胎仔由来細胞保護メタボローム・セロフェンド酸の生理・薬理作用に関する研究

• Project/Area Number: 17790059
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Kyoto University
• Principal Investigator: 久米 利明 京都大学, 薬学研究科, 助手 (10303843)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: メタボローム / 生理活性物質 / 薬理学 / 生理学 / 脳・神経 / セロフェンド酸 / ウシ胎仔血清 / ニューロン死 / アストロサイト / アポトーシス / ミトコンドリア / カスパーゼ

Research Abstract

胎仔由来細胞保護メタボロームであるセロフェンド酸の脳疾患への応用の可能性を検討する目的でin vivo実験系でのセロフェンド酸の有効性を検討する研究を中心に実験を実施した。動物実験モデルとしてはラット一過性中大脳動脈閉塞モデルを用いた。虚血開始30分後にセロフェンド酸を脳室内投与すると再灌流48時間後の環状切片における梗塞巣体積が有意に減少した。また、行動学的検討を行うためにneurological deficit scoresを測定したところ、セロフェンド酸投与によりvehicle群と比較して有意なスコアの改善が観察された。また、対照薬として用いたエダラボンを脳室内投与したところ、虚血側の梗塞巣体積は有意に減少したが、行動学的指標となるneurological deficit scoresへは影響を与えなかった。セロフェンド酸投与が生理機能への影響を与えているか否かについて、生理学的パラメータと脳血流量の測定を行った。セロフェンド酸は血液内の各種イオンおよび酸素分圧、二酸化炭素分圧には影響を与えなかった。また、脳虚血時に減少する脳血流量に関してもvehicle群との優位な差は観察されなかった。セロフェンド酸は脳室内に投与することにより脳虚血障害に対して有意な抑制作用を発現し、また既存の治療薬であるエダラボンよりもより有用な作用を発現した。このことはセロフェンド酸の脳疾患への応用の可能性を示唆するものである。

Research Products

• [Journal Article] Thrombin-induced delayed injury involves multiple and distinct signaling pathways in the cerebral cortex and the striatum in organotypic slice cultures. (2006)
  • Author(s): Fujimoto, S., Katsuki, H., Kume, T., Akaike, A.
  • Journal Title: Neurobiology of Disease 22 Pages: 130-142
  • NAID: 120002468469
• [Journal Article] Contribution of endogenous glycine site NMDA agonists to excitotoxic retinal damage in vivo. (2006)
  • Author(s): Hama, Y., Katsuki, H., Tochikawa, Y., Suminaka, C., Kume, T., Akaike, A.
  • Journal Title: Neurosci.Res. 56 Pages: 279-285
  • NAID: 10019272913
• [Journal Article] A critical role of TRPM2 in neuronal cell death by hydrogen peroxide. (2006)
  • Author(s): Kaneko, S., Kawakami, S., Hara, Y., Wakamori, M., Itoh, E., Minami, T., Takada, Y., Kume, T., Katsuki, H., Mori, Y., Akaike, A.
  • Journal Title: J.Pharmacol.Sci. 101 Pages: 66-76
  • NAID: 10018237407
• [Journal Article] Serofendic acid, a neuroprotective substance derived from fetal calf serum, inhibits mitochondrial membrane depolarization and caspase-3 activation. (2006)
  • Author(s): Kume, T., Taguchi, R., Katsuki, H., Akao, M., Sugimoto, H., Kaneko, S., Akaike, A.
  • Journal Title: Eur.J.Pharmacol. 542 Pages: 69-76
• [Journal Article] Glutamate excitotoxicity is involved in cell death caused by tributyltin in cultured rat cortical neurons. (2006)
  • Author(s): Nakatsu, Y., Kotake, Y., Komasaka, K., Hakozaki, H., Taguchi, R., Kume, T., Akaike, A., Ohta.S.
  • Journal Title: Toxicol.Sci. 89 Pages: 235-242
• [Journal Article] c-jun N-terminal kinase inhibition and α-tocopherol protect midbrain dopaminergic neurons from interferon-g/lipopolysaccharide-induced injury without affecting nitric oxide production. (2006)
  • Author(s): Shibata, H., Katsuki, H., Okawara, M., Kume, T., Akaike
  • Journal Title: J.Neruosci.Res. 83 Pages: 102-109
• [Journal Article] Aminoglutethimide prevents excitotoxic and ischemic injuries in cortical neurons. (2006)
  • Author(s): Shirakawa, H., Katsuki, H., Kume, T., Kaneko, S., Akaike, A.
  • Journal Title: British J.Pharmacol. 147 Pages: 729-736
  • NAID: 120002468468
• [Journal Article] Nitric oxide-mediated effect of nipradilol, α- and β-adrenergic blocker, on glutamate neurotoxicity in rat cortical cultures. (2006)
  • Author(s): Taguchi, R., Shirakawa, H., Yamaguchi, T., Kume, T., Katsuki, H., Akaike, A.
  • Journal Title: Eur.J.Pharmacol. 535 Pages: 86-94
• [Journal Article] Neuroprotective effects of galanthamine and tacrine against glutamate neurotoxicity. (2006)
  • Author(s): Takada-Takatori, Y., Kume, T., Sugimoto, M., Katsuki, H., Niidome, T., Sugimoto, H., Fujii, T., Okabe, S., Akaike, A.
  • Journal Title: Eur.J.Pharmacol. 549 Pages: 19-26
• [Journal Article] Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. (2006)
  • Author(s): Takada-Takatori, Y., Kume, T., Sugimoto, M., Katsuki, H., Sugimoto, H., Akaike, A.
  • Journal Title: Neuropharmacology 51 Pages: 474-486
• [Journal Article] Serofendic acid, a novel substance extracted from fetal calf serum, protects against oxidative stress in neonatal rat cardiac myocytes. (2006)
  • Author(s): Takeda, T., Akao, M., Matsumoto-Ida, M., Kato, M., Takenaka, H., Kihara, Y., Kume, T., Akaike, A., Kita, T.
  • Journal Title: J.American College.Cardiology 47 Pages: 1882-1890
• [Journal Article] Synthesis and neuroprotective effects of serofendic acid analogues. (2006)
  • Author(s): Terauchi, T., Doko, T., Yonaga, M., Kajiwara, A., Niidome, T., Taguchi, R., Kume, T., Akaike, A., Sugimoto, H.
  • Journal Title: Bioorg.Med.Chem.Lett. 16 Pages: 5080-5083
• [Journal Article] Nitric oxide-producing microglia mediate thrombin-induced degeneration of dopaminergic neurons in rat midbrain slice culture. (2006)
  • Author(s): Katsuki, H., Okawara, M., Shibata, H., Kume, T., Akaike
  • Journal Title: J.Neurochem 97 Pages: 1232-1242
  • NAID: 120002468470
• [Journal Article] Nitric oxide-mediated effect of nipradilol, an alpha- and beta-adrenergic blocker, on glutamate neurotoxicity in (2006)
  • Author(s): Taguchi R, Shirakawa H, et al.
  • Journal Title: Eur.J.Pharmacol 535 Pages: 86-94
• [Journal Article] Glutamate excitotoxicity is involved in cell death caused by tributyltin in cultured rat cortical neurons. (2006)
  • Author(s): Nakatsu Y, Kotake Y. et al.
  • Journal Title: Toxicol Sci. 89 Pages: 235-242
• [Journal Article] Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat (2005)
  • Author(s): Kume, T., Sugimoto, M, et al.
  • Journal Title: Eur.J.Pharmacol. 527 Pages: 77-85
• [Journal Article] Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH- (2005)
  • Author(s): Izumi, Y., Sawada, H, et al.
  • Journal Title: J.Neruosci.Res. 82 Pages: 126-137
• [Journal Article] Protective effect of serofendic acid on glutamate-induced neurotoxicity in rat cultured motor neurons. (2005)
  • Author(s): Kume, T., Kawai, Y.et al.
  • Journal Title: Neurosci.Lett. 383 Pages: 199-202
• [Journal Article] p-Quinone mediates 6-hydroxydopomine-induced dopaminergic neuronal death and ferrous iron accelerates the (2005)
  • Author(s): Izumi, Y., Sawada, H.et al.
  • Journal Title: J.Neruosci.Res. 79 Pages: 849-860