ミトコンドリアと神経細胞死

• 研究課題/領域番号: 21659018
• 研究種目: 挑戦的萌芽研究
• 配分区分: 補助金
• 研究分野: 生物系薬学
• 研究機関: 金沢大学
• 研究代表者: 米田 幸雄 金沢大学, 薬学系, 教授 (50094454)
• 研究期間 (年度): 2009 – 2011
• 研究課題ステータス: 完了 (2011年度)
• 配分額: 3,280千円 (直接経費: 3,100千円、間接経費: 180千円); 2011年度: 780千円 (直接経費: 600千円、間接経費: 180千円); 2010年度: 600千円 (直接経費: 600千円); 2009年度: 1,900千円 (直接経費: 1,900千円)
• キーワード: ミトコンドリア / 神経細胞死 / NMDA / グルタミン酸 / 脳虚血 / NMDAレセプター / UCP2 / 人口チャネル / Ca2+蛍光イメージング / NMDA受容体 / ミトコンドリア膜電位 / ミトコンドリア内カルシウム濃度 / mPTP / 海馬神経細胞 / 細胞内遊離カルシウム濃度

研究概要

GluやNMDAに対する脆弱性相違に、ミトコンドリア膜電位、mPTP形成能、ミトコンドリア内Ca^<2+>濃度、およびUCP2発現量等の相違が少なくとも一部は関与する可能性が判明した。人工的NMDARチャネルにさらにUCP2発現ベクターを導入すると、NMDA曝露に伴ってミトコンドリア内遊離Ca^<2+>濃度の著明な上昇とともに、著明な細胞死が出現した。海馬神経細胞におけるNMDA毒性脆弱性の出現には、ミトコンドリア内膜に発現するUCP2発現量が関与すると推察される。

研究成果

• [雑誌論文] Possible involvement of mitochondrial uncoupling protein-2 in cytotoxicity mediated by acquired N-methyl-D-aspartate receptor channels (2012)
  • 著者名/発表者名: Fukumori R, Takarada T, Kambe Y, Nakazato R, Fujikawa K & Yoneda Y
  • 雑誌名: Neurochem Int 巻: (in press) 号: 4 ページ: 498-505
  • DOI: 10.1016/j.neuint.2012.03.019
  • 査読あり
• [雑誌論文] Possible modulation of process extension by N-methyl-D-aspartate receptor expressed in osteocytic MLO-Y4 cells (2012)
  • 著者名/発表者名: Fujita H, Hinoi E, Nakatani E, Yamamoto T, Takarada T & Yoneda Y
  • 雑誌名: J Pharmacol Sci 巻: (in press)
  • NAID: 10030760551
  • 査読あり
• [雑誌論文] Amelioration by the natural polyamine, spermine, of cartilage and bone destruction in rats with collagen-induced arthritis (2012)
  • 著者名/発表者名: Iezaki T, Hinoi E, Yamamoto T, Ishiura R, Ogawa S & Yoneda Y
  • 雑誌名: J Pharmacol Sci 巻: (in press)
  • NAID: 10030760536
  • 査読あり
• [雑誌論文] Delayed Mitochondrial Membrane Potential Disruption by ATP in Cultured Rat Hippocampal Neurons Exposed to <I>N</I>-Methyl-D-Aspartate (2012)
  • 著者名/発表者名: Fujikawa K, Nakamichi N, Kato S, Fukumori R, Hida M, Takarada T & YonedaY
  • 雑誌名: Journal of Pharmacological Sciences 巻: 119 号: 1 ページ: 20-29
  • DOI: 10.1254/jphs.12034FP
  • NAID: 10030760182
  • ISSN: 1347-8613, 1347-8648
  • 査読あり
• [雑誌論文] Osteoclastogenesis is negatively regulated by D-serine produced by osteoblasts (2012)
  • 著者名/発表者名: Takeshi Takarada, Mika Takarada-Iemata, Yoshifumi Takahata, Daisuke Yamada, Tomomi Yamamoto, Yukari Nakamura, Eiichi Hinoi, Yukio Yoneda
  • 雑誌名: J Cell Physiol 巻: (in press) 号: 10 ページ: 3477-87
  • DOI: 10.1002/jcp.24048
  • 査読あり
• [雑誌論文] Natural polyamines spermidine and spermine prevent bone loss through preferential disturbance of osteoclastic activation in ovariectomized mice (2012)
  • 著者名/発表者名: Yamamoto T, Hinoi E, Fujita H, Iezaki T, Takahata Y, Takamori M & Yoneda Y
  • 雑誌名: Br J Pharmacol 巻: (in press)
  • 査読あり
• [雑誌論文] Positive regulation of osteoclastic differentiation by growth differentiation factor-15 up-regulated in osteocytic cells under hypoxia (2012)
  • 著者名/発表者名: Hinoi E, Ochi H, Takarada T, Nakatani E, Iezaki T, Nakajima H, Fujita H, Takahata Y, Hidano S, Kobayashi T, Takeda S & Yoneda Y
  • 雑誌名: J Bone Miner Res 巻: (in press)
  • 査読あり
• [雑誌論文] Possible modulation of process extension by N-methyl-D-aspartate receptor expressed in osteocytic MLO-Y4 cells (2012)
  • 著者名/発表者名: Fujita H, Hinoi E
  • 雑誌名: J Pharmacol Sci 巻: (in press)
  • 査読あり
• [雑誌論文] Amelioration by the natural polyamine, spermine, of cartilage and bone destruction in rats with collagen-induced arthritis (2012)
  • 著者名/発表者名: Iezaki T, Hinoi E
  • 雑誌名: J Pharmacol Sci 巻: (in press)
  • 査読あり
• [雑誌論文] Positive regulation of osteoclastic differentiation by growth differentiation factor-15 up-regulated in osteocytic cells under hypoxia (2012)
  • 著者名/発表者名: Eiichi Hinoi, Hiroki Ochi, Takeshi Takarada, Eri Nakatani, Takashi Iezaki, Hiroko Nakajima, Hiroyuki Fujita, Yoshifumi Takahata, Shinya Hidano, Takashi Kobayashi, Shu Takeda, Yukio Yoneda
  • 雑誌名: J Bone Miner Res 巻: 4 号: 4 ページ: 938-949
  • DOI: 10.1002/jbmr.1538
  • 査読あり
• [雑誌論文] Transferrin receptor-1 suppresses neurite outgrowth in neuroblastoma Neuro2A cells (2011)
  • 著者名/発表者名: Yukary Nakamura, Noritaka Nakamichi, Takeshi Takarada, Kiyokazu Ogita, Yukio Yoneda
  • 雑誌名: Neurochem.Int. 巻: 60 号: 5 ページ: 448-457
  • DOI: 10.1016/j.neuint.2011.08.018
  • 査読あり
• [雑誌論文] γ-aminobutyric acid, type B receptors negatively regulate osteoblast ogenesis toward disturbance of osteoclastogenesis mediated by receptor activator of nuclear factor κB ligand in mouse bone (2011)
  • 著者名/発表者名: Yoshifumi Takahata, Takeshi Takarada, Eiichi Hinoi, Yukari Nakamura, Hiroyuki Fujita, Yukio Yoneda
  • 雑誌名: J Biol Chem 巻: 286 号: 38 ページ: 32906-32917
  • DOI: 10.1074/jbc.m111.253526
  • 査読あり
• [雑誌論文] Selective Upregulation of Per1 mRNA Expression by ATP Through Activation of P2X7 Purinergic Receptors Expressed in Microglial Cells (2011)
  • 著者名/発表者名: Nakazato R, Takarada T
  • 雑誌名: Journal of Pharmacological Sciences 巻: 116 号: 4 ページ: 350-361
  • DOI: 10.1254/jphs.11069FP
  • NAID: 10029895565
  • ISSN: 1347-8613, 1347-8648
  • 査読あり
• [雑誌論文] Positive regulation by GABABR1 subunit of leptin expression through gene transactivation in adipocytes (2011)
  • 著者名/発表者名: Yukari Nakamura, Eiichi Hinoi, Takeshi Takarada, Yoshifumi Takahata, Tomomi Yamamoto, Hiroyuki Fujita, Saya Takada, Syota Hashizume, Yukio Yoneda
  • 雑誌名: PLoS ONE 巻: 6 号: 5 ページ: e20167-e20167
  • DOI: 10.1371/journal.pone.0020167
  • 査読あり
• [雑誌論文] A pivotal role of mitochondrial free calcium in neurotoxicity mediated by pN-methyl-D-aspartate receptors in cultured rat hippocampal neurons. (2011)
  • 著者名/発表者名: Kambe Y
  • 雑誌名: Neurochem Int 巻: in press
  • 査読あり
• [雑誌論文] Exacerbated vulnerability to oxidative stress in astrocytic C6 glioma cells with stable overexpression of the glutamine transporter slc38a1 (2011)
  • 著者名/発表者名: Ogura M
  • 雑誌名: Neurochem Int 巻: 58 ページ: 501-511
  • 査読あり
• [雑誌論文] Gradual downregulation of protein expression of the partner GABABR2 subunit during postnatal brain development in mice defective of GABABR1 subunit. (2011)
  • 著者名/発表者名: Fukui M, Ozawa S
  • 雑誌名: J Pharmacol Sci 巻: 115 ページ: 45-55
  • 査読あり
• [雑誌論文] Requirement of both NR3A and NR3B subunits for dominant negative properties on Ca2+ mobilization mediated by acquired N-methyl-D-aspartate receptor channels into mitochondria. (2010)
  • 著者名/発表者名: Fukumori R
  • 雑誌名: Neurochem Int 巻: 57 ページ: 730-737
  • 査読あり
• [雑誌論文] Preferential inhibition by antidiarrheic 2-methoxy-4-methylphenol of Ca^<2+> influx across acquired N-methyl-D-aspartate receptor channels composed of NR1/NR2B subunit assembly. (2010)
  • 著者名/発表者名: Nakamichi N., Fukumori R., Takarada T., Kambe Y., Yamamoto T., Matsushima N., Moriguchi N., Yoneda Y.
  • 雑誌名: J.Neurosci.Res. (in press)
  • 査読あり
• [雑誌論文] Induced tolerance to glutamate neurotoxicity through downregulation of NR2 subunits of N-methyl-D-aspartate receptors in cultured rat striatal neurons. (2010)
  • 著者名/発表者名: Kambe Y., Nakamichi N., Takarada T., Fukumori R., Yoneda Y.
  • 雑誌名: J.Neurosci.Res. (in press)
  • 査読あり
• [雑誌論文] Inhibition by 2-methoxy-4-ethylphenol of Ca^<2+> influx through acquired and native N-methyl-D-aspartate receptor channels. (2010)
  • 著者名/発表者名: Fukumori R., Nakamichi N., Takarada T., Kambe Y., Matsushima N., Moriguchi N., Yoneda Y.
  • 雑誌名: J.Pharmacol.Sci. (in press)
  • NAID: 10027744270
  • 査読あり
• [雑誌論文] ITZ-1 a client-selective Hsp90 inhibitor efficiently induces heat shock factor 1 activation. (2010)
  • 著者名/発表者名: Kimura H., Yukitake H., Tajima Y., Suzuki H., Chikatsu T., Morimoto S., Funabashi Y., Omae H., Ito T., Yoneda Y., Takizawa M.
  • 雑誌名: Chemistry and Biology 17 ページ: 18-27
  • 査読あり
• [雑誌論文] Cytokine receptor-like factor 1 is highly expressed in damaged human knee osteoarthritic cartilage and is involved in osteoarthritis downstream of TGF-β. (2010)
  • 著者名/発表者名: Tsuritani K., Takeda J., Sakagami J., Ishii A., Eiksson T., Hara T., Ishibashi H., Koshihara Y., Yamada K., Yoneda Y.
  • 雑誌名: Calcif.Tissue Int. 86 ページ: 47-57
  • 査読あり
• [雑誌論文] Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. (2009)
  • 著者名/発表者名: Ibi D., Nagai T., Koike H., Kitahara Y., Mizoguchi H., Niwa M., Jaaro-Peled H., Nitta A., Yoneda Y., Nabeshima T., Sawa A., Yamada K.
  • 雑誌名: Behav.Brain Res 206 ページ: 32-37
  • 査読あり
• [雑誌論文] Neonatal, phehcyclidine treatment in mice induces behavioral, histological and neurochemical abnormalities in adulthood. (2009)
  • 著者名/発表者名: Nakatani-Pawlak A., Yamaguchi K., Tatsumi Y., Mizoguchi H., Yoneda Y.
  • 雑誌名: Biol.Pharm.Bull. 32 ページ: 1576-1583
  • 査読あり
• [雑誌論文] Transcriptional induction and translational inhibition of Arc and Cugbp2 in mice hippocampus after transient global ischemia under normothermic condition. (2009)
  • 著者名/発表者名: Otsuka N., Tsuritani K., Sakurai T., Kato K., Matoba R., Itoh J., Okuyama S., Yamada K., Yoneda Y.
  • 雑誌名: Brain Res. 1287 ページ: 136-145
  • 査読あり
• [雑誌論文] Interference by adrenaline with chondrogenic differentiation through suppression of gene transactivation mediated by Sox9 family members. (2009)
  • 著者名/発表者名: Takarada T., Hojo H., Iemata M., Sahara., Kodama A., Nakamura N., Hinoi E., Yoneda Y.
  • 雑誌名: Bone 45 ページ: 568-578
  • 査読あり
• [雑誌論文] A protein-protein interaction of stress-responsive myosin VI endowed to inhibit neural progenitor self-replication with RNA binding protein, TLS, in marine hippocampus. (2009)
  • 著者名/発表者名: Takarada T., Tamaki K., Takumi T., Ogura M., Ito Y., Nakamichi N., Yoneda Y.
  • 雑誌名: J.Neurochem. 110 ページ: 1457-1468
  • 査読あり
• [雑誌論文] Neonatal polyl : C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. (2009)
  • 著者名/発表者名: Ibi D., Nagai T., Kitahara Y., Mizoguchi H., Koike H., Shiraki A., Takuma K., Kamei H., Noda Y., Nitta A., Nabeshima T., Yoneda Y., Yamada K.
  • 雑誌名: Neurosci.Res. 64 ページ: 297-305
  • 査読あり
• [雑誌論文] Behavioral abnormality and pharmacologic response in social isolation-reared mice. (2009)
  • 著者名/発表者名: Koike H., Ibi D., Mizoguchi H., Nagai T., Nitta A., Takuma K., Nabeshima T., Yoneda Y, Yamada K.
  • 雑誌名: Behav.Brain Res. 202 ページ: 114-121
  • 査読あり
• [雑誌論文] Neurogenesis mediated by γ-aminobutyric acid and glutamate signaling. (2009)
  • 著者名/発表者名: Nakamichi N., Takarada T., Yoneda Y.
  • 雑誌名: J.Pharmacol.Sci. 110 ページ: 133-149
  • NAID: 10025736951
  • 査読あり
• [雑誌論文] Interference with cellular differentiation by D-serine through antagonism at N-methyl-D-aspartate receptors composed of NR1 and NR3A subunits in chondrocytes. (2009)
  • 著者名/発表者名: Takarada T., Takahata Y., Iemata M., Hinoi E., Uno K., Hirai T., Yamamoto T., Yoneda Y.
  • 雑誌名: J.Cell.Physiol. 220 ページ: 756-764
  • 査読あり
• [雑誌論文] Possible promotion of neuronal differentiation in fetal rat brainneural progenitor cells after sustained exposure to static magnetism. (2009)
  • 著者名/発表者名: Nakamichi N., Ishioka Y., Hirai T., Ozawa S., Tachibana M., Nakamura N., Takarada T., Yoneda Y.
  • 雑誌名: J.Neurosci.Res. 87 ページ: 2406-2417
  • 査読あり
• [雑誌論文] Predominant promotion by tacrolimus of chondrogenic differentiation to proliferating chondrocytes. (2009)
  • 著者名/発表者名: Nakamura Y., Takarada T., Kodama A., Hinoi E., Yoneda Y.
  • 雑誌名: J.Pharmacol.Sci. 109 ページ: 413-423
  • NAID: 10025735254
  • 査読あり
• [雑誌論文] Clarithromycin prevents smoke-induced emphysema in mice. (2009)
  • 著者名/発表者名: Nakanishi Y., Kobayashi D., Asano Y., Sakurai T., Kashimura M., Okuyama S., Yoneda Y., Shapiro S.D., Takayama K.
  • 雑誌名: Amer.J.Resp.Crit.Care Med. 179 ページ: 271-278
  • 査読あり
• [雑誌論文] Transactivation by runt related factor-2 of matrix metalloprotginase-13 in astrocytes. (2009)
  • 著者名/発表者名: Takarada T., Yoneda Y.
  • 雑誌名: Neurosci.Lett. 451 ページ: 99-104
  • 査読あり
• [雑誌論文] Possible protection by notoginsenoside R1 against neurotoxicity of N-methyl-D-aspartate receptor composed of an NRI/NT2B heteromeric assembly. (2009)
  • 著者名/発表者名: Gu B., Nakamichi N., Zhang W.-S., Nakamura Y., Kambe Y., Fukumori R., Takuma K, Yamada K., Takarada T., Taniura H., Yoneda Y.
  • 雑誌名: J.Neurosci.Res. 87 ページ: 2145-2156
  • 査読あり
• [雑誌論文] Protection against kainate neurotoxicity by ginsenosides : Attenuation of convulsive behavior, mitochondrial dysfunction, and oxidative stress. (2009)
  • 著者名/発表者名: Shin E.-J., Jeong J.H., Kim A.-Y., Koh Y.H., Nah S.-Y., Kim W.-K., Ko K.H., Kim H.J., Wie M.-B., Kwon Y.S., Yoneda Y., Kim H.-C.
  • 雑誌名: J.Neurosci.Res. 87 ページ: 710-722
  • 査読あり
• [雑誌論文] Tacrolimus(FK506)suppresses rt-PA-induced hemorrhagic transformation in a rat thrombotic ischemia stroke model. (2009)
  • 著者名/発表者名: Maeda M., Furuichi Y., Noto T., Matsuoka N., Mutoh S., Yoneda Y.
  • 雑誌名: Brain Res. 1254 ページ: 99-108
  • 査読あり
• [雑誌論文] Functional expression of beta2 adrenergic receptors responsible for protection against oxidative stress through promotion of glutathione synthesis after Nrf2 upregulation in undifferentiated mesenchymal C3H10T1/2 stem cells. (2009)
  • 著者名/発表者名: Takahata Y., Takarada T., Iemata M., Yamamoto T., Nakamura Y., Kodama A., Yoneda Y.
  • 雑誌名: J.Cell.Physiol. 218 ページ: 268-275
  • 査読あり
• [学会発表] Neurotoxic NMDA signals mediated by mitochondria (2012)
  • 著者名/発表者名: Yoneda Y
  • 学会等名: APSN/ISNN euroscience School
  • 発表場所: Tangdu Hospital, The Fourth Military Medical University(China)
  • 年月日: 2012-02-15
• [学会発表] Neurotoxic NMDA signals mediated by mitochondria (2012)
  • 著者名/発表者名: 米田幸雄
  • 学会等名: APSN/ISN Neuroscience School
  • 発表場所: Tangdu Hospital, The Fourth Military Medical University(中国)(招待講演)
  • 年月日: 2012-02-15
• [学会発表] NMDA NEUROTOXICITYMEDIATED BY MITOCHONDRIA (2011)
  • 著者名/発表者名: Yoneda Y
  • 学会等名: The Glutamatergic Synapse
  • 発表場所: Megaron Athens International Conference Centre(Greece)
  • 年月日: 2011-09-02
• [学会発表] NMDA NEUROTOXICITY MEDIATED BY MITOCHONDRIA (2011)
  • 著者名/発表者名: 米田幸雄
  • 学会等名: The Glutamatergic Synapse
  • 発表場所: Megaron Athens International Conference Centre(ギリシャ)(招待講演)
  • 年月日: 2011-09-02
• [備考]
  • URL: http://www.p.kanazawa-u.ac.jp/~yakubutu/
• [備考]
  • URL: http://www.p.kanazawa-u.ac.jp/~yakubutu/
• [産業財産権] 神経細胞新生促進組成物 (2010)
  • 発明者名: 米田幸雄,宝田剛志,川越博文
  • 権利者名: 金沢大学
  • 産業財産権番号: 2010-254320
  • 出願年月日: 2010-11-12
• [産業財産権] 神經細胞新生促進租成物 (2010)
  • 発明者名: 米田幸雄, 宝田剛志, 川越博文
  • 権利者名: 金沢大学
  • 産業財産権番号: 2010-254320
  • 出願年月日: 2010-11-12