ミトコンドリアと神経細胞死

2009 Fiscal Year Annual Research Report

• Project/Area Number: 21659018
• Research Institution: Kanazawa University
• Principal Investigator: 米田 幸雄 Kanazawa University, 薬学系, 教授 (50094454)
• Keywords: グルタミン酸 / NMDA受容体 / 細胞内遊離カルシウム濃度 / 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 / 神経細胞死

Research Abstract

本研究では、グルタミン酸(Glu)の神経毒性出現メカニズムにおけるミトコンドリアの関与を解明する目的で、ラット脳由来培養神経細胞の生存率と機能変化について解析した。海馬由来神経細胞をGluまたはN-メチル-D-アスパラギン酸(NMDA)に1時間曝露すると、その24時間後には著明な細胞死が誘発されたが、大脳皮質由来細胞ではこのような細胞死は観察されなかった。しかしながら、NMDA曝露に伴う細胞内遊離Ca^<2+>濃度上昇には両部位間細胞に相違は見られなかった。海馬神経細胞では、NMDA曝露に伴って急速なミトコンドリア膜電位の脱分極とともに、cytochrome C放出担体mitochondrial permeability transition pore(mPTP)の形成が観察された。これに対して、大脳皮質神経細胞ではこのような変化はいずれも招来されなかった。Cyclophilin D等のmPTPを構成する分子群のmRNA発現量やmPTPを活性化する薬物の添加の影響には、いずれも両部位由来の神経細胞間で差異は見られなかったが、NMDA曝露後のミトコンドリア内Ca^<2+>濃度上昇は海馬の方が大脳皮質よりも2倍以上高いことが判明した。しかしながら、プロトン勾配形成に関与する電子伝達系分子のmRNA発現量は、両脳内部位由来神経細胞間で相違は見られなかった。以上の結果より、海馬神経細胞におけるNMDA毒性脆弱性の出現には、NMDA受容体活性化後のミトコンドリア膜電位の破綻が強く関与する可能性が示唆される。

Research Products

• [Journal Article] 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)
  • Author(s): Nakamichi N., Fukumori R., Takarada T., Kambe Y., Yamamoto T., Matsushima N., Moriguchi N., Yoneda Y.
  • Journal Title: J.Neurosci.Res. (in press)
  • Peer Reviewed
• [Journal Article] Induced tolerance to glutamate neurotoxicity through downregulation of NR2 subunits of N-methyl-D-aspartate receptors in cultured rat striatal neurons. (2010)
  • Author(s): Kambe Y., Nakamichi N., Takarada T., Fukumori R., Yoneda Y.
  • Journal Title: J.Neurosci.Res. (in press)
  • Peer Reviewed
• [Journal Article] Inhibition by 2-methoxy-4-ethylphenol of Ca^<2+> influx through acquired and native N-methyl-D-aspartate receptor channels. (2010)
  • Author(s): Fukumori R., Nakamichi N., Takarada T., Kambe Y., Matsushima N., Moriguchi N., Yoneda Y.
  • Journal Title: J.Pharmacol.Sci. (in press)
  • Peer Reviewed
• [Journal Article] ITZ-1 a client-selective Hsp90 inhibitor efficiently induces heat shock factor 1 activation. (2010)
  • Author(s): Kimura H., Yukitake H., Tajima Y., Suzuki H., Chikatsu T., Morimoto S., Funabashi Y., Omae H., Ito T., Yoneda Y., Takizawa M.
  • Journal Title: Chemistry and Biology 17 Pages: 18-27
  • Peer Reviewed
• [Journal Article] Cytokine receptor-like factor 1 is highly expressed in damaged human knee osteoarthritic cartilage and is involved in osteoarthritis downstream of TGF-β. (2010)
  • Author(s): Tsuritani K., Takeda J., Sakagami J., Ishii A., Eiksson T., Hara T., Ishibashi H., Koshihara Y., Yamada K., Yoneda Y.
  • Journal Title: Calcif.Tissue Int. 86 Pages: 47-57
  • Peer Reviewed
• [Journal Article] Combined effect of neonatal immune activation and mutant DISC1 on phenotypic changes in adulthood. (2009)
  • Author(s): 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.
  • Journal Title: Behav.Brain Res 206 Pages: 32-37
  • Peer Reviewed
• [Journal Article] Neonatal, phehcyclidine treatment in mice induces behavioral, histological and neurochemical abnormalities in adulthood. (2009)
  • Author(s): Nakatani-Pawlak A., Yamaguchi K., Tatsumi Y., Mizoguchi H., Yoneda Y.
  • Journal Title: Biol.Pharm.Bull. 32 Pages: 1576-1583
  • Peer Reviewed
• [Journal Article] Transcriptional induction and translational inhibition of Arc and Cugbp2 in mice hippocampus after transient global ischemia under normothermic condition. (2009)
  • Author(s): Otsuka N., Tsuritani K., Sakurai T., Kato K., Matoba R., Itoh J., Okuyama S., Yamada K., Yoneda Y.
  • Journal Title: Brain Res. 1287 Pages: 136-145
  • Peer Reviewed
• [Journal Article] Interference by adrenaline with chondrogenic differentiation through suppression of gene transactivation mediated by Sox9 family members. (2009)
  • Author(s): Takarada T., Hojo H., Iemata M., Sahara., Kodama A., Nakamura N., Hinoi E., Yoneda Y.
  • Journal Title: Bone 45 Pages: 568-578
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Takarada T., Tamaki K., Takumi T., Ogura M., Ito Y., Nakamichi N., Yoneda Y.
  • Journal Title: J.Neurochem. 110 Pages: 1457-1468
  • Peer Reviewed
• [Journal Article] Neonatal polyl : C treatment in mice results in schizophrenia-like behavioral and neurochemical abnormalities in adulthood. (2009)
  • Author(s): 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.
  • Journal Title: Neurosci.Res. 64 Pages: 297-305
  • Peer Reviewed
• [Journal Article] Behavioral abnormality and pharmacologic response in social isolation-reared mice. (2009)
  • Author(s): Koike H., Ibi D., Mizoguchi H., Nagai T., Nitta A., Takuma K., Nabeshima T., Yoneda Y, Yamada K.
  • Journal Title: Behav.Brain Res. 202 Pages: 114-121
  • Peer Reviewed
• [Journal Article] Neurogenesis mediated by γ-aminobutyric acid and glutamate signaling. (2009)
  • Author(s): Nakamichi N., Takarada T., Yoneda Y.
  • Journal Title: J.Pharmacol.Sci. 110 Pages: 133-149
  • Peer Reviewed
• [Journal Article] Interference with cellular differentiation by D-serine through antagonism at N-methyl-D-aspartate receptors composed of NR1 and NR3A subunits in chondrocytes. (2009)
  • Author(s): Takarada T., Takahata Y., Iemata M., Hinoi E., Uno K., Hirai T., Yamamoto T., Yoneda Y.
  • Journal Title: J.Cell.Physiol. 220 Pages: 756-764
  • Peer Reviewed
• [Journal Article] Possible promotion of neuronal differentiation in fetal rat brainneural progenitor cells after sustained exposure to static magnetism. (2009)
  • Author(s): Nakamichi N., Ishioka Y., Hirai T., Ozawa S., Tachibana M., Nakamura N., Takarada T., Yoneda Y.
  • Journal Title: J.Neurosci.Res. 87 Pages: 2406-2417
  • Peer Reviewed
• [Journal Article] Predominant promotion by tacrolimus of chondrogenic differentiation to proliferating chondrocytes. (2009)
  • Author(s): Nakamura Y., Takarada T., Kodama A., Hinoi E., Yoneda Y.
  • Journal Title: J.Pharmacol.Sci. 109 Pages: 413-423
  • Peer Reviewed
• [Journal Article] Clarithromycin prevents smoke-induced emphysema in mice. (2009)
  • Author(s): Nakanishi Y., Kobayashi D., Asano Y., Sakurai T., Kashimura M., Okuyama S., Yoneda Y., Shapiro S.D., Takayama K.
  • Journal Title: Amer.J.Resp.Crit.Care Med. 179 Pages: 271-278
  • Peer Reviewed
• [Journal Article] Transactivation by runt related factor-2 of matrix metalloprotginase-13 in astrocytes. (2009)
  • Author(s): Takarada T., Yoneda Y.
  • Journal Title: Neurosci.Lett. 451 Pages: 99-104
  • Peer Reviewed
• [Journal Article] Possible protection by notoginsenoside R1 against neurotoxicity of N-methyl-D-aspartate receptor composed of an NRI/NT2B heteromeric assembly. (2009)
  • Author(s): Gu B., Nakamichi N., Zhang W.-S., Nakamura Y., Kambe Y., Fukumori R., Takuma K, Yamada K., Takarada T., Taniura H., Yoneda Y.
  • Journal Title: J.Neurosci.Res. 87 Pages: 2145-2156
  • Peer Reviewed
• [Journal Article] Protection against kainate neurotoxicity by ginsenosides : Attenuation of convulsive behavior, mitochondrial dysfunction, and oxidative stress. (2009)
  • Author(s): 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.
  • Journal Title: J.Neurosci.Res. 87 Pages: 710-722
  • Peer Reviewed
• [Journal Article] Tacrolimus(FK506)suppresses rt-PA-induced hemorrhagic transformation in a rat thrombotic ischemia stroke model. (2009)
  • Author(s): Maeda M., Furuichi Y., Noto T., Matsuoka N., Mutoh S., Yoneda Y.
  • Journal Title: Brain Res. 1254 Pages: 99-108
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Takahata Y., Takarada T., Iemata M., Yamamoto T., Nakamura Y., Kodama A., Yoneda Y.
  • Journal Title: J.Cell.Physiol. 218 Pages: 268-275
  • Peer Reviewed