15 phosphorylation (Cdk5-pTyr15) is enriched in the mouse striatum, where dopaminergic stimulation inhibited phosphorylation of Tyr15-Cdk5 by acting through the D2 class dopamine receptors. Moreover, in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model, dopamine deficiency caused increased phosphorylation of both Tyr15-Cdk5 and Thr75-DARPP-32 in the striatum, which could be attenuated by administration of L-3,4-dihydroxyphenylalanine and imatinib (STI-571), a selective c-Abl inhibitor. Our results suggest a functional link of Cdk5-pTyr15 with postsynaptic dopamine and glutamate signals through the c-Abl kinase activity in the striatum.
(徳島大学機関リポジトリ): ● Metadata: 114613
(出版サイトへのリンク): ● Publication site (DOI): 10.3389/fncel.2013.00012
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23420105; ● Search Scopus @ Elsevier (PMID): 23420105; ● Search Scopus @ Elsevier (DOI): 10.3389/fncel.2013.00012

(徳島大学機関リポジトリ: 114613, DOI: 10.3389/fncel.2013.00012, PubMed: 23420105) Ryoma Morigaki, Wataru Sako, Shinya Okita, Jiro Kasahara, Hironori Yokoyama, Shinji Nagahiro, Ryuji Kaji and Satoshi Goto :
Cyclin-dependent kinase 5 with phosphorylation of tyrosine 15 residue is enriched in striatal matrix compartment in adult mice,
Neuroscience, Vol.189, 25-31, 2011.

(要約): Accumulating evidence suggests that the striosome-matrix systems have a tight link with motor and behavioral brain functions and their disorders. Cyclin-dependent kinase 5 (Cdk5) is a versatile protein kinase that plays a role in synaptic functions and cell survival in adult brain, and its kinase activity is stimulated by phosphorylation at tyrosine 15 residue (pY15). In this study, we used an immunohistochemical method to show differential localization of Cdk5-pY15 in the striatal compartments of adult mice, with a heightened density of Cdk5-pY15 labeling in the matrix relative to the striosomes. Our findings indicate that Cdk5-pY15 can be a new marker for the striatal matrix compartment, and suggest a possible involvement of Cdk5-mediated signaling in compartment-specific neurotransmission and disease pathology in the striatum.
(キーワード): Animals / Corpus Striatum / Cyclin-Dependent Kinase 5 / 免疫組織化学 (immunohistochemistry) / Mice / リン酸化 (phosphorylation) / Tyrosine
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.neuroscience.2011.05.055
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21640796; ● Summary page in Scopus @ Elsevier: 2-s2.0-79960905477

(DOI: 10.1016/j.neuroscience.2011.05.055, PubMed: 21640796, Elsevier: Scopus) Hironori Yokoyama, Hayato Kuroiwa, Jiro Kasahara and Tsutomu Araki :
Neuropharmacological approach against MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine)-induced mouse model of Parkinson's disease.,
Acta Neurobiologiae Experimentalis, Vol.71, No.2, 269-280, 2011.

(要約): Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. PD is well known to be a chronic and progressive neurodegenerative disease produced by a selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. The main clinical features of PD include tremor, bradykinesia, rigidity and postural instability. Most insights into pathogenesis of PD come from investigations performed in experimental models of PD, especially those produced by neurotoxins. The biochemical and cellular alterations that occur after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) treatment are remarkably similar to that observed in idiopathic PD. Furthermore, it is well known that acute treatment with MPTP can cause a severe loss of tyrosine hydroxylase and dopamine transporter protein levels and dopamine contents in the striatum of mice, as compared to continuous MPTP treatment. Thus these findings may support the validity of acute MPTP treatment model for unraveling in the neurodegenerative processes in PD. In this review, we discuss the neuroprotective effects of various compounds against neuronal cell loss in an MPTP model of PD. This review may lead to a much better understanding of PD as well as provide novel clues to new targets for therapeutic interventions in PD patients.
(キーワード): Animals / Antiparkinson Agents / Corpus Striatum / Disease Models, Animal / Dopamine / Dose-Response Relationship, Drug / Drug Interactions / Glial Fibrillary Acidic Protein / Mice / Models, Biological / Parkinsonian Disorders / Time Factors / Tyrosine 3-Monooxygenase
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21731080; ● Search Scopus @ Elsevier (PMID): 21731080

(PubMed: 21731080) Hironori Yokoyama, Hiroto Uchida, Hayato Kuroiwa, Jiro Kasahara and Tsutomu Araki :
Role of glial cells in neurotoxin-induced animal models of Parkinson's disease.,
Neurological Sciences, Vol.32, No.1, 1-7, 2011.

(要約): Dopaminergic neurons are selectively vulnerable to oxidative stress and inflammatory attack. The neuronal cell loss in the substantia nigra is associated with a glial response composed markedly of activated microglia and, to a lesser extent, of reactive astrocytes although these glial responses may be the source of neurotrophic factors and can protect against oxidative stress such as reactive oxygen species and reactive nitrogen species. However, the glial response can also mediate a variety of deleterious events related to the production of pro-inflammatory, pro-oxidant reactive species, prostaglandins, cytokines, and so on. In this review, we discuss the possible protective and deleterious effects of glial cells in the neurodegenerative diseases and examine how these factors may contribute to the pathogenesis of Parkinson's disease. This review suggests that further investigation concerning glial reaction in Parkinson's disease may lead to disease-modifying therapeutic approaches and may contribute to the pathogenesis of this disease.
(キーワード): Animals / Animals, Genetically Modified / Disease Models, Animal / Humans / Neuroglia / Neurotoxins / Parkinson Disease
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s10072-010-0424-0
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21107876; ● Search Scopus @ Elsevier (PMID): 21107876; ● Search Scopus @ Elsevier (DOI): 10.1007/s10072-010-0424-0

(DOI: 10.1007/s10072-010-0424-0, PubMed: 21107876) Minami Adachi, Manami Abe, Taeko Sasaki, Hiroyuki Kato, Jiro Kasahara and Tsutomu Araki :
Role of inducible or neuronal nitric oxide synthase in neurogenesis of the dentate gyrus in aged mice,
Metabolic Brain Disease, Vol.25, 419-424, 2010.

(要約): We evaluated mainly the iNOS (inducible nitric oxide synthase) and nNOS (neuronal NOS) expression in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus in young adult (8-week-old) and aged (60-week-old) mice. The present study demonstrates that the expression of nNOS was more pronounced than that of iNOS expression in the dentate gyrus of aged mice. Our study also suggests that aged mice exhibited a significant loss of motor activity as compared with young adult animals. Furthermore, our results provide that no significant change in the number of Neu N (Neuronal nuclei)-immunopositive neurons and GFAP (glial fibrillary acidic protein)-immunopositive astrocytes was observed in the dentate gyrus between young adult and aged mice. In contrast, a significant change in the number of Iba 1(ionized calcium-binding adaptor molecule 1)-immunopositive microglia in aged mice was observed in the dentate gyrus as compared to young adult animals. These results provide the novel evidence showing that the expression of nNOS may be crucial for the role of neurogenesis of the SGZ of the dentate gyrus in aged mice. Furthermore, our present findings demonstrate that the inhibition of nNOS expression in the SGZ of the dentate gyrus during aging processes may offer novel therapeutic strategies for anti-aging in humans.
(キーワード): Aging / Animals / Calcium-Binding Proteins / Dentate Gyrus / Glial Fibrillary Acidic Protein / Immunohistochemistry / Locomotion / Male / Mice / Mice, Inbred ICR / Mice, Knockout / Microglia / Nerve Tissue Proteins / Neurogenesis / Neurons / Nitric Oxide Synthase Type I / Nitric Oxide Synthase Type II / Nuclear Proteins / Postural Balance
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11011-010-9224-8
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21082337; ● Search Scopus @ Elsevier (PMID): 21082337; ● Search Scopus @ Elsevier (DOI): 10.1007/s11011-010-9224-8

(DOI: 10.1007/s11011-010-9224-8, PubMed: 21082337) R Eto, M Abe, H Kimoto, E Imaoka, H Kato, Jiro Kasahara and Tsutomu Araki :
Alterations of interneurons in the striatum and frontal cortex of mice during postnatal development,
International Journal of Developmental Neuroscience, Vol.28, No.5, 359-370, 2010.

(要約): We investigated the postnatal alterations of neuronal nuclei (NeuN)-positive neurons, parvalbumin (PV)-positive interneurons, neuronal nitric oxide synthase (nNOS)-positive interneurons, and neurotrophic factors in the mouse striatum and frontal cortex using immunohistochemistry. NeuN, PV, nNOS, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) immunoreactivity were measured in 1-, 2-, 4- and 8-week-old mice. Total number of NeuN-positive neurons was unchanged in the mouse striatum and frontal cortex from 1 up to 8 weeks of age. In contrast, a significant decrease in the number of PV-positive interneurons was observed in the striatum and frontal cortex of 1-, 2- and 4-week-old mice. Furthermore, a significant increase of nNOS-positive interneurons was found in the striatum and frontal cortex of 1- and/or 2-week-old mice. NGF-positive neurons were unchanged in the mouse striatum from 1 up to 8 weeks of age. In the frontal cortex, a significant increase in the number of NGF-positive neurons was observed only in 1-week-old mice. In contrast, a significant increase in the number of NGF-positive glia 1 cells was found in the striatum and frontal cortex of 4-week-old mice. Our double-labeled immunostaining showed that nNOS immunoreactivity was not found in PV-immunopositive interneurons. Furthermore, BDNF immunoreactivity was observed in both nNOS-positive and PV-positive interneurons in the striatum of 1- or 2-week-old mice. These results show that the maturation of nNOS-immunopositive interneurons precedes the maturation of PV-immunopositive interneurons in the striatum and frontal cortex during postnatal development. Furthermore, our results demonstrate that the expression of BDNF may play some role in the maturation of interneurons in the striatum and frontal cortex during postnatal development. Moreover, our findings suggest that the expression of NGF in glia cells may play some role in the maturation of glial cells and PV-positive interneurons in the striatum and frontal cortex during postnatal development.
(キーワード): Aging / Animals / Animals, Newborn / Brain-Derived Neurotrophic Factor / Cell Differentiation / Corpus Striatum / Frontal Lobe / Interneurons / Male / Mice / Mice, Inbred ICR / Nerve Growth Factor / Nerve Growth Factors / Nerve Tissue Proteins / Neurogenesis / Nitric Oxide Synthase Type I / Nuclear Proteins / Parvalbumins
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijdevneu.2010.04.004
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20406674; ● Search Scopus @ Elsevier (PMID): 20406674; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijdevneu.2010.04.004

(DOI: 10.1016/j.ijdevneu.2010.04.004, PubMed: 20406674) M Abe, H Kimoto, R Eto, T Sasaki, H Kato, Jiro Kasahara and Tsutomu Araki :
Postnatal Development of Neurons, Interneurons and Glial Cells in the Substantia Nigra of Mice,
Cellular and Molecular Neurobiology, Vol.30, No.6, 917-928, 2010.

(要約): We investigated postnatal alterations of neurons, interneurons and glial cells in the mouse substantia nigra using immunohistochemistry. Tyrosine hydroxylase (TH), neuronal nuclei (NeuN), parvalbumin (PV), neuronal nitric oxide synthase (nNOS), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba 1), CNPase (2',3'-cyclic nucleotide 3'-phosphodiesterase), brain-derived neurotrophic factor (BDNF) and glial cell-line-derived neurotrophic factor (GDNF) immunoreactivity were measured in 1-, 2-, 4- and 8-week-old mice. In the present study, the maturation of NeuN-immunopositive neurons preceded the production of TH in the substantia nigra during postnatal development in mice. Furthermore, the maturation of nNOS-immunopositive interneurons preceded the maturation of PV-immunopositive interneurons in the substantia nigra during postnatal development. Among astrocytes, microglia and oligodendrocytes, in contrast, the development process of oligodendrocytes is delayed in the substantia nigra. Our double-labeled immunohistochemical study suggests that the neurotrophic factors such as BDNF and GDNF secreted by GFAP-positive astrocytes may play some role in maturation of neurons, interneurons and glial cells of the substantia nigra during postnatal development in mice. Thus, our findings provide valuable information on the development processes of the substantia nigra.
(キーワード): Animals / Animals, Newborn / Brain-Derived Neurotrophic Factor / Calcium-Binding Proteins / Glial Cell Line-Derived Neurotrophic Factor / Glial Fibrillary Acidic Protein / Interneurons / Male / Mice / Mice, Inbred ICR / Microfilament Proteins / Nerve Tissue Proteins / Neuroglia / Nitric Oxide Synthase Type I / Nuclear Proteins / Parvalbumins / Phosphoric Diester Hydrolases / Staining and Labeling / Substantia Nigra / Tyrosine 3-Monooxygenase
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s10571-010-9521-0
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20414716; ● Search Scopus @ Elsevier (PMID): 20414716; ● Search Scopus @ Elsevier (DOI): 10.1007/s10571-010-9521-0

(DOI: 10.1007/s10571-010-9521-0, PubMed: 20414716) H Uchida, Y Fujita, M Matsueda, M Umeda, S Matsuda, H Kato, Jiro Kasahara and Tsutomu Araki :
Damage to Neurons and Oligodendrocytes in the Hippocampal CA1 Sector after Transient Focal Ischemia in Rats,
Cellular and Molecular Neurobiology, Vol.30, No.7, 1125-1134, 2010.

(要約): Focal brain lesions such as transient focal cerebral ischemia can lead to neuronal damage in remote areas, including the ipsilateral substantia nigra and hippocampus, as well as in the ischemic core. In this study, we investigated acute changes in the ipsilateral hippocampus from 1 up to 7 days after 90 min of transient focal cerebral ischemia in rats, using anti-NeuN (neuronal nuclei), anti-Cu/Zn-superoxide dismutase (Cu/Zn-SOD), anti-Mn-SOD, anti-neuronal nitric oxide synthase (nNOS), anti-inducible NOS (iNOS), anti-glial fibrillary acidic protein (GFAP), anti-ionized calcium-binding adaptor molecule 1(Iba 1) and anti-2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) antibodies. In our western blot and histochemical analyses, present results show that transient focal cerebral ischemia in rats can cause a severe and acute damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector. The present findings also demonstrate that the expression of iNOS produced by Iba 1-immunopositive microglia precedes the damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector after transient focal cerebral ischemia. In contrast, our results suggest that increased reactive oxygen species (ROS) production during reperfusion cannot lead to damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector after transient focal cerebral ischemia, because of an insufficient expression of Cu/Zn-SOD and Mn-SOD. Our double-labeled immunohistochemical study demonstrates that the overexpression of iNOS produced by Iba 1-immunopositive microglia may play a pivotal role in the damage of neurons and oligodendrocytes in the ipsilateral hippocampal CA1 sector at an acute stage after transient focal cerebral ischemia.
(キーワード): 2',3'-Cyclic-Nucleotide Phosphodiesterases / Animals / CA1 Region, Hippocampal / Calcium-Binding Proteins / Glial Fibrillary Acidic Protein / Ischemic Attack, Transient / Isoenzymes / Male / Microfilament Proteins / Neurons / Nitric Oxide Synthase Type I / Nitric Oxide Synthase Type II / Oligodendroglia / Rats / Rats, Sprague-Dawley / Superoxide Dismutase
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s10571-010-9545-5
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20625811; ● Search Scopus @ Elsevier (PMID): 20625811; ● Search Scopus @ Elsevier (DOI): 10.1007/s10571-010-9545-5

(DOI: 10.1007/s10571-010-9545-5, PubMed: 20625811) 黒岩勇人, 横山宏典, 内田裕人, 塚田竜矢, 加藤宏之, 笠原二郎, 荒木勉 :
MPTP誘発パーキンソン病モデルマウスに対するPARP阻害薬およびPPAR作動薬の神経細胞保護効果に関する研究ーzonisamideとの比較研究ー,
脳21, Vol.13, No.3, 116-116-1161-16, 2010年. Hironori Yokoyama, Ryohei Yano, Hayato Kuroiwa, Tatsuya Tsukada, Hiroto Uchida, Hiroyuki Kato, Jiro Kasahara and Tsutomu Araki :
Therapeutic effect of a novel anti-parkinsonian agent zonisamide against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)neurotoxicity in mice.,
Metabolic Brain Disease, Vol.25, No.2, 135-143, 2010.

(要約): We investigated the therapeutic effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice, using Western blot analysis, immunohistochemistry and behavioral test. Our Western blot analysis and immunohistochemical study showed that the post-treatment with zonisamide prevented significantly dopaminergic cell damage, the depletion of tyrosine-hydroxylase (TH) protein levels and the proliferation of microglia in the striatum and/or substantia nigra 8 days after MPTP treatment. Furthermore, our behavioral study showed that the post-treatment with zonisamide attenuated significantly the motor deficits 7 days after MPTP treatment. These results show that zonisamide has the therapeutic effect in the MPTP model of Parkinson's disease (PD) in mice. Our study also demonstrates the neuroprotective effect of zonisamide against dopaminergic cell damage after MPTP treatment in mice. Thus our present findings suggest that therapeutic strategies targeted to the activation of TH protein and/or the inhibition of microglial activation with zonisamide may offer a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with PD.
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11011-010-9191-0
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20424905; ● Search Scopus @ Elsevier (PMID): 20424905; ● Search Scopus @ Elsevier (DOI): 10.1007/s11011-010-9191-0

(DOI: 10.1007/s11011-010-9191-0, PubMed: 20424905) Keizo Takao, Koichi Tanda, Kenji Nakamura, Jiro Kasahara, Kazuki Nakao, Motoya Katsuki, Kazuo Nakanishi, Nobuyuki Yamasaki, Keiko Toyama, Minami Adachi, Masahiro Umeda, Tsutomu Araki, Kohji Fukunaga, Hisatake Kondo, Hiroyuki Sakagami and Tsuyoshi Miyakawa :
Comprehensive behavioral analysis of calcium/calmodulin-dependent protein kinase IV knockout mice.,
PLoS ONE, Vol.5, No.3, 2010.

(要約): Calcium-calmodulin dependent protein kinase IV (CaMKIV) is a protein kinase that activates the transcription factor CREB, the cyclic AMP-response element binding protein. CREB is a key transcription factor in synaptic plasticity and memory consolidation. To elucidate the behavioral effects of CaMKIV deficiency, we subjected CaMKIV knockout (CaMKIV KO) mice to a battery of behavioral tests. CaMKIV KO had no significant effects on locomotor activity, motor coordination, social interaction, pain sensitivity, prepulse inhibition, attention, or depression-like behavior. Consistent with previous reports, CaMKIV KO mice exhibited impaired retention in a fear conditioning test 28 days after training. In contrast, however, CaMKIV KO mice did not show any testing performance deficits in passive avoidance, one of the most commonly used fear memory paradigms, 28 days after training, suggesting that remote fear memory is intact. CaMKIV KO mice exhibited intact spatial reference memory learning in the Barnes circular maze, and normal spatial working memory in an eight-arm radial maze. CaMKIV KO mice also showed mildly decreased anxiety-like behavior, suggesting that CaMKIV is involved in regulating emotional behavior. These findings indicate that CaMKIV might not be essential for fear memory or spatial memory, although it is possible that the activities of other neural mechanisms or signaling pathways compensate for the CaMKIV deficiency.
(出版サイトへのリンク): ● Publication site (DOI): 10.1371/journal.pone.0009460
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20209163; ● Search Scopus @ Elsevier (PMID): 20209163; ● Search Scopus @ Elsevier (DOI): 10.1371/journal.pone.0009460

(DOI: 10.1371/journal.pone.0009460, PubMed: 20209163) Miyohiko Takemura, Toshiaki Mishima, Yan Wang, Jiro Kasahara, Kohji Fukunaga, Kazumasa Ohashi and Kensaku Mizuno :
Ca2+/calmodulin-dependent protein kinase IV-mediated LIM kinase activation is critical for calcium signal-induced neurite outgrowth.,
The Journal of Biological Chemistry, Vol.284, No.42, 28554-28562, 2009.

(要約): Actin cytoskeletal remodeling is essential for neurite outgrowth. LIM kinase 1 (LIMK1) regulates actin cytoskeletal remodeling by phosphorylating and inactivating cofilin, an actin filament-disassembling factor. In this study, we investigated the role of LIMK1 in calcium signal-induced neurite outgrowth. The calcium ionophore ionomycin induced LIMK1 activation and cofilin phosphorylation in Neuro-2a neuroblastoma cells. Knockdown of LIMK1 or expression of a kinase-dead mutant of LIMK1 suppressed ionomycin-induced cofilin phosphorylation and neurite outgrowth in Neuro-2a cells. Ionomycin-induced cofilin phosphorylation and neurite outgrowth were also blocked by KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinases (CaMKs), and STO-609, an inhibitor of CaMK kinase. An active form of CaMKIV but not CaMKI enhanced Thr-508 phosphorylation of LIMK1 and increased the kinase activity of LIMK1. Moreover, the active form of CaMKIV induced cofilin phosphorylation and neurite outgrowth, and a dominant negative form of CaMKIV suppressed ionomycin-induced neurite outgrowth. Taken together, our results suggest that LIMK1-mediated cofilin phosphorylation is critical for ionomycin-induced neurite outgrowth and that CaMKIV mediates ionomycin-induced LIMK1 activation.
(キーワード): Actins / Animals / Calcium / Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Cell Line, Tumor / Cofilin 1 / Cytoskeleton / Enzyme Activation / Ionomycin / Lim Kinases / Mice / Mutation / Neurites / Phosphorylation / Signal Transduction
(出版サイトへのリンク): ● Publication site (DOI): 10.1074/jbc.M109.006296
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19696021; ● Search Scopus @ Elsevier (PMID): 19696021; ● Search Scopus @ Elsevier (DOI): 10.1074/jbc.M109.006296

(DOI: 10.1074/jbc.M109.006296, PubMed: 19696021) Shenuarin Md Bhuiyan, Yoko Takada, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara and Kohji Fukunaga :
Cardioprotective effect of vanadyl sulfate on ischemia/reperfusion-induced injury in rat heart in vivo is mediated by activation of protein kinase B and induction of FLICE-inhibitory protein.,
Cardiovascular Therapeutics, Vol.26, No.1, 10-23, 2008.

(要約): Here we explored the mechanism of cardioprotective action of a tyrosine phosphatase inhibitor vanadyl sulfate on myocardial infarction and cardiac functional recovery in rats subjected to myocardial ischemia/reperfusion (MI/R) in vivo. Male Sprague-Dawley rats underwent 30 min heart ischemia by left coronary artery occlusion followed by 24-h reperfusion. Rats were randomized to receive either vehicle or vanadyl sulfate (1 and 5 mg/kg) intraperitoneally 0 min and 30 min after the start of reperfusion. Posttreatment with vanadyl sulfate significantly reduced the infarct size and significantly decreased the elevated left ventricular end diastolic pressure, improved left ventricular developed pressure, and left ventricular contractility (+/- dP/dt) after 72-h reperfusion in a dose-dependent manner. Moreover, treatment with vanadyl sulfate also significantly inhibited the apoptosis-related Caspase-3 and Caspase-9 processing, thereby elicited the antiapoptotic effect. The cardioprotective effect of vanadyl sulfate was closely associated with restoration of reduced protein kinase B (Akt) activity following MI/R injury. The recovered Akt activity correlated with increased phosphorylation of forkhead transcription factors, FKHR and FKHRL-1, thereby inhibiting apoptotic signaling. Furthermore, treatment with vanadyl sulfate significantly increased FLICE-inhibitory protein (FLIP) expression, and decreased expression of Fas ligand and Bim in cardiomyocytes. Taken together, rescue of cardiomyocytes by posttreatment with vanadyl sulfate from MI/R injury was mediated by increased FLIP expression and decreased Fas ligand and Bim expression via activation of Akt. These results demonstrate that treatment with vanadyl sulfate exerts significant cardioprotective effects along with cardiac functional recovery.
(キーワード): Animals / Apoptosis / Blood Pressure / Blotting, Western / CASP8 and FADD-Like Apoptosis Regulating Protein / Cardiotonic Agents / Caspases / Cell Survival / Enzyme Activation / Fas Ligand Protein / Forkhead Transcription Factors / Heart Rate / Injections, Intraperitoneal / Male / Myocardial Reperfusion Injury / Myocardium / Oncogene Protein v-akt / Protein Tyrosine Phosphatases / Proto-Oncogene Proteins c-akt / Rats / Rats, Sprague-Dawley / Rats, Wistar / Signal Transduction / Vanadium Compounds
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/j.1527-3466.2008.00039.x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18466417; ● Search Scopus @ Elsevier (PMID): 18466417; ● Search Scopus @ Elsevier (DOI): 10.1111/j.1527-3466.2008.00039.x

(DOI: 10.1111/j.1527-3466.2008.00039.x, PubMed: 18466417) Ying-Mei Lu, Norifumi Shioda, Feng Han, Shigeki Moriguchi, Jiro Kasahara, Yasufumi Shirasaki, Zheng-Hong Qin and Kohji Fukunaga :
Imbalance between CaM kinase II and calcineurin activities impairs caffeine-induced calcium release in hypertrophic cardiomyocytes.,
Biochemical Pharmacology, Vol.74, No.12, 1727-1737, 2007.

(要約): Cardiac hypertrophy impairs Ca(2+) handling in the sarcoplasmic reticulum, thereby impairing cardiac contraction. To identify the mechanisms underlying impaired Ca(2+) release from the sarcoplasmic reticulum in hypertrophic cardiomyocytes, we assessed Ca(2+)-dependent signaling and the phosphorylation of phospholamban, which regulates Ca(2+) uptake during myocardial relaxation and is in turn regulated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and calcineurin. In cultured rat cardiomyocytes, treatment with endothelin-1, angiotensin II, and phenylephrine-induced hypertrophy and increased CaMKII autophosphorylation and calcineurin expression. The calcineurin level reached its maximum at 72h and remained elevated for at least 96h after endothelin-1 or angiotensin II treatment. By contrast, CaMKII autophosphorylation, phospholamban phosphorylation, and caffeine-induced Ca(2+) mobilization all peaked 48h after these treatments. By 96h after treatment, CaMKII autophosphorylation and phospholamban phosphorylation had returned to baseline, and caffeine-induced Ca(2+) mobilization was impaired relative to baseline. A similar biphasic change was observed in dystrophin levels in endothelin-1-induced hypertrophic cardiomyocytes, and treatment with the novel CaM antagonists DY-9760e and DY-9836 significantly inhibited the hypertrophy-induced dystrophin breakdown. Taken together, the abnormal Ca(2+) regulation in cardiomyocytes following hypertrophy is in part mediated by an imbalance in calcineurin and CaMKII activities, which leads to abnormal phospholamban activity.
(キーワード): Angiotensin II / Animals / Calcineurin / Calcium / Calcium-Binding Proteins / Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Cardiomegaly / Cells, Cultured / Endothelin-1 / Immunohistochemistry / Indazoles / Phenylephrine / Phosphorylation / Rats / Rats, Wistar
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bcp.2007.08.022
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17888407; ● Search Scopus @ Elsevier (PMID): 17888407; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bcp.2007.08.022

(DOI: 10.1016/j.bcp.2007.08.022, PubMed: 17888407) Shenuarin Md Bhuiyan, Masatoshi Shibuya, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Yosiharu Iwabuchi and Kohji Fukunaga :
Cytoprotective effect of bis(1-oxy-2-pyridinethiolato)oxovanadiun(IV) on myocardial ischemia/reperfusion injury elicits inhibition of Fas ligand and Bim expression and elevation of FLIP expression.,
European Journal of Pharmacology, Vol.571, No.2-3, 180-188, 2007.

(要約): VO(OPT), bis(1-oxy-2-pyridinethiolato)oxovanadium(IV), has been shown to increase tyrosine phosphorylation of proteins and promote the insulin receptor signaling, thereby elicit anti-diabetic action. We here investigated the cytoprotective action of VO(OPT) on myocardial infarction and cardiac functional recovery in rats subjected to myocardial ischemia/reperfusion and defined mechanisms underlying its cytoprotective action. Rats underwent 30 min myocardial ischemia by left anterior descending coronary artery occlusion followed by 24 h reperfusion. Post-ischemic treatment with VO(OPT) significantly reduced infarct size and improved cardiac function (left ventricular developed pressure and +/-dP/dt) after 72 h reperfusion and in a dose-dependent manner. Moreover, VO(OPT) treatment also dose-dependently significantly inhibited caspases-3, -9 and -7 processing, thereby elicited the anti-apoptotic effect. The cytoprotective effect of VO(OPT) was closely associated with restoration of Akt activity. The recovered Akt activity correlated with increased phosphorylation of Bad and forkhead transcription proteins, thereby inhibiting apoptotic signaling. Furthermore, treatment with VO(OPT) significantly increased FLIP expression, and decreased expression of Fas ligand and Bim in cardiomyocytes. Taken together, cardiomyocytes rescue following post-treatment with VO(OPT) from ischemia/reperfusion injury was mediated by increased FLIP expression and decreased Fas ligand and Bim expression via activation of Akt. These results demonstrate that treatment with VO(OPT) exerts significant cytoprotective effects along with improvement of cardiac functional recovery.
(キーワード): Animals / Apoptosis / Apoptosis Regulatory Proteins / Blood Pressure / CASP8 and FADD-Like Apoptosis Regulating Protein / Cardiotonic Agents / Caspases / Coronary Vessels / Cytoprotection / Disease Models, Animal / Dose-Response Relationship, Drug / Enzyme Inhibitors / Fas Ligand Protein / Forkhead Transcription Factors / Ligation / Male / Membrane Proteins / Myocardial Infarction / Myocardial Ischemia / Myocardial Reperfusion Injury / Organometallic Compounds / Phosphorylation / Proto-Oncogene Proteins / Proto-Oncogene Proteins c-akt / Rats / Rats, Sprague-Dawley / Signal Transduction / Ventricular Function, Left / Ventricular Pressure / bcl-Associated Death Protein
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejphar.2007.05.046
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17658509; ● Search Scopus @ Elsevier (PMID): 17658509; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ejphar.2007.05.046

(DOI: 10.1016/j.ejphar.2007.05.046, PubMed: 17658509) Daniela Tardito, Ettore Tiraboschi, Jiro Kasahara, Giorgio Racagni and Maurizio Popoli :
Reduced CREB phosphorylation after chronic lithium treatment is associated with down-regulation of CaM kinase IV in rat hippocampus.,
The International Journal of Neuropsychopharmacology, Vol.10, No.4, 491-496, 2006.

(要約): Lithium is widely used in the treatment of bipolar disorder, although its mechanism of action is not fully clear. This study was undertaken to assess the effects of prolonged lithium administration on cAMP responsive element-binding protein (CREB) phosphorylation and CaM kinase IV (CaMKIV), one of the main kinases phosphorylating CREB in neurons following synaptic activation. CREB total protein expression and phosphorylation (Ser133), as well as CaMKIV enzymatic activity, phosphorylation of Thr196 (the activator residue) and kinase expression level were assessed in total homogenates and nuclei from the hippocampus and prefrontal/frontal cortex following 5 wk lithium treatment. Whereas no significant effects were found in prefrontal/frontal cortex, lithium administration reduced CREB phosphorylation and at the same time down-regulated CaMKIV (enzymatic activity, phospho-Thr196 and protein expression level) in cell nuclei from the hippocampus. These data suggest for the first time the involvement of CaMKIV in the mechanism of action of lithium.
(キーワード): Animals / Antimanic Agents / Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Calcium-Calmodulin-Dependent Protein Kinases / Cell Nucleus / Cyclic AMP Response Element-Binding Protein / Down-Regulation / Hippocampus / Lithium Carbonate / Male / Phosphorylation / Prefrontal Cortex / Rats / Rats, Sprague-Dawley / Time Factors
(出版サイトへのリンク): ● Publication site (DOI): 10.1017/S1461145706007140
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16923323; ● Search Scopus @ Elsevier (PMID): 16923323; ● Search Scopus @ Elsevier (DOI): 10.1017/S1461145706007140

(DOI: 10.1017/S1461145706007140, PubMed: 16923323) Takuya Sasaki, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Koichi Ishiguro and Kohji Fukunaga :
Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model.,
Brain Research, Vol.1108, No.1, 98-106, 2006.

(要約): Lithium used in bipolar mood disorder therapy protects neurons from brain ischemic cell death. Here, we documented that lithium administration under microsphere-embolism (ME)-induced brain ischemia restored decreased protein kinase B (Akt) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activities 24 h after ischemia in rat brain. Akt activation was associated with increased phosphorylation of its potential targets forkhead transcription factor (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). In parallel with decreased CaMKII autophosphorylation, we also found marked dephosphorylation of tau proteins 24-72 h after ME. Increased protein phosphatase 2A (PP2A) activity was found 24 h after ME. Inhibition of increased PP2A activity by lithium treatment apparently mediated restored tau phosphorylation. Taken together, activation of Akt and CaMKII by lithium was associated with neuroprotective activity in ME-induced neuronal injury.
(キーワード): Animals / Antimanic Agents / Brain Infarction / Brain Ischemia / Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Calcium-Calmodulin-Dependent Protein Kinases / Disease Models, Animal / Enzyme Activation / Forkhead Transcription Factors / Glycogen Synthase Kinase 3 / Intracranial Embolism / Lithium Chloride / Male / Nerve Tissue Proteins / Neuroprotective Agents / Phosphoprotein Phosphatases / Protein Phosphatase 2 / Proto-Oncogene Proteins c-akt / Rats / Rats, Wistar / Serine / Up-Regulation / tau Proteins
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.brainres.2006.06.009
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16843447; ● Search Scopus @ Elsevier (PMID): 16843447; ● Search Scopus @ Elsevier (DOI): 10.1016/j.brainres.2006.06.009

(DOI: 10.1016/j.brainres.2006.06.009, PubMed: 16843447) Kohji Fukunaga, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara and Yasufumi Shirasaki :
DY-9760e, a novel calmodulin inhibitor, exhibits cardioprotective effects in the ischemic heart.,
Cardiovascular Drug Reviews, Vol.24, No.2, 88-100, 2006.

(要約): DY-9760e (3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride-3.5 hydrate) inhibits Ca(2+)/CaM-dependent nitric oxide synthase (NOS), thereby inhibiting nitric oxide (NO) production. In cardiomyocytes from ischemic rat heart NO and superoxide levels are increased causing protein tyrosine nitration. In hearts subjected to ischemia/reperfusion DY-9760e totally abolishes protein tyrosine nitration. Notably, DY-9760e also inhibits calpain and cas-pase-3 activation that occurs prior to apoptosis in cardiomyocytes. In ischemic hearts fodrin is the substrate for calpain. DY-9760e inhibits fodrin breakdown in the peri-infarct area rather than in the infarct core. In the ischemic rat brain DY-9760e inhibits caspase-3-induced proteolysis of calpastatin, an endogenous calpain inhibitor, suggesting that crosstalk between calpain and caspase-3 is mediated by calpastatin breakdown. Thus, DY-9760e rescues neurons and cardiomyocytes from ischemic injury by inhibiting crosstalk between calpain and caspase-3 as well as protein tyrosine nitration.
(キーワード): Animals / Calmodulin / Cardiotonic Agents / Disease Models, Animal / Humans / Indazoles / Models, Cardiovascular / Molecular Structure / Myocardial Ischemia / Myocardial Reperfusion Injury
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/j.1527-3466.2006.00088.x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16961723; ● Search Scopus @ Elsevier (PMID): 16961723; ● Search Scopus @ Elsevier (DOI): 10.1111/j.1527-3466.2006.00088.x

(DOI: 10.1111/j.1527-3466.2006.00088.x, PubMed: 16961723) Hiroyuki Sakagami, Akifumi Kamata, Hideki Nishimura, Jiro Kasahara, Yuji Owada, Yusuke Takeuchi, Makoto Watanabe, Kohji Fukunaga and Hisatake Kondo :
Prominent expression and activity-dependent nuclear translocation of Ca2+/calmodulin-dependent protein kinase Idelta in hippocampal neurons.,
The European Journal of Neuroscience, Vol.22, No.11, 2697-2707, 2005.

(要約): Multifunctional Ca2+/calmodulin-dependent protein kinases (CaMKs) including CaMKI, II and IV, are thought to regulate a variety of neuronal functions. Unlike CaMKII, which is regulated by autophosphorylation, CaMKI as well as CaMKIV are activated by CaMKK. In this study, we examined the cellular and subcellular localization of CaMKIdelta, a recently identified fourth isoform of CaMKI, in the mature brain. In situ hybridization analysis demonstrated wide expression of CaMKIdelta mRNA in the adult mouse brain with prominent expression in the hippocampal pyramidal cells. FLAG-tagged CaMKIdelta was localized at the cytoplasm and neurites without nuclear immunoreactivity in approximately 80% of the transfected primary hippocampal neurons. The stimulation with either KCl depolarization or glutamate triggered the nuclear localization of FLAG-tagged CaMKIdelta by two-fold with a peak at 1 min. In contrast, the catalytically inactive mutants of CaMKIdelta remained cytoplasmic without nuclear translocation during KCl depolarization, indicating the requirement of its activation for the nuclear translocation. Furthermore, we showed that immunoprecipitated CaMKIdelta could phosphorylate cAMP response element binding protein (CREB)alphain vitro and that the over-expression of CaMKIdelta enhanced GAL4-CREB-luciferase activity in PC12 cells stimulated by KCl depolarization. Our present study provides the first evidence for the possible involvement of CaMKIdelta in nuclear functions through its nuclear translocation in response to stimuli that trigger intracellular Ca2+ influx.
(キーワード): Animals / Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Calcium-Calmodulin-Dependent Protein Kinases / Cell Nucleus / Cyclic AMP Response Element-Binding Protein / DNA, Complementary / Female / Genetic Vectors / Glutamic Acid / Hippocampus / In Situ Hybridization / Luciferases / Mice / Mice, Inbred C57BL / Neurons / Phosphorylation / Potassium Chloride / Pregnancy / Protein Transport / Rats / Rats, Wistar / Subcellular Fractions / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/j.1460-9568.2005.04463.x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16324104; ● Search Scopus @ Elsevier (PMID): 16324104; ● Search Scopus @ Elsevier (DOI): 10.1111/j.1460-9568.2005.04463.x

(DOI: 10.1111/j.1460-9568.2005.04463.x, PubMed: 16324104) Hiroyuki Nagase, Tohru Yamakuni, Kentaro Matsuzaki, Yuji Maruyama, Jiro Kasahara, Yoshimi Hinohara, Shunzo Kondo, Yoshihiro Mimaki, Yutaka Sashida, William A Tank, Kohji Fukunaga and Yasushi Ohizumi :
Mechanism of neurotrophic action of nobiletin in PC12D cells.,
Biochemistry, Vol.44, No.42, 13683-13691, 2005.

(要約): Nobiletin is a nonpeptide compound with a low molecular weight from a citrus fruit and has the activity to rescue bulbectomy-induced memory impairment. Here we describe that nobiletin itself induces neurite outgrowth in PC12D cells, a rat pheochromocytoma cell line, like NGF, and the molecular mechanism of its neurotrophic action. As cultured in the presence of nobiletin or NGF for 48 h and then assayed using a scanning electron microscope, PC12D cells treated with nobiletin showed morphology with flatter and larger cell bodies than the cells cultured with NGF. Nobiletin-induced neurite outgrowth was inhibited by PD98059 and U0126 but not K252a. Consistently, nobiletin caused a concentration-dependent enhancement of Erk/MAP kinase phosphorylation and a sustained increment of phosphorylation of MEK and Erk/MAP kinase, resulting in a stimulation of CREB phosphorylation and CRE-mediated transcription. This compound also increased intracellular cAMP and CRE-mediated transcription in the presence of forskolin and enhanced PKA activity to stimulate phosphorylation of multiple PKA substrates in PC12D cells. Furthermore, nobiletin preferentially inhibited Ca2+/CaM-dependent phosphodiesterase in vitro. This compound failed to stimulate phosphorylation of Erk5, which is known to be induced by NGF/TrkA signaling. These results suggest that nobiletin induces neurite outgrowth by activating a cAMP/PKA/MEK/Erk/MAP kinase-dependent but not TrkA-dependent signaling pathway coupling with CRE-mediated gene transcription and may thus become a novel type of biochemical probe for elucidation of the molecular mechanism of neuronal differentiation.
(キーワード): Animals / Cells, Cultured / Cyclic AMP Response Element-Binding Protein / Enzyme Activation / Flavones / Hippocampus / MAP Kinase Signaling System / Microscopy, Electron, Scanning / Neurons / PC12 Cells / Phosphorylation / Rats / Transcription, Genetic
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/bi050643x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16229458; ● Search Scopus @ Elsevier (PMID): 16229458; ● Search Scopus @ Elsevier (DOI): 10.1021/bi050643x

(DOI: 10.1021/bi050643x, PubMed: 16229458) Takashi Shirakura, Feng Han, Norifumi Shiota, Shigeki Moriguchi, Jiro Kasahara, Toshiyuki Sato, Yasufumi Shirasaki and Kohji Fukunaga :
Inhibition of nitric oxide production and protein tyrosine nitration contribute to neuroprotection by a novel calmodulin antagonist, DY-9760e, in the rat microsphere embolism.,
Biological & Pharmaceutical Bulletin, Vol.28, No.9, 1658-1661, 2005.

(要約): Microsphere embolism (ME)-induced ischemia model in rat resembles to multiple brain embolism in human with several clinical features. We here tested whether nitric oxide (NO) production contributes to the neuronal injury in the ME model. A novel calmodulin antagonist, DY-9760e, having a potent inhibitory effect on neuronal nitric oxide synthase (nNOS), reduced brain infarct size in the ME-induced brain ischemia. Consistent with our previous observation with gerbil ischemia/reperfusion model, DY-9760e completely inhibited NO production immediately after and 24 or 48 h after ME. Unlike the gerbil ischemia/reperfusion model, protein tyrosine nitration markedly increased 6-48 h after ME. DY-9760e treatment completely inhibited the marked increase in the protein tyrosine nitration at 24 h after ME. These results suggest that the inhibition of NO production and protein tyrosine nitration by DY-9760e contribute to its neuroprotective action in the ME-induced brain damage.
(キーワード): Animals / Blotting, Western / Brain / Calmodulin / Cerebral Infarction / Indazoles / Injections, Intraperitoneal / Intracranial Embolism / Microdialysis / Microspheres / Neostriatum / Neuroprotective Agents / Nitrates / Nitric Oxide / Rats / Tyrosine
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.28.1658
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16141535; ● Search Scopus @ Elsevier (PMID): 16141535; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.28.1658

(DOI: 10.1248/bpb.28.1658, PubMed: 16141535) Masami Hashimoto, Yoko Takada, Yusuke Takeuchi, Jiro Kasahara, Hiroaki Hisa, Yasufumi Shirasaki and Kohji Fukunaga :
Cytoprotective effect of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e) against ischemia/reperfusion-induced injury in rat heart involves inhibition of fodrin breakdown and protein tyrosine nitration.,
Journal of Pharmacological Sciences, Vol.98, No.2, 142-150, 2005.

(要約): We here assessed the effects of 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate (DY-9760e), a novel calmodulin antagonist, on infarct size in the rat heart subjected to ischemia/reperfusion. Rats were subjected to a 30-min coronary occlusion followed by a 24-h reperfusion. DY-9760e was intravenously infused for 20 min, starting at 20 min after coronary occlusion. Treatment with DY-9760e (10 mg/kg) significantly reduced the infarct size in the risk area assessed by Evans Blue/TTC (triphenyltetrazolium chloride) staining. DY-9760e treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. DY-9760e significantly inhibited fodrin breakdown and caspase-3 activation. The inhibitory effect of DY-9760e on the fodrin breakdown was prominent in the rim rather than in the center of the risk area. DY-9760e also blocked protein tyrosine nitration associated with infarction. These results suggest that the cardioprotective effect of DY-9760e involved inhibition of calpain/caspase activation and protein tyrosine nitration.
(キーワード): Animals / Blotting, Western / Carrier Proteins / Caspase 3 / Caspases / Enzyme Activation / Indazoles / Male / Microfilament Proteins / Myocardial Reperfusion Injury / Proteins / Rats / Rats, Sprague-Dawley / Tyrosine / Ventricular Function, Left
(出版サイトへのリンク): ● Publication site (DOI): 10.1254/jphs.FP0040551
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15937403; ● Search Scopus @ Elsevier (PMID): 15937403; ● Search Scopus @ Elsevier (DOI): 10.1254/jphs.FP0040551

(DOI: 10.1254/jphs.FP0040551, PubMed: 15937403) Ettore Tiraboschi, Daniela Tardito, Jiro Kasahara, Stefania Moraschi, Paolo Pruneri, Massimo Gennarelli, Giorgio Racagni and Maurizio Popoli :
Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades.,
Neuropsychopharmacology, Vol.29, No.10, 1831-1840, 2004.

(要約): Regulation of gene expression is purported as a major component in the long-term action of antidepressants. The transcription factor cAMP-response element-binding protein (CREB) is activated by chronic antidepressant treatments, although a number of studies reported different effects on CREB, depending on drug types used and brain areas investigated. Furthermore, little is known as to what signaling cascades are responsible for CREB activation, although cAMP-protein kinase A (PKA) cascade was suggested to be a central player. We investigated how different drugs (fluoxetine (FLX), desipramine (DMI), reboxetine (RBX)) affect CREB expression and phosphorylation of Ser(133) in the hippocampus and prefrontal/frontal cortex (PFCX). Acute treatments did not induce changes in these mechanisms. Chronic FLX increased nuclear phospho-CREB (pCREB) far more markedly than pronoradrenergic drugs, particularly in PFCX. We investigated the function of the main signaling cascades that were shown to phosphorylate and regulate CREB. PKA did not seem to account for the selective increase of pCREB induced by FLX. All drug treatments markedly increased the enzymatic activity of nuclear Ca2+/calmodulin (CaM) kinase IV (CaMKIV), a major neuronal CREB kinase, in PFCX. Activation of this kinase was due to increased phosphorylation of the activatory residue Thr196, with no major changes in the expression levels of alpha- and beta-CaM kinase kinase, enzymes that phosphorylate CaMKIV. Again in PFCX, FLX selectively increased the expression level of MAP kinases Erk1/2, without affecting their phosphorylation. Our results show that FLX exerts a more marked effect on CREB phosphorylation and suggest that CaMKIV and MAP kinase cascades are involved in this effect.
(キーワード): Adrenergic Agents / Animals / Antidepressive Agents, Second-Generation / Blotting, Western / Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Calcium-Calmodulin-Dependent Protein Kinases / Cell Nucleus / Cyclic AMP Response Element-Binding Protein / Cyclic AMP-Dependent Protein Kinases / Fluoxetine / Hippocampus / Immunoprecipitation / Male / Mitogen-Activated Protein Kinases / Phosphorylation / Prefrontal Cortex / Rats / Rats, Sprague-Dawley / Reverse Transcriptase Polymerase Chain Reaction / Serotonin Uptake Inhibitors / Signal Transduction
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/sj.npp.1300488
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15138445; ● Search Scopus @ Elsevier (PMID): 15138445; ● Search Scopus @ Elsevier (DOI): 10.1038/sj.npp.1300488

(DOI: 10.1038/sj.npp.1300488, PubMed: 15138445) Chiara Cavazzin, Cristian Bonvicini, Annachiara Nocera, Marco Racchi, Jiro Kasahara, Daniela Tardito, Massimo Gennarelli, Stefano Govoni, Giorgio Racagni and Maurizio Popoli :
Expression and phosphorylation of delta-CaM kinase II in cultured Alzheimer fibroblasts.,
Neurobiology of Aging, Vol.25, No.9, 1187-1196, 2004.

(要約): Dysregulation of calcium homeostasis is among the major cellular alterations in Alzheimer's disease (AD). We studied Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II), one of the major effectors regulating neuronal responses to changes in calcium fluxes, in cultured skin fibroblasts from subjects with sporadic AD. We found, by using PCR and Western analysis, that human fibroblasts express the delta-isoform of this kinase, and that CaM kinase II is the major Ca(2+)/calmodulin-dependent kinase in these cells. Protein expression level of the kinase was not significantly different in AD fibroblasts. However, the total activity of the kinase (stimulated by Ca(2+)/calmodulin) was significantly reduced in AD cell lines, whereas Ca(2+)-independent activity was significantly enhanced. The percent autonomy of the kinase (%Ca(2+)-independent/Ca(2+)-dependent activity) in AD cell lines was 62.8%, three-fold the corresponding percentage in control fibroblasts. The abnormal calcium-independent activity was not due to enhanced basal autophosphorylation of Thr(287). The observed abnormalities, if present in brain tissue, may be implicated either in dysfunction of neuroplasticity and cognitive functions or in dysregulation of cell cycle.
(キーワード): Aged / Alzheimer Disease / Calcium / Calcium Signaling / Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Calcium-Calmodulin-Dependent Protein Kinases / Calmodulin / Cells, Cultured / Cognition Disorders / Female / Fibroblasts / Humans / Isoenzymes / Male / Middle Aged / Neuronal Plasticity / Phosphorylation / RNA, Messenger / Signal Transduction / Threonine
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.neurobiolaging.2003.12.003
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15312964; ● Search Scopus @ Elsevier (PMID): 15312964; ● Search Scopus @ Elsevier (DOI): 10.1016/j.neurobiolaging.2003.12.003

(DOI: 10.1016/j.neurobiolaging.2003.12.003, PubMed: 15312964) Yoko Takada, Masami Hashimoto, Jiro Kasahara, Kazuyuki Aihara and Kohji Fukunaga :
Cytoprotective effect of sodium orthovanadate on ischemia/reperfusion-induced injury in the rat heart involves Akt activation and inhibition of fodrin breakdown and apoptosis.,
The Journal of Pharmacology and Experimental Therapeutics, Vol.311, No.3, 1249-1255, 2004.

(要約): In a rat model of myocardial ischemic infarction, sodium orthovanadate rescued cells from ischemia/reperfusion injuries. Rats underwent 30 min of myocardial ischemia by occluding the left coronary artery followed by 24 h of reperfusion. Post-treatment with orthovanadate reduced infarct size in a dose-dependent manner. Orthovanadate treatment also ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion. The cytoprotective action of orthovanadate treatment was closely associated with inhibition of fodrin breakdown. Since orthovanadate is a potent inhibitor for protein tyrosine phosphatases, thereby activating tyrosine kinases and phosphatidylinositol 3-kinase (PI3K) pathways, we investigated activities of protein kinase B (Akt), a downstream target of PI3K in cardiomyocytes. Orthovanadate-induced cytoprotection was associated with partial restoration of reduced Akt activity following myocardial infarction. Restoration of Akt activity by orthovanadate treatment correlated positively with increased phosphorylation of glycogen synthase kinase-3beta and Bad in cardiomyocytes. Furthermore, orthovanadate treatment inhibited caspase-3 activation induced by ischemia. Taken together, orthovanadate post-treatment rescued cardiomyocytes from ischemia/reperfusion injuries via Akt activation and inhibition of fodrin breakdown, thereby inhibiting apoptosis.
(キーワード): Animals / Apoptosis / Blood Pressure / Blotting, Western / Carrier Proteins / Caspase 3 / Caspases / Male / Microfilament Proteins / Myocardial Infarction / Myocardial Reperfusion Injury / Myocardium / Myocytes, Cardiac / Protein-Serine-Threonine Kinases / Proto-Oncogene Proteins / Proto-Oncogene Proteins c-akt / Rats / Rats, Sprague-Dawley / Signal Transduction / Vanadates / Ventricular Function, Left
(出版サイトへのリンク): ● Publication site (DOI): 10.1124/jpet.104.070839
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15292457; ● Search Scopus @ Elsevier (PMID): 15292457; ● Search Scopus @ Elsevier (DOI): 10.1124/jpet.104.070839

(DOI: 10.1124/jpet.104.070839, PubMed: 15292457) Eiko Iwahana, Masashi Akiyama, Kazuko Miyakawa, Ayumi Uchida, Jiro Kasahara, Kohji Fukunaga, Toshiyuki Hamada and Shigenobu Shibata :
Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase-3 protein expression in the mouse suprachiasmatic nuclei.,
The European Journal of Neuroscience, Vol.19, No.8, 2281-2287, 2004.

(要約): A circadian clock located in the suprachiasmatic nucleus (SCN) regulates the period of physiological and behavioural rhythms to approximately 24 h. Lithium can lengthen the period of circadian rhythms in most organisms although little is known about the underlying mechanism. In the present study, we examined Drosophila shaggy ortholog glycogen synthase kinase-3 (GSK-3) protein expression in the SCN after lithium treatment. When locomotor activity was assessed, we found an association between the effect of lithium and the period of circadian oscillation as well as the level of GSK-3 protein expression. The decreased expression of GSK-3 and increased expression of phosphorylated GSK-3 (pGSK-3) resulted in an antiphasic circadian rhythm between the two in the SCN of lithium-treated mice housed under both light-dark and constant dark conditions. The enzyme activity of GSK-3 in the SCN was low when the level of pGSK-3 protein was high, as examined by immunoblotting analysis. Thus, GSK-3 enzyme activity has a correlation with the expression of GSK-3 protein in the SCN. Although both GSK-3 and pGSK-3 proteins are also expressed in the arcuate nucleus, lithium did not affect their expression. Based on the association that we found between lengthened circadian period and GSK-3 protein and GSK-3 activity in the SCN, we suggest that GSK-3 plays a role in regulating the period of the mammalian circadian pacemaker.
(キーワード): Animals / Circadian Rhythm / Enzyme Activation / Gene Expression Regulation, Enzymologic / Glycogen Synthase Kinase 3 / Lithium Carbonate / Male / Mice / Mice, Inbred C57BL / Motor Activity / Suprachiasmatic Nucleus / Up-Regulation
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/j.0953-816X.2004.03322.x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15090054; ● Search Scopus @ Elsevier (PMID): 15090054; ● Search Scopus @ Elsevier (DOI): 10.1111/j.0953-816X.2004.03322.x

(DOI: 10.1111/j.0953-816X.2004.03322.x, PubMed: 15090054) E Carlos Semino, Jiro Kasahara, Yasunori Hayashi and Shuguang Zhang :
Entrapment of migrating hippocampal neural cells in three-dimensional peptide nanofiber scaffold.,
Tissue Engineering, Vol.10, No.3-4, 643-655, 2004.

(要約): Isolation and expansion of self-renewing neural cells ex vivo are required for neural tissue repair in regenerative medicine. Neurogenesis occurs in restricted areas of postnatal mammalian brain including dentate gyrus and subventricular zone. We developed a simple method to entrap migrating neural cells (potential neuroprogenitors) from postnatal hippocampal organotypic cultures in three-dimensional (3-D) peptide nanofiber scaffolds. A few hours after placing the hippocampal slices in culture, cell proliferation activity at the "interface zone" between the tissue slice and the membrane culture surface was observed. Pulse-chase experiments using 5-bromodeoxyuridine (BrdU), which measures mitotic activity, showed that a number of cells incorporated BrdU at the interface zone. The number of BrdU(+) cells increased exponentially during the first 3 days of exposure to the label. The BrdU(+) cells also stained positive for glial fibrillary acidic protein (2.2 +/- 0.5%), a marker for astroglia; and for betaIII tubulin (7.3 +/- 2.8%) and nestin (2.7 +/- 0.9%), markers for neural progenitors. When hippocampal slices were cultured on a peptide nanofiber scaffold layer (~500 microm thick), a more extended interface zone between each tissue slice and the scaffold was formed. Moreover, the migrating BrdU(+) cell population entrapped in the 3-D peptide scaffold was readily isolated by mechanically disrupting the scaffold and then used for conventional 2-D culture systems for further studies. This simple method may be useful not only in developing technology for neural progenitor cell isolation and enrichment in vitro, but also for expanding cells for cell-based therapies of regenerative medicine.
(キーワード): Animals / Cell Division / Cell Movement / Hippocampus / Neuroglia / Neurons / Oligopeptides / Rats / Tissue Culture Techniques / Tissue Engineering
(出版サイトへのリンク): ● Publication site (DOI): 10.1089/107632704323061997
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15165480; ● Search Scopus @ Elsevier (PMID): 15165480; ● Search Scopus @ Elsevier (DOI): 10.1089/107632704323061997

(DOI: 10.1089/107632704323061997, PubMed: 15165480) Akiyoshi Uezu, Kohji Fukunaga, Jiro Kasahara and Eishichi Miyamoto :
Activation of Ca²⁺/calmodulin-dependent protein kinase I in cultured rat hippocampal neurons.,
Journal of Neurochemistry, Vol.82, No.3, 585-593, 2002.

(要約): We have focused on activation mechanisms of calcium/calmodulin-dependent protein kinase (CaM) kinase I in the hippocampal neurons and compared them with that of CaM kinase IV. Increased activation of CaM kinase I occurred by stimulation with glutamate and depolarization in cultured rat hippocampal neurons. Similar to CaM kinases II and IV, CaM kinase I was essentially activated by stimulation with the NMDA receptor. Although both CaM kinases I and IV seem to be activated by CaM kinase kinase, the activation of CaM kinase I was persistent during stimulation with glutamate in contrast to a transient activation of CaM kinase IV. In addition, CaM kinase I was activated in a lower concentration of glutamate than that of CaM kinase IV. Depolarization-induced activation of CaM kinase I was also evident in the cultured neurons and was largely blocked by nifedipine. In the experiment with 32P-labeled cells, phosphorylation of CaM kinase I was stimulated by glutamate treatment and depolarization. The glutamate- and depolarization-induced phosphorylation was inhibited by the NMDA receptor antagonist and nifedipine, respectively. These results suggest that, although CaM kinases I and IV are activated by the NMDA receptor and depolarization stimulation, these kinase activities are differently regulated in the hippocampal neurons.
(キーワード): Animals / Antibody Specificity / Calcium Channel Blockers / Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Calcium-Calmodulin-Dependent Protein Kinases / Cells, Cultured / Enzyme Activation / Enzyme Inhibitors / Excitatory Amino Acid Agonists / Excitatory Amino Acid Antagonists / Glutamic Acid / Hippocampus / Neurons / Nifedipine / Phosphorylation / Rats / Rats, Wistar / Receptors, N-Methyl-D-Aspartate
(出版サイトへのリンク): ● Publication site (DOI): 10.1046/j.1471-4159.2002.00984.x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12153482; ● Search Scopus @ Elsevier (PMID): 12153482; ● Search Scopus @ Elsevier (DOI): 10.1046/j.1471-4159.2002.00984.x

(DOI: 10.1046/j.1471-4159.2002.00984.x, PubMed: 12153482) Jiro Kasahara, K Fukunaga and E Miyamoto :
Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region.,
The Journal of Biological Chemistry, Vol.276, No.26, 24044-24050, 2001.

(要約): The importance of well characterized calcium/calmodulin-dependent protein kinase (CaMK) II in hippocampal long term potentiation (LTP) is widely well established; however, several CaMKs other than CaMKII are not yet clearly characterized and understood. Here we report the activation of CaMKIV, which is phosphorylated by CaMK kinase and localized predominantly in neuronal nuclei, and its functional role as a cyclic AMP-responsive element-binding protein (CREB) kinase in high frequency stimulation (HFS)-induced LTP in the rat hippocampal CA1 region. CaMKIV was transiently activated in neuronal nuclei after HFS, and the activation returned to the basal level within 30 min. Phosphorylation of CREB, which is a CaMKIV substrate, and expression of c-Fos protein, which is regulated by CREB, increased during LTP. This increase was inhibited mainly by CaMK inhibitors and also by an inhibitor for mitogen-activated protein kinase cascade, although to a lesser extent. Our results suggest that CaMKIV functions as a CREB kinase and controls CREB-regulated gene expression during HFS-induced LTP in the rat hippocampal CA1 region.
(キーワード): Animals / Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Calcium-Calmodulin-Dependent Protein Kinases / Calmodulin / Culture Techniques / Cyclic AMP Response Element-Binding Protein / Cyclic AMP-Dependent Protein Kinases / Electric Stimulation / Enzyme Activation / Enzyme Inhibitors / Hippocampus / Long-Term Potentiation / MAP Kinase Kinase 1 / Male / Mitogen-Activated Protein Kinase 1 / Mitogen-Activated Protein Kinase Kinases / Phosphorylation / Protein-Serine-Threonine Kinases / Proto-Oncogene Proteins c-fos / Rats / Rats, Wistar
(出版サイトへのリンク): ● Publication site (DOI): 10.1074/jbc.M100247200
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11306573; ● Search Scopus @ Elsevier (PMID): 11306573; ● Search Scopus @ Elsevier (DOI): 10.1074/jbc.M100247200

(DOI: 10.1074/jbc.M100247200, PubMed: 11306573) Jiro Kasahara, K Fukunaga and E Miyamoto :
Activation of CA(2+)/calmodulin-dependent protein kinase IV in cultured rat hippocampal neurons.,
Journal of Neuroscience Research, Vol.59, No.5, 594-600, 2000.

(要約): Ca(2+)/calmodulin-dependent protein kinase IV (CaM kinase IV) is a multifunctional enzyme that is abundantly present in the nuclei of neurons. We report the properties of phosphorylation and activation of CaM kinase IV in comparison to CaM kinase II in cultured rat hippocampal neurons. Phosphorylation and activity of CaM kinase IV as well as CaM kinase II were increased by treatment of neurons either with glutamate or high K(+). Glutamate-induced phosphorylation and activity of CaM kinase IV were blocked by N-methyl-D-asparate (NMDA) antagonists, and NMDA application instead of glutamate did increase CaM kinase IV phosphorylation. CaM kinase IV phosphorylation was also increased by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and was blocked by an inhibitor of NMDA receptor. The AMPA-induced phosphorylation was blocked by tetrodotoxin, a Na(+) channel blocker, that was expected to block endogenous glutamate transmission indirectly. On the other hand, high K(+)-induced phosphorylation and activation were not blocked by inhibitors of glutamate receptors, and effectively blocked by nifedipine, an L-type Ca(2+) channel blocker. These properties were similar between CaM kinase IV and CaM kinase II.
(キーワード): Animals / Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Calcium-Calmodulin-Dependent Protein Kinases / Cells, Cultured / Enzyme Activation / Excitatory Amino Acid Agonists / Glutamic Acid / Hippocampus / Neurons / Phosphorylation / Potassium / Rats / Rats, Wistar
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10686587; ● Search Scopus @ Elsevier (PMID): 10686587

(PubMed: 10686587) T Osaki, M Omotezako, R Nagayama, M Hirata, S Iwanaga, Jiro Kasahara, J Hattori, I Ito, H Sugiyama and S Kawabata :
Horseshoe crab hemocyte-derived antimicrobial polypeptides, tachystatins, with sequence similarity to spider neurotoxins.,
The Journal of Biological Chemistry, Vol.274, No.37, 26172-26178, 1999.

(要約): Antimicrobial peptides, named tachystatins A, B, and C, were identified from hemocytes of the horseshoe crab Tachypleus tridentatus. Tachystatins exhibited a broad spectrum of antimicrobial activity against Gram-negative and Gram-positive bacteria and fungi. Of these tachystatins, tachystatin C was most effective. Tachystatin A is homologous to tachystatin B, but tachystatin C has no significant sequence similarity to tachystatins A and B. Tachystatins A and B showed sequence similarity to omega-agatoxin-IVA of funnel web spider venom, a potent blocker of voltage-dependent calcium channels. However, they exhibited no blocking activity of the P-type calcium channel in rat Purkinje cells. Tachystatin C also showed sequence similarity to several insecticidal neurotoxins of spider venoms. Tachystatins A, B, and C bound significantly to chitin. A causal relationship was observed between chitin binding activity and antifungal activity. Tachystatins caused morphological changes against a budding yeast, and tachystatin C had a strong cell lysis activity. The septum between mother cell and bud, a chitin-rich region, was stained by fluorescence-labeled tachystatin C, suggesting that the primary recognizing substance on the cell wall is chitin. As horseshoe crab is a close relative of the spider, tachystatins and spider neurotoxins may have evolved from a common ancestral peptide, with adaptive functions.
(キーワード): Amino Acid Sequence / Animals / Anti-Bacterial Agents / Antimicrobial Cationic Peptides / Base Sequence / Blood Proteins / Hemocytes / Horseshoe Crabs / Molecular Sequence Data / Neurotoxins / Rats / Spider Venoms
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10473569; ● Search Scopus @ Elsevier (PMID): 10473569

(PubMed: 10473569) Jiro Kasahara, K Fukunaga and E Miyamoto :
Differential effects of a calcineurin inhibitor on glutamate-induced phosphorylation of Ca2+/calmodulin-dependent protein kinases in cultured rat hippocampal neurons.,
The Journal of Biological Chemistry, Vol.274, No.13, 9061-9067, 1999.

(要約): Calcium/calmodulin-dependent protein kinases (CaM kinases) are major multifunctional enzymes that play important roles in calcium-mediated signal transduction. To characterize their regulatory mechanisms in neurons, we compared glutamate-induced phosphorylation of CaM kinase IV and CaM kinase II in cultured rat hippocampal neurons. We observed that dephosphorylation of these kinases followed different time courses, suggesting different regulatory mechanisms for each kinase. Okadaic acid, an inhibitor of protein phosphatase (PP) 1 and PP2A, increased the phosphorylation of both kinases. In contrast, cyclosporin A, an inhibitor of calcineurin, showed different effects: the phosphorylation and activity of CaM kinase IV were significantly increased with this inhibitor, but those of CaM kinase II were not significantly increased. Cyclosporin A treatment of neurons increased phosphorylation of Thr196 of CaM kinase IV, the activated form with CaM kinase kinase, which was recognized with an anti-phospho-Thr196 antibody. Moreover, recombinant CaM kinase IV was dephosphorylated and inactivated with calcineurin as well as with PP1, PP2A, and PP2C in vitro. These results suggest that CaM kinase IV, but not CaM kinase II, is directly regulated with calcineurin.
(キーワード): Animals / Calcineurin / Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Calcium-Calmodulin-Dependent Protein Kinases / Cells, Cultured / Cyclosporine / Enzyme Inhibitors / Glutamic Acid / Hippocampus / Neurons / Okadaic Acid / Phosphoprotein Phosphatases / Phosphorylation / Rats / Recombinant Proteins
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 10085155; ● Search Scopus @ Elsevier (PMID): 10085155

(PubMed: 10085155) Jiro Kasahara and H Sugiyama :
Modulation of glutamate sensitivities by inhibitors of a protein kinase and a protein phosphatase in cultured rat Purkinje cells.,
Neuroscience Letters, Vol.247, No.2-3, 139-142, 1998.

(要約): We examined the effects of inhibitors of calcium-calmodulin-dependent protein kinase II (CaM kinase II) and protein phosphatases on the glutamate (Glu) responses in cultured rat cerebellar Purkinje cells. CaM kinase II inhibitors significantly potentiated Glu responses, and activation of metabotropic Glu receptors facilitated this potentiation. In contrast, a phosphatase inhibitor calyculin A significantly reduced Glu responses. It was suggested that the Glu responsiveness of Purkinje cells may be regulated by the dynamic balance of phosphorylation and dephosphorylation of receptors or other relevant factors under basal conditions.
(キーワード): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / 6-Cyano-7-nitroquinoxaline-2,3-dione / Animals / Benzylamines / Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Calcium-Calmodulin-Dependent Protein Kinases / Cells, Cultured / Enzyme Inhibitors / Excitatory Amino Acid Antagonists / Glutamic Acid / Iontophoresis / Nerve Tissue Proteins / Oxazoles / Protein Tyrosine Phosphatases / Purkinje Cells / Rats / Receptors, AMPA / Sulfonamides
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 9655612; ● Search Scopus @ Elsevier (PMID): 9655612

(PubMed: 9655612) K Fujii, Jiro Kasahara, K Nakamura and H Sugiyama :
Differential selectivity of M1 and M3 type muscarinic acetylcholine receptors in coupling with a G protein G01 alpha examined in Xenopus oocytes.,
Neuroscience Letters, Vol.215, No.2, 131-133, 1996.

(要約): The coupling specificities between muscarinic acetylcholine receptors (porcine M1 and M3 subtypes) and a heterotrimeric GTP binding protein (bovine G01) were examined by analysing receptor-stimulated, phospholipase C (PLC)-mediated chloride current responses in Xenopus oocyte expression system. M1-stimulated responses were suppressed by G01 alpha, and this suppression was reversed by expressing exogenous G beta and G gamma, whereas M3-stimulated responses were enhanced by G01 alpha in the presence or absence of G beta and G gamma. G01 alpha itself, when activated directly by intracellular fluoride injection, efficiently activated PLC and stimulated chloride current responses. The results indicate that M1 receptor does not couple with G01, while M3 receptor activates G01 effectively.
(キーワード): Animals / Cattle / Electrophysiology / Female / GTP-Binding Protein alpha Subunits, Gi-Go / GTP-Binding Proteins / Microinjections / Oocytes / Peptides / RNA, Messenger / Receptors, Muscarinic / Sensitivity and Specificity / Swine / Type C Phospholipases / Xenopus
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 8888013; ● Search Scopus @ Elsevier (PMID): 8888013

(PubMed: 8888013) Jiro Kasahara and H Sugiyama :
Inositol phospholipid metabolism in Xenopus oocytes mediated by endogenous G(o) and Gi proteins.,
FEBS Letters, Vol.355, No.1, 41-44, 1994.

(要約): To characterize G-proteins which mediate the signal transduction from ligand stimulated receptor to phospholipase C (PLC), we injected antisense DNAs complementary to Xenopus G(o) alpha or Gi-l alpha to suppress these endogenous G-proteins, together with the mRNAs encoding metabotropic glutamate receptor 1 (mGluR1), 5 (mGluR5) or with M1 type muscarinic receptor into oocytes. Receptor-stimulated chloride current responses were reduced by the suppression of Xenopus G(o) alpha regardless of the types of receptors. However, injection of Gi-1 antisense DNA resulted in the reduction of M1-stimulated responses but not mGluR-stimulated responses. These results suggested that all these receptors could use G(o) alpha, and M1 receptors, but not mGluRs, could also use Gi-1 proteins, to activate PLC in Xenopus oocytes.
(キーワード): Acetylcholine / Animals / Base Sequence / Chloride Channels / Enzyme Activation / GTP-Binding Proteins / Glutamic Acid / Inositol 1,4,5-Trisphosphate / Molecular Sequence Data / Oligonucleotides, Antisense / Oocytes / Phosphatidylinositols / Quinuclidinyl Benzilate / RNA, Messenger / Receptors, Metabotropic Glutamate / Receptors, Muscarinic / Signal Transduction / Type C Phospholipases / Xenopus
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 7957959; ● Search Scopus @ Elsevier (PMID): 7957959

(PubMed: 7957959)

MISC

笠原二郎 :
笘ヶ島の再評価と考証,
相撲趣味, Vol.196, No.1, 14, 2022年.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1050013552710187264

(CiNii: 1050013552710187264) 笠原二郎 :
「雲早山」を名乗った力士たち,
相撲趣味, Vol.191, No.191, 31-40, 2021年.

(徳島大学機関リポジトリ): ● Metadata: 116064
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1050851398260897408

(徳島大学機関リポジトリ: 116064, CiNii: 1050851398260897408) 笠原二郎 :
阿波力士三ッノ海茂八の軌跡をたどる,
相撲趣味, Vol.186, 1-6, 2019年.

(徳島大学機関リポジトリ): ● Metadata: 114095
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1050001339320656640

(徳島大学機関リポジトリ: 114095, CiNii: 1050001339320656640)

総説・解説

宮本英七, 福永浩司, 竹内有輔, 山本秀幸, 笠原二郎, 劉杰 :
カルシウムシグナリングと脳機能,
日本薬理学雑誌, Vol.120, No.Suppl, 1-5, 2002年11月.

(要約): Calcium signaling plays a critical role in various cell types by activation of receptors and Ca2+ channels in response to neurotransmitters, hormones, growth, factors etc. Although a variety of functions of intracellular Ca2+ are reported, Ca2+/calmodulin-dependent protein kinases (CaMK) are involved in their mediation. We have been studying on CaMK I, II, III, IV and K in the dynamic regulation in the cells in relation to functions. In this study, we elucidated the structures of the isoforms of CaMKII subunits with nuclear translocation signal (NTS). NTS is included in the variable domain following the regulatory domain with a sequence of KKRK. The isoforms of CaMK subunits such as alpha B, gamma A, gamma A.B, delta 3 and delta 7 contain NTS in the sequences of the structures. Transfection of the isoforms with NTS into NG108-15 cells stimulated the expression of brain-derived neurotrophic factor in the cytoplasm. Activation of CaMKII and IV and mitogen-activated protein kinase (MAPK) was observed during long-term potentiation (LTP) induction in the CA1 area of hippocampus. The activation of CaMKII was sustained for a long period, whereas that of CaMKIV and MAPK was transient. The results suggest that CaMKII is involved in LTP induction, while CaMKIV and MAPK are rather involved in LTP maintenance. We present and discuss our recent studies on regulation of CaMKs in neuronal functions.
(キーワード): Brain / Brain-Derived Neurotrophic Factor / Calcium / Calcium Signaling / Calcium-Calmodulin-Dependent Protein Kinases / Gene Expression Regulation, Developmental / Hippocampus / Humans / Long-Term Potentiation / Neuronal Plasticity
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12491766; ● Search Scopus @ Elsevier (PMID): 12491766

(PubMed: 12491766)

講演・発表

Yuka Torii, Sohei Tsugita, Yukuto Ogawa, Hiten Iwamoto, Jiro Kasahara, Masaki Takeuchi, Masamitsu Iiyama, Toshio Takayanagi and Hitoshi Mizuguchi :
Dopamine monitoring in a mouse brain using a microdialysis-integrated HPLC equipped with a track-etched membrane double-electrode detector,
10th International Conference on Advanced Materials Development and Performance (AMDP2024), Tokushima, Sep. 2024. Hitoshi Mizuguchi, Yuka Torii, Sohei Tsugita, Yukuto Ogawa, Hiten Iwamoto, Masaki Takeuchi, Masamitsu Iiyama, Toshio Takayanagi and Jiro Kasahara :
A Microdialysis-Integrated HPLC System Constructed Using Track-Etched Membrane Electrodes for Dopamine Monitoring in Mouse Brain,
19th Asia-Pacific International Symposium on Microscale Separations and Analysis 2023 (APCE 2023), Kuala Lumpur, Oct. 2023. Yuka Torii, Sohei Tsugita, Yukuto Ogawa, Hiten Iwamoto, Jiro Kasahara, Masaki Takeuchi, Masamitsu Iiyama, Toshio Takayanagi and Hitoshi Mizuguchi :
Dopamine monitoring in a mouse brain using a microdialysis-integrated HPLC equipped with a track-etched membrane double-electrode detector,
Royal Society of Chemistry Tokyo International Conference 2023 (RSC-TIC 2023), Chiba, Sep. 2023. Ryoma Morigaki, Maya Anzai, Joji Fujikawa, Teruo Oda, Hayasawa Hiroaki, Matsuda Taku, Jiro Kasahara and Yasushi Takagi :
Changes in phosphodiesterase 10A in mice model of levodopa-induced dyskinesia,
The 13th Scientific meeting of Asian Australasian Society for Stereotactic and Functional Neurosurgery (AASSFN 2023), Osaka, Apr. 2023. Jiro Kasahara, 政宗宏子, 多田羅瑞樹 and 村上夏子 :
Imipramine ameliorates cognitive dysfunction with facilitatiing differentiation of the hippocampal CA1 neurons in a rat model of cerebral ischemia.,
Neuro2019, Niigata, Jul. 2019. Jiro Kasahara :
Post-ischemic depression and the hippocampal neurodegeneration,
WCP2018, Kyoto, Jul. 2018. Jiro Kasahara :
Poststroke depression and hippocampal neurodegeneration,
徳島とイタリアをつなぐ脳科学研究の潮流(徳島大学脳科学クラスター国際シンポジウム), Jul. 2016. Jiro Kasahara :
KAMIKATSU, a tiny rural village with plentiful resources for health and wellness in Tokushima, Japan,
Botanicals for Nutrition and Health: from Nagoya protocol to the international cooperation, Jul. 2015. Jiro Kasahara, Yamamura Yukio, Tanabe Akie, Ryoma Morigaki, Ryuji Kaji and Satoshi Goto :
Inhibition of c-Abelson tyrosine kinase (c-Abl) as a possible strategy for treatment of PD: Study in MPTP-induced mice model,
The 12th International Conference on Alzheimers's and Parkinson;s Disease: AD/PD 2015, Mar. 2015. Jiro Kasahara :
Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model for Parkinson's disease,
6th International Conference on Drug Discovery & Therapy, Dubai, UAE, Feb. 2014. Jiro Kasahara, Adachi Minami, Ohmura Koji, Fukunaga Kohji and Tsutomu Araki :
Serotonin (5-HT)-induced CREB phosphorylation in the cortical neurons of mice,
Soc. Abst. Neurosci., Vol.40, 741-18, Nov. 2010. Jiro Kasahara, Kohji Fukunaga and Hiroyuki Sakagami :
Requirement of calcium/calmodulin-dependent protein kinase IV (CaMKIV)-activity for the effects of antidepressants in mouse brain.,
Soc.Neurosci.Abst., Vol.37, 807.7, Nov. 2007. Jiro Kasahara, Kohji Fukunaga and Hiroyuki Sakagami :
Calcium/calmodulin-dependent protein kinase IV is important to regulate depression-related behaviors and sensitivity to antidepressants,
Soc.Neurosci.Abst., Vol.36, 768.18, Oct. 2006. Jiro Kasahara and Kohji Fukunaga :
CaMKK activities in the hippocampal neurons,
Soc.Neurosci.Abst., Vol.34, 298.11, Nov. 2004. Jiro Kasahara, Akiyoshi Uezu, Kohji Fukunaga and Eishichi Miyamoto :
Subtype specific profiles of phosphorylation and activation of calcium/calmodulin-dependent protein kinases in rat hippocampal neurons.,
XII International Symposium on Calcium-Binding Proteins and Calcium Function in Healh and Disease, Vol.12, 79, Feb. 2002. Jiro Kasahara, Kohji Fukunaga and Eishichi Miyamoto :
Characterization of CaM kinase IV in rat hippocampal neurons and LTP.,
Soc.Neurosci.Abst., Vol.30, 262.2, Nov. 2000. Jiro Kasahara, Akiyoshi Uezu, Kohji Fukunaga and Eishichi Miyamoto :
CaM kinases in hippocampal neurons: localization and phosphorylation.,
International Symposium on Neuronal Signaling and Protein Phosphorylation-Dephosphorylation, May 2000. Jiro Kasahara, Kohji Fukunaga and Eishichi Miyamoto :
Acication and regulation of CaM kinase IV in neurons.,
International Symposium on Calcium-Binding Proteins and Calcium Function in Healh and Disease, Vol.11, IV-6, Oct. 1999. 笠原二郎, 坂下美宙, 岩本緋天, 小川允利 :
パーキンソン病モデルマウスの運動症状に対するアリピプラゾールの薬効,
第97回日本薬理学会年会(兵庫，神戸国際会議場), 2023年12月. 鳥井優花, 次田宗平, 小川起人, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
トラックエッチ膜フィルター二重電極を用いる微小透析/HPLCシステムー脳内ドーパミンモニタリングシステムの開発ー,
第59回フローインジェクション分析講演会, 2023年11月. 次田宗平, 鳥井優花, 小川起人, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
トラックエッチ膜電極を用いるHPLC/電量検出法によるドーパミン放出挙動のin vivoモニタング,
第59回フローインジェクション分析講演会, 2023年11月. 次田宗平, 鳥井優花, 小川起人, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
トラックエッチ膜電極を用いるHPLC/電量検出法によるin vivoモニタリング -マウス線条体でのドーパミンの放出制御の観測-,
2023年日本化学会中国四国支部大会山口大会, 2023年11月. 坂下美宙, 岩本緋天, 小川允利, 笠原二郎 :
片側パーキンソン病モデルマウスを用いたアリピプラゾールの薬効評価,
第62回日本薬学会中国四国支部学術大会(高知，高知県立大学), 2023年10月. 鳥井優花, 次田宗平, 小川起人, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
トラックエッチ膜フィルター二重電極を用いたHPLCおよび微小透析による脳内ドーパミンモニタリングシステムの開発,
第25回活性アミンに関するワークショップ, 2023年8月. 鳥井優花, 小川起人, 次田宗平, 佐藤采, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
トラックエッチ膜フィルター電極を用いたHPLCおよび微小透析法によるマウス線条体でのドーパミン放出挙動の解析,
第83回分析化学討論会, 2023年5月. 小川起人, 次田宗平, 鳥井優花, 佐藤采, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
マウス線条体ドーパミンのin vivo測定のためのHPLC/トラックエッチ膜電量検出装置の開発,
第58回フローインジェクション分析講演会, 2022年11月. 鳥井優花, 小川起人, 次田宗平, 岩本緋天, 佐藤采, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
微小透析およびHPLCによるマウス線条体でのドーパミン放出挙動の解析,
第58回フローインジェクション分析講演会, 2022年11月. 次田宗平, 小川起人, 鳥井優花, 佐藤采, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
トラックエッチ膜フィルター二重電極を検出器とするキャピラリーHPLCによるマウス脳内ドーパミンのin vivo測定,
第58回フローインジェクション分析講演会, 2022年11月. 小川起人, 次田宗平, 鳥井優花, 佐藤采, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
トラックエッチ膜電極を用いるHPLC/電量検出法によるマウス線条体ドーパミンのin vivoモニタリング,
2022年日本化学会中国四国支部大会広島大会, 2022年11月. 次田宗平, 小川起人, 佐藤采, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
トラックエッチ膜フィルター二重電極を検出器とする微小透析法-HPLCによるドーパミンのin vivo測定,
第82回分析化学討論会, 2022年5月. 小川起人, 佐藤采, 岩本緋天, 笠原二郎, 竹内政樹, 飯山真充, 髙栁俊夫, 水口仁志 :
微小透析法-キャピラリーHPLC-トラックエッチ膜フィルター電量検出装置の開発と脳内ドーパミンのin situ測定,
日本分析化学会第70年会, 2021年9月. Jiro Kasahara, 小川允利, 周禹, 辻諒佑 and 後藤惠 :
Intrastriatal infusion of memantine with a programmable pump in a mouse model of hemi-parkinsonism,
第43回日本神経科学大会, Jul. 2020. 笠原二郎, 小川允利, 周禹, 辻諒佑, 後藤惠 :
パーキンソン病モデルマウスにおけるメマンチンの脳内インフュージョンと薬効評価,
第93回日本薬理学会年会, Vol.93, No.0, 3-O-104, 2020年3月.

(要約): Parkinson's disease is a neurodegenerative disorder cased by loss of nigrostriatal dopaminergic neurons. For over 40 years, levodopa had been established as a gold standard for PD treatment. However, long-term treatment with levodopa is often complicated by the development of adverse effects such as abnormal involuntary movements (AIMs), referred to as levodopa-induced dyskinesia (LIDs). We here report the pharmacological effects of the intrastriatal infusion of memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, in a 6-OHDA-lesioned mouse model of hemiparkinsonism. Spontaneous and apomorphine-induced rotational activities with an abnormal hind limb stepping were assessed as Parkinsonian symptoms. Daily intraperitoneal injection of levodopa (15 mg/kg) was performed for 21 days, with assessing AIMs score as an index of LID development. Intrastriatal memantine infusion targeted into the right dorsal striatum, using an iPRECIOTM programmable micro infusion pump with a brain infusion kit, was examined with 4 doses (3 days/dose). Infusion of memantine significantly alleviated Parkinsonian symptoms, and it also reduced AIMs score with a dose-dependent manner. These results support the idea that over-activation of the striatal NMDA receptor function might generate both Parkinsonian symptoms and LIDs.
(キーワード): parkinsonism / N-methyl-D-aspartate (NMDA) receptor
(出版サイトへのリンク): ● Publication site (DOI): 10.1254/jpssuppl.93.0_3-O-104
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390846609813260928; ● Search Scopus @ Elsevier (DOI): 10.1254/jpssuppl.93.0_3-O-104

(DOI: 10.1254/jpssuppl.93.0_3-O-104, CiNii: 1390846609813260928) 村上夏子, 政宗宏子, 多田羅瑞樹, 笠原二郎 :
一過性脳虚血モデルラットの海馬における神経幹細胞の解析,
第58回日本薬学会中国四国支部学術大会, 2019年11月. 小川允利, 周禹, 辻諒佑, 後藤惠, 笠原二郎 :
片側パーキンソン病モデルマウスにおける用量可変型インフュージョンポンプを用いたメマンチンの薬効評価,
第58回日本薬学会中国四国支部学術大会, 2019年11月. 笠原二郎, 政宗宏子, 村上夏子 :
脳虚血モデルラットにおける慢性イミプラミン投与が認知機能と海馬 CA1 領域の神経分化に及ぼす効果,
2019年8月. 小川允利, 周禹, 辻諒佑, 後藤惠, 笠原二郎 :
片側パーキンソン病モデルマウスにおける Brain infusion system を用いた薬効評価,
第23回活性アミンに関するワークショップ, 2019年8月. 富田陽子, 坂根亜由子, 三宅一央, 佐川幾子, 笠原二郎, 佐々木卓也 :
分子内結合が調節するJRABのLIMドメインによるアクチン細胞骨格の再編成,
第60回日本生化学会中国・四国支部例会, 2019年5月. 小川允利, 周禹, 辻諒佑, 後藤惠, 笠原二郎 :
片側パーキンソン病モデルマウスにおける後肢の解析とL-dopaの薬効評価,
第57回日本薬学会中国四国支部学術大会, 2018年11月. YU ZHOU and Jiro Kasahara :
The c-Abl inhibitor Imatinib is a potential therapeutic for Parkinson's disease,
第21回活性アミンに関するワークショップ, Aug. 2017. 周禹, 笠原二郎 :
Imatinib, serving as a potential therapeutic for Parkinson's disease,
第55回日本薬学会中国四国支部学術大会, 2016年11月. 志賀未規, 笠原二郎 :
PC12細胞におけるNF-κB活性評価系の確立と阻害化合物の評価,
第55回日本薬学会中国四国支部学術大会, 2016年11月. 笠原二郎, 内田裕人, 手塚健太, 岡奈々恵 :
一過性脳虚血ラットの梗塞後慢性期に悪化するアンヘドニアは海馬歯状回の神経変性を伴う,
第20回活性アミンに関するワークショップ, 2016年8月. 笠原二郎 :
パーキンソン病治療薬ゾニサミドの線条体における薬理作用機構基礎研究,
PD EXPERT CONFERENCE in Fukuoka, 2015年2月. 山村行生, 笠原二郎, 森垣龍馬, 後藤惠 :
イマチニブのパーキンソン病治療薬としての可能性,
第53回日本薬学会中国四国支部学術大会, 2014年11月. 福井裕行, 縄田萌, 水口博之, 原井川晶悟, 笠原二郎 :
パーキンソンモデル動物に対する天然物由来タンパクキナーゼCδ抑制薬投与によるカタレプシー改善作用,
第36回日本生物科学的精神医学会・第57回日本神経化学会・合同年会, 2014年9月. 田邉彬恵, 山村行生, 笠原二郎, 森垣龍馬, 梶龍兒, 後藤惠 :
MPTPマウスモデルにおける線条体c-Ablチロシンキナーゼを標的としたパーキンソン病治療研究,
第18回活性アミンに関するワークショップ, 2014年8月. 福井裕行, 縄田萌, 水口博之, 原井川晶悟, 笠原二郎 :
ケルセチンによるパーキンソン病モデルマウスのCatalepsy症状改善,
第31回和漢医薬学会学術大会, 2014年8月. 縄田萌, 水口博之, 原井川晶悟, 笠原二郎, 福井裕行 :
タンパクキナーゼCδシグナルを標的とするパーキンソン病治療戦略,
第125回日本薬理学会近畿部会, 2014年6月. 笠原二郎, 山村行生, 田邉彬恵, 森垣龍馬, 梶龍兒, 後藤惠 :
MPTP誘発パーキンソン病モデルマウスにおけるc-Abl阻害薬の薬効評価,
第21回カテコールアミンと神経疾患研究会, 2014年4月. 中西智子, 石澤啓介, 阿部真治, 中瀬真理, 柴田洋文, 佐藤智恵美, 新垣尚捷, 佐藤陽一, 山﨑尚志, 笠原二郎, 東満美, 山﨑哲男, 山内あい子, 滝口祥令, 土屋浩一郎 :
アドバンスト演習を通した問題解決能力向上のための症例解析手法の検討-プロダクトからの分析,
日本薬学会第134年会, 2014年3月. 田邉彬恵, 山村行生, Jiro Kasahara, 森垣龍馬, 梶龍兒, 永廣信治 and 後藤惠 :
A novel target for PD therapeutics: A c-Abl inhibitor improved striatal motor dysfunction in MPTP mice,
第87回日本薬理学会年会, Mar. 2014. 川端修平, 手塚健太, 笠原二郎 :
一過性局所脳虚血モデルラットのentorhinal cortexにみられる神経細胞死,
第52回日本薬学会中国四国支部学術大会, 2013年10月. 田邉彬恵, 山村行生, 笠原二郎, 森垣龍馬, 梶龍兒, 永廣信治, 後藤惠 :
線条体ニューロンの細胞内シグナルを標的にした新たなパーキンソン病治療戦略,
第52回日本薬学会中国四国支部学術大会, 2013年10月. 岡部真二, 門口直仁, 山村行生, 深野達也, 横山宏典, 笠原二郎 :
パーキンソン病モデルマウスにおける抗うつ薬ミルタザピンの薬効と作用機序,
第52回日本薬学会中国四国支部学術大会, 2013年10月. 深野達也, 今井智江利, 岡部真二, 横山宏典, 笠原二郎 :
パーキンソン病モデルマウスにおけるドーパミン神経細胞マーカーおよび神経保護因子の発現変化,
第52回日本薬学会中国四国支部学術大会, 2013年10月. 中西智子, 石澤啓介, 阿部真治, 中瀬真理, 柴田洋文, 佐藤智恵美, 新垣尚捷, 佐藤陽一, 山﨑尚志, 笠原二郎, 東満美, 山﨑哲男, 山内あい子, 滝口祥令, 土屋浩一郎 :
アドバンスト演習を通した問題解決能力向上のための症例解析手法の検討,
第52回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2013年10月. 山村行生, 森垣龍馬, 笠原二郎, 横山宏典, 田邊彬恵, 大北真哉, 小泉英貴, 永廣信治, 梶龍兒, 後藤惠 :
ドーパミンシグナルはマウス線条体サイクリン依存性キナーゼ5 (Cdk5) のチロシン15残基リン酸化を抑制的に制御する,
第17回活性アミンに関するワークショップ, 2013年8月. 岡部真二, 門口直仁, 山村行生, 横山宏典, 笠原二郎 :
ミルタザピンのパーキンソン病治療薬としての可能性,
第17回活性アミンに関するワークショップ, 2013年8月. 山村行生, 森垣龍馬, 笠原二郎, 横山宏典, 田邊彬恵, 大北真哉, 小泉英貴, 永廣信治, 梶龍兒, 後藤惠 :
ドーパミンシグナルはマウス線条体サイクリン依存性キナーゼ5 (Cdk5) のチロシン15残基リン酸化を抑制的に制御する,
Neuro2013, 2013年6月. 門口直仁, 岡部真二, 山村行生, 深野達也, 横山宏典, 笠原二郎 :
MPTP誘発パーキンソン病モデルマウスに対するノルアドレナリン作動性・特異的セロトニン作動性抗うつ薬ミルタザピンの治療効果,
Neuro2013, 2013年6月. 笠原二郎, 内田裕人, 藤田有貴, 手塚健太 :
ラット海馬歯状回における遅発性神経細胞死を伴った脳梗塞後うつモデル,
Neuro2013, 2013年6月. 山村行生, 森垣龍馬, 笠原二郎, 横山宏典, 田邊彬恵, 大北真哉, 小泉英貴, 永廣信治, 梶龍兒, 後藤惠 :
ドーパミンシグナルはマウス線条体サイクリン依存性キナーゼ5 (Cdk5) のチロシン15残基リン酸化を抑制的に制御する,
第20回カテコールアミンと神経疾患研究会, 2013年4月. 岡部真二, 門口直仁, 山村行生, 横山宏典, 笠原二郎 :
ミルタザピンのパーキンソン病治療薬としての可能性,
第20回カテコールアミンと神経疾患研究会, 2013年4月. 横山宏典, 松枝美里, 矢野遼平, 笠原二郎 :
MPTPパーキンソン病モデルマウスにおける黒質線条体ドーパミン神経細胞に対するゾニサミドの治療効果,
第85回日本薬理学会年会, 2012年3月. 笠原二郎, 塚田竜矢, 黒岩勇人, 岡部真二, 深野達也, 内田裕人, 横山宏典 :
MPTPパーキンソン病モデルマウスにおけるPioglitazoneの神経保護効果,
第85回日本薬理学会年会, 2012年3月. 内田裕人, 藤田有貴, 笠原二郎 :
一過性局所脳虚血ラットの海馬歯状回顆粒細胞にみられる遅発性神経細胞死と高次脳機能障害,
第85回日本薬理学会年会, 2012年3月. 安達みなみ, 大村幸司, 福永浩司, 笠原二郎 :
マウス大脳皮質神経細胞におけるセロトニンによる CREB リン酸化反応と細胞内シグナル経路,
第50回日本薬学会中国四国支部学術大会, 2011年11月. 塚田竜矢, 黒岩勇人, 深野達也, 岡部真二, 横山宏典, 内田裕人, 笠原二郎 :
MPTPパーキンソン病モデルマウスにおけるPioglitazoneの神経保護効果,
第50回日本薬学会中国四国支部学術大会, 2011年11月. 内田裕人, 藤田有貴 and Jiro Kasahara :
一過性局所脳虚血モデルラットの海馬歯状回における遅発性神経細胞死,
第34回日本神経科学大会, Sep. 2011. 横山宏典, 矢野遼平, 加藤宏之, 荒木勉, 笠原二郎 :
MPTPモデルマウスにおけるパーキンソン病様症状に対するゾニサミドの治療効果,
第84回日本薬理学会年会, 2011年3月. Jiro Kasahara, Ohmura Kohji, Adachi Minami, Fukunaga Kohji and Tsutomu Araki :
Serotonin (5-HT)-induced CREB phosphorylation mediated by calcium/calmodulin-dependent protein kinase IV (CaMKIV) and extracellular signal-regulated protein kinase (ERK) in cultured cortical neurons of mice,
Neuro2010, Vol.49, No.2,3, 527, Sep. 2010. 荒木勉, 黒岩勇人, 横山宏典, 門口直仁, 笠原二郎 :
MPTP誘発パーキンソン病モデルマウスに対するプロテアソーム阻害剤の神経保護効果,
第117回日本薬理学会近畿部会プログラム·要旨集, 13-13, 2010年7月. 笠原二郎, 安達みなみ, 大村幸司, 福永浩司, 荒木勉 :
マウス大脳皮質ニューロンにおいてセロトニンはCREBリン酸化反応を惹起する,
第117回日本薬理学会近畿部会プログラム·要旨集, 11-11, 2010年7月. 笠原二郎, 大村幸司, 安達みなみ, 福永浩司, 荒木勉 :
マウス大脳皮質におけるセロトニンを介したCREBリン酸化反応,
第51回日本生化学会中国・四国支部例会, 59, 2010年5月. 笠原二郎, 大村幸司, 福永浩司 :
マウス大脳皮質初代培養神経細胞におけるセロトニンによるCREBリン酸化反応はCaMKIVとMAPK(ERK)を介する,
Journal of Pharmacological Sciences, Vol.112, No.S1, 103, 2010年3月. 笠原二郎, 大村幸司, 福永浩司 :
マウス大脳皮質初代培養神経細胞におけるセロトニンによるCREBリン酸化反応,
Neuroscience Research, Vol.65, No.S1, S84, 2009年9月.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.neures.2009.09.331
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.neures.2009.09.331

(DOI: 10.1016/j.neures.2009.09.331) 笠原二郎, 長井智史, 澁谷正俊, 岩渕好治, 荒木令江, 福永浩司 :
バナジウム化合物とメラトニンによるドパミン神経障害の保護効果,
Neuroscience Research, Vol.61, No.S1, P3r04, 2008年7月. 笠原二郎, 阪上洋行, 福永浩司 :
マウス脳における抗うつ薬慢性投与によるカルモジュリンキナーゼIVの活性化とCREBリン酸化反応,
第81回日本薬理学会年会, 2008年3月. 笠原二郎, 阪上洋行, 近藤尚武, 福永浩司 :
マウス脳におけるCaMKIV活性は抗うつ薬の効果発現に必要である,
日本生化学会東北支部第73回例会, 2007年5月. Jiro Kasahara, Hiroyuki Sakagami and Kohji Fukunaga :
CaMKIV is important to regulate the sensitivity to antidepressants.,
神経化学, Vol.45, No.2,3, IS2-6, Sep. 2006. 笠原二郎, 阪上洋行, 近藤尚武, 福永浩司 :
カルモジュリン依存性キナーゼIVノックアウトマウスに見られるうつ傾向と抗うつ薬感受性の変化,
第29回日本神経科学大会, Vol.55, No.S1, PS3P-I131, 2006年7月. Jiro Kasahara, Kohji Fukunaga and Hiroyuki Sakagami :
Assessments of depression and the sensitivity to antidepressants in calcium/calmodulin-dependent protein kinase IV-knockout mice,
Japan. J. Physiol., Vol.3S, 42H2, Mar. 2006. 笠原二郎, 阪上洋行, 近藤尚武, 福永浩司 :
カルシウム/カルモデュリン依存性プロテインキナーゼIV欠損マウスにおけるうつ評価と抗うつ薬感受性,
第79回日本薬理学会年会, Vol.100, No.S1, O2H5-2, 2006年3月. 笠原二郎, 福永浩司 :
ラット海馬神経細胞におけるCaM kinase kinase活性の測定,
第27回日本神経科学大会, Vol.51, No.S1, O2H-01, 2004年9月. 笠原二郎, 福永浩司 :
ラット海馬神経細胞におけるCaM kinase kinase活性の測定,
日本生化学会東北支部第70回例会, 2004年5月. Jiro Kasahara, Akiyoshi Uezu and Kohji Fukunaga :
The regulatory mechanisms of CaM kinases I and IV in the hippocampal neurons,
神経化学, Vol.42, No.2,3, N148-MS6-3, Sep. 2003. 笠原二郎, 上江洲章吉, 福永浩司, 宮本英七 :
ラット脳および培養海馬神経細胞におけるCaM キナーゼキナーゼ分子の発現とリン酸化反応,
第43回日本神経化学会, 2000年9月. 笠原二郎, 福永浩司, 宮本英七 :
ラット海馬CA1領域LTPに伴うカムキナーゼIVの活性化反応とCREBリン酸化反応,
第23回日本神経科学大会, 2000年7月. 笠原二郎, 上江洲章吉, 福永浩司, 宮本英七 :
ラット培養海馬神経細胞におけるCaMキナーゼの局在とリン酸化反応,
第73回日本薬理学会年会, 2000年3月. 笠原二郎, 福永浩司, 宮本英七 :
培養海馬神経細胞におけるCaMキナーゼIVのリン酸化反応と活性化反応,
第42回日本神経化学会, 1999年9月. 笠原二郎, 福永浩司, 宮本英七 :
CaM kinase IVを制御する脱リン酸化酵素に関する研究,
第22回神経科学大会, 1999年7月. 笠原二郎, 福永浩司, 宮本英七 :
培養海馬神経細胞における脱リン酸化酵素阻害剤のCaMキナーゼリン酸化反応に対する効果,
第72回日本薬理学会年会, 1999年3月. 笠原二郎, 福永浩司, 宮本英七 :
ラット培養海馬神経細胞におけるCaMキナーゼIVのリン酸化および活性化反応に関する研究,
第51回日本薬理学会西南部会, 1998年11月. 笠原二郎, 杉山博之 :
培養プルキンエ細胞のグルタミン酸応答に対するリン酸化，脱リン酸化酵素阻害剤の影響,
第20回日本神経科学大会, 1997年7月. 笠原二郎, 中村康司, 杉山博之 :
アフリカツメガエル卵母細胞における受容体とGタンパク質との共役特異性,
第17回日本神経科学大会, 1994年11月.

研究会・報告書: 笠原二郎, 坂下美宙, 岩本緋天, 小川允利 :
パーキンソン病モデルマウスにおけるアリピプラゾールの薬効評価,
第25回活性アミンに関するワークショップ(福岡，久留米大学医学部), 2023年8月. 笠原二郎, 周禹, 後藤惠 :
パーキンソン病モデルマウスの運動症状に対するイマチニブの薬効,
第24回活性アミンに関するワークショップ(大阪大学), 2022年8月. 笠原二郎, 小川允利, 周禹, 辻諒佑, 後藤惠 :
片側パーキンソン病モデルマウスにおけるメマンチンの脳内インフュージョン,
カテコールアミンと神経疾患研究会2021, 2021年4月. 笠原二郎, 内田裕人, 手塚健太, 藤田有貴 :
一過性局所脳虚血後ラットの海馬歯状回にみられる神経変性とその病態生理学的意義,
第16回活性アミンに関するワークショップ, 2012年8月. 笠原二郎 :
パーキンソン病治療薬ゾニサミドの薬理作用機構に関する基礎研究:ドーパミン合成代謝機構への関与について,
第19回カテコールアミンと神経疾患研究会, 2012年5月. 塚田竜矢, 黒岩勇人, 深野達也, 岡部真二, 横山宏典, 内田裕人, 笠原二郎 :
MPTPパーキンソン病モデルマウスにおけるPioglitazoneの神経保護効果,
第15回活性アミンに関するワークショップ, 2011年8月. 横山宏典, 矢野遼平, 笠原二郎 :
パーキンソン病治療薬ゾニサミドのマウス黒質線条体神経細胞に対する薬効作用解析,
第15回活性アミンに関するワークショップ, 2011年8月. 笠原二郎, 安達みなみ, 大村幸司, 福永浩司 :
マウス大脳皮質ニューロンにおけるセロトニンを介したCREBリン酸化反応の解析,
第15回活性アミンに関するワークショップ, 2011年8月. 黒岩勇人, 横山宏典, 塚田竜矢, 笠原二郎, 荒木勉 :
MPTP誘発パーキンソン病モデルマウスに対するPARP阻害剤及びPPAR作動薬の神経細胞保護効果に関する研究ーzonisamideとの比較研究,
第18回カテコールアミンと神経変性疾患研究会要旨集 pp 11, 2010年4月. 笠原二郎 :
神経新生から考えるストレス反応機構について,
第8回ブレインサイエンス研究会・教育セミナー, 2006年6月. 笠原二郎 :
中枢神経組織におけるプロテインキナーゼ・フォスファターゼ活性の測定,
第6回ブレインサイエンス研究会・テクニカルセミナー, 2004年5月.

特許: 研究者総覧に該当データはありませんでした。
作品: 研究者総覧に該当データはありませんでした。
補助金・競争的資金: アポリポタンパク質によるHDL産生・代謝調節機構の物理化学的基盤解明と創薬展開 (研究課題/領域番号: 25293006 )
ストレス脆弱性と抗うつに関わる中枢神経細胞内分子機構の基礎研究 (研究課題/領域番号: 21790376 )
脂肪酸結合蛋白質によるドパミン受容体調節と神経機能における役割 (研究課題/領域番号: 20659008 )
新規抗うつ薬スクリーニング系の確立を目指したマウスによる分子基盤研究 (研究課題/領域番号: 19790280 )
脳血管障害治療に有効な新しい作用機序を有する脳保護薬の開発 (研究課題/領域番号: 19390150 )
中枢神経細胞におけるCaM kinase kinaseの活性動態と機能 (研究課題/領域番号: 15700283 )
中枢興奮薬の逆耐性現象における神経可塑性を標的とした創薬研究 (研究課題/領域番号: 15650068 )
虚血性脳障害におけるシグナル伝達セラピーの創薬科学研究 (研究課題/領域番号: 14370035 )
遺伝子発現の脳可塑性形成への必須性に関する研究 (研究課題/領域番号: 12878149 )
cDNAの異所性細胞への導入と脳シグナルトランスダクションモデルの確立 (研究課題/領域番号: 12557011 )
脳海馬長期増強誘導,維持の分子機構に関する研究 (研究課題/領域番号: 12053258 )
カルモデュリン依存性プロテインキナーゼIIの神経細胞内局在とシナプス機能の調節 (研究課題/領域番号: 12031218 )
カルモデュリン依存性キナーゼIVの活性制御機構と神経機能との関わり (研究課題/領域番号: 11780562 )
シナプス伝達効率調節に関する分子細胞生物学的研究 (研究課題/領域番号: 11694295 )
脳のカルモデュリン依存性プロテインキナーゼIIの可変領域の多様性とその生理的意義 (研究課題/領域番号: 11680758 )
興奮性シナプスに発現するクラスタリング分子の神経薬理学的研究 (研究課題/領域番号: 11470025 )
海馬シナプス可塑性におけるカルモデュリンキナーゼIIの役割 (研究課題/領域番号: 11170244 )
カルモデュリン依存性蛋白質燐酸化反応による脳由来神経栄養因子産生の調節機構 (研究課題/領域番号: 11157226 )
神経活動依存性遺伝子発現活性化機構の研究 (研究課題/領域番号: 10878141 )
カルモデュリン依存性蛋白質燐酸化反応による神経栄養因子産生の調節に関する研究 (研究課題/領域番号: 10176228 )
海馬シナプス伝達長期増強・長期抑圧の誘発と維持におけるプロテインキナーゼの役割 (研究課題/領域番号: 10155224 )
側頭葉てんかん脳での神経突起の形成異常と蛋白質燐酸化反応の分子細胞生物学的研究 (研究課題/領域番号: 09680766 )
シナプス可塑性におけるカルモデュリン依存性キナーゼIIの作用機構 (研究課題/領域番号: 09670096 )
培養細胞を用いての細胞内Ca^<2+>シグナリングに関する分子細胞生物学的研究 (研究課題/領域番号: 09480223 )
蛋白質燐酸化反応と障害神経細胞での軸索とシナプス再形成に関する分子生物学的研究 (研究課題/領域番号: 09280229 )
海馬シナプス伝達長期増強の誘発と維持におけるプロテインキナーゼの役割 (研究課題/領域番号: 09259230 )
脳海馬における長期増強,長期抑圧に関する分子細胞生物学的研究 (研究課題/領域番号: 09044324 )
神経伝達物質による細胞増殖,分化機構の研究 (研究課題/領域番号: 08878147 )
cDNA導入による安定細胞系の確立と創薬のための薬物効果判定モデルの作製 (研究課題/領域番号: 07557195 )
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専門分野・研究分野: 薬学 (Pharmacy)
所属学会・所属協会: 研究者総覧に該当データはありませんでした。
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受賞: 2014年4月, 2013後期共通教育賞 (全学共通教育センター)
2023年8月, 優秀講演賞 (第25回活性アミンに関するワークショップ)
活動: 東京工業大学社会人教育院 (講師 [2009年6月〜2010年6月])
BMC Neuroscience (Associate Editor [2009年12月〜2018年12月])

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Jグローバル最終確認日: 2024/11/9 01:03
氏名（漢字）: 笠原二郎
氏名（フリガナ）: カサハラジロウ
氏名（英字）: Kasahara Jiro
所属機関: 徳島大学准教授

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researchmap最終確認日: 2024/11/10 01:28
氏名（漢字）: 笠原二郎
氏名（フリガナ）: カサハラジロウ
氏名（英字）: Kasahara Jiro
プロフィール: 1994. 3. 九州大学理学部生物学科卒業
1996. 3. 九州大学大学院理学研究科生物学専攻修士課程修了
1996. 4. 日本学術振興会DC1特別研究員
1997. 3. 九州大学大学院医学系研究科分子生命科学系専攻中退
1997. 4. 熊本大学医学部薬理学第一講座助手
2000. 1. 博士（理学）（九州大学）
2001. 4. 日本学術振興会海外特別研究員 (Post doctoral fellow, Center for Learning and Memory, Massachusetts Institute of Technology, MA, USA)
2002. 10. 東北大学大学院薬学研究科薬理学分野助手
2004. 4. 同講師
2009. 12. 徳島大学大学院ヘルスバイオサイエンス研究部 (薬科学教育部) 神経病態解析学分野准教授
2015. 4. 同大学院医歯薬学研究部（薬学域）神経病態解析学分野に組織改称
登録日時: 2010/4/6 00:00
更新日時: 2024/9/21 15:00
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所属ID: 0344012000
所属: 徳島大学
部署: 大学院医歯薬学研究部（薬学部）神経病態解析学分野
職名: 准教授
学位: 博士（理学）
学位授与機関: 九州大学
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ＫＡＫＥＮで最新データを確認する

2024年11月9日更新

研究者番号: 10295131

所属（現在）: 2024/4/1 : 徳島大学, 大学院医歯薬学研究部(薬学域), 准教授

所属（過去の研究課題 情報に基づく）*注記: 2015/4/1 – 2016/4/1 : 徳島大学, 大学院医歯薬学研究部, 准教授
2013/4/1 – 2014/4/1 : 徳島大学, ヘルスバイオサイエンス研究部, 准教授
2009/4/1 – 2010/4/1 : 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授
2007/4/1 – 2009/4/1 : 東北大学, 大学院・薬学研究科, 講師
2004/4/1 : 東北大学, 大学院・薬学研究科, 講師
2003/4/1 : 東北大学, 大学院・薬学研究科, 助手
1997/4/1 – 2001/4/1 : 熊本大学, 医学部, 助手

審査区分/研究分野

研究代表者

複合領域 / 神経科学(含脳科学) / 神経化学・神経薬理学
総合・新領域系 / 総合領域 / 神経科学 / 神経化学・神経薬理学
生物系 / 医歯薬学 / 基礎医学 / 実験病理学

研究代表者以外

複合領域 / 神経科学(含脳科学) / 神経化学・神経薬理学
総合・新領域系 / 総合領域 / 神経科学 / 神経化学・神経薬理学
生物系 / 医歯薬学 / 境界医学 / 応用薬理学
生物系 / 医歯薬学 / 薬学 / 生物系薬学
生物系 / 医歯薬学 / 薬学 / 物理系薬学
医学 / 生理 / 薬理学一般
生物系

キーワード

研究代表者

カルシウム / カルモデュリン / カムキナーゼIV / CREB / リン酸化 / 海馬神経細胞 / CA1 / LTP / 脱リン酸化 / 細胞内情報伝達機構 / プロテインキナーゼ / ニューロン / 海馬 / 細胞内局在 / 活性 / CaM kinase kinase / CaM kinaswe I / 活性測定 / 脳神経疾患 / 薬理学 / シグナル伝達 / モデル動物 / リン酸化反応 / 細胞内カルシウム / うっ病モデル / 神経新生 / 抗うつ薬 / セロトニン / 可塑性 / うつ病 / 疾患モデル動物 / ストレス / カルシウムシグナル / 神経再生

研究代表者以外

CAKβ / Pyk2 / チロシンキナーゼ / MAPキナーゼ / カルシウムイオン / CaMキナーゼII / 遺伝子組替え実験 / 初代培養神経細胞 / グルタミン酸受容体 / 遺伝子組換え実験 / 培養細胞 / シナプス可塑性 / 海馬 / 長期増強 / プロテインホスファターゼ2A / NMDA受容体 / カルモデュリン / NG108-15細胞 / 核内移行シグナル / 顆粒細胞 / カルシウム / 小脳 / 脳由来神経栄養因子(BDNF) / CamキナーゼII / BDNF / CAI領域 / 転写調節 / カルモデュリンキナーゼII / 小脳顆粒細胞 / シナプス伝達長期増強 / 学習 / 長期記憶 / 遺伝子発現 / 神経活動依存性 / 脳由来神経栄養因子 / 記憶 / 転写因子 / 阻害薬 / 神経細胞死 / プロモーター解析 / long-term potemtiation / CaMキナーゼIV / プロテインホスファターゼ / CREB / long-term potentiation / AMPA受容体 / クラスタリング分子 / SAP102 / PSD-95 / アストロサイト / インスリン分泌反応 / シナプシンI / MIN6細胞 / 燐酸化特異抗体 / 海馬CA1 / 海馬初代培養神経細胞 / グルタミン酸 / CaMキナーゼキナーゼ / 活性化反応 / カルシニューリン / メタンフェタミン / 逆耐性現象 / 統合失調症 / ドパミン受容体 / NF-κB / 覚醒剤中毒 / D2受容体 / 薬物治療学 / 脳血管障害 / 内皮型一酸化窒素合成酵素 / 脳血管保護作用 / 嗅球摘出マウス / アルツハイマー病 / 神経新生 / 認知機能 / バナジウム化合物 / 内皮型-酸化窒素合成酵素 / 心臓型脂肪酸結合蛋白質 / ドパミンD2受容体 / 線条体 / カタレプシー / アセチルコリン / ノックアウトマウス / 多価不飽和脂肪酸 / 帯状回皮質 / 恐怖行動 / アポリポタンパク質 / HDL / コンフォメーション / 抗体 / アミロイド / 脂質膜 / 糖鎖 / ＨＤＬ / コレステロール代謝 / 脂質異常症 / アミロイドーシス / ABCトランスポーター / 細胞モデル / cDNA / 遺伝子強制導入 / 安定クローン細胞 / 強制発現 / 核移行シグナル / サブユニットアイソフォーム / 発現細胞 / MAP2 / CaMキナーゼ / PC12細胞 / 神経突起伸展反応 / ジブチリルcAMP / 自己燐酸化反応 / Cellular model / Calcium ion / CaM kinase II / Gene insertion / Cloned stable cell / Overexpression / Nuclear localization signal / 蛋白質脱燐酸化反応 / 後シナプス細胞 / 蛋白質燐酸化反応 / hippocampus / learning / memory / MAP kinase / protein phosphatase / protein dephosphorylation / 受容体 / 細胞内Ca^<2+> / 細胞内情報伝達 / 細胞機能 / 受容体刺激 / 細胞内応答 / δサブユニット / 脳由来神経成長因子 / Receptor / Signal transduction / Cultured cell / CaM kinase IV / Calcineurin / Cellular functions / CA1 / LTP / スパイン / autophosphorylation / synaptic plasticity / NMDA receptor / protein phosphatase 2A / カルモデュリンキナーザII / 細胞骨格蛋白質 / 神経突起形成 / 側頭葉てんかん / Cキナーゼ / MARCKS / Brain-derived neurotrophic factor (BDNF) / Ca^<2+> / calmodulin-dependent protein kinase II / Cytoskeletal proteins / Hippocampus / Naurite outgrowth / NG108-15 cells / Temporal lobe epilepsy / scaffold protein / ドーパミン受容体 / 興奮性シナプス / scafold protein / シナプス / PDZドメイン / カリウムチャネル / excitatory synapse / postsynaptic density / NE-dlg / SAPI02 / インスリン分泌細胞 / 可変領域 / ゴルジ体 / 小胞体 / Astrocyte / Gene expression / Insulin secretion / Synapsin I / Brain-derived neurotrophic factor / MIN6 cells / 後シナプス神経細胞 / 蛋白質リン酸化反応 / gene expression / ドーパミンD2受容体 / 異所性遺伝子発現 / Ca^<2+>シグナル / CaMキナーゼIIサブタイプ / CaM kivases / Ca^<2+> signaling / dopamine D2 receptor / nuclear localization signal / NG108--15 cell / brain-derived neurotrophic factor / cell model / 脳虚血 / 心筋虚血 / カルモデュリン阻害剤 / 脳浮腫 / 一酸化窒素 / カルパイン / 脳保護薬 / 中大脳動脈閉塞モデル / バナジウム / Akt / 遅発性神経細胞死 / 脳梗塞 / 虚血耐性 / プロテインキナーゼ / Fasリガンド / Forkhead transcription factor / ニトロチロシン / brain ischemia / myocardial ischemia / calmodulin antagonist / nitric oxide / brain edema / calpain / vanadium compound

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2019年11月12日

パーキンソン病治療における脳内薬物インフュージョンシステムの開発（後藤惠）

後藤惠森垣龍馬牟礼英生笠原二郎梶龍兒永廣信治

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笠原 二郎

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笠原二郎