Elucidation of protective mechanisms of endogenous low-molecular-weight compounds on neuronal death in central nervous system

• Project/Area Number: 17390157
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Kyoto University
• Principal Investigator: AKAIKE Akinori Kyoto University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (80135558)
• Co-Investigator(Kenkyū-buntansha): KATSUKI Hiroshi Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (40240733) ; KUME Toshiaki Kyoto University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 薬学研究科, 助手 (10303843)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥15,100,000 (Direct Cost: ¥15,100,000); Fiscal Year 2006: ¥5,500,000 (Direct Cost: ¥5,500,000); Fiscal Year 2005: ¥9,600,000 (Direct Cost: ¥9,600,000)
• Keywords: Neuronal death / Excitotoxicity / Nitric oxide / Serofendic acid / Donepezil / Nicotinic receptor

Research Abstract

We focused on the low-molecular-weight substances that controlled the neuronal death induced by glutamate and radical stress. 1, Serofendic acid, a low-molecular-weight substance of atisane-type diterpenoids derived from fetal calf serum, prevents glutamate-induced apoptosis in cultured cortical neurons by the prevention of loss of mitochondrial membrane potential and the reduction of the process of caspase-3 activation. 2, We investigated the effect of serofendic acid on ischemic injury induced by a transient occlusion of the middle cerebral artery in rats. Serofendic acid significantly reduced total infarct volume, similar to edaravone, a free radical scavenger. These results suggest that intracerebroventricular administration of serofendic acid prevents the neurodegeneration induced by a transient focal cerebral ischemia and reperfusion. 3, We found that donepezil and galanthamine prevented glutamate neurotoxicity through α4-and α7-nAChRs, followed by the PI3K-Akt pathway, and that tacrine protected neuronal cells through a different pathway. 4, We examined the mechanisms of thrombin cytotoxicity in the striatum in vivo. Thrombin induced neuronal death and microglial activation around the injection site. Neuronal loss without any sign of nuclear fragmentation was observed. Thrombin-induced damage was partially but significantly reduced by concomitant administration of inhibitors of MAPK pathways. Thus, MAPK pathways and microglial activation may serve as therapeutic targets of pathogenic conditions associated with hemorrhagic stroke. 5, We examined the role of endogenous agonists at the glycine site of NMDA receptors in excitotoxic retinal damage in vivo. Endogenous D-serine is at least in part involved in pathological processes mediated by NMDA receptor over-activation in the retina. The levels of endogenous glycine site agonists influence the severity of NMDA receptor-mediated excitotoxic retinal damage in vivo. Both glycine and D-serine contribute to the excitotoxic processes in the retina.

Research Products

• [Journal Article] Preclinical evidence of neuroprotection by cholinesterase inhibitors. (2006)
  • Author(s): Akaike, A.
  • Journal Title: Alzheimer Dis. Assoc. Disord. 20
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Amyloid β-peptide preconditioning reduces glutamate-induced neurotoxicity by pormoting endocytosis of NMDA receptor. (2006)
  • Author(s): Goto, Y., Niidome, T., Akaike, A., Kihara, T., Sugimoto, H.
  • Journal Title: Biochem. Biophys. Res. Commun. 351 Pages: 259-265
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mechanisms of cell death of neural progenitor cells caused by trophic support deprivation. (2006)
  • Author(s): Niidome, T., Morimoto, N., Iijima, S., Akaike A., Kihara, T., Sugimoto, H.
  • Journal Title: Eur. J. Pharmacol. 548 Pages: 1-8
  • Description: 「研究成果報告書概要(和文)」より
• [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, A.
  • Journal Title: J. Neruosci. Res. 83 Pages: 102-109
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of selegiline on antioxidant systems in the nigrostriatum in rat. (2006)
  • Author(s): Takahata, K., Shimazu, S., Katsuki, H., Yoneda, F., Akaike, A.
  • Journal Title: J. Neural Transm. 113 Pages: 151-158
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Improvement of focal ischemia-induced rat dopaminergic dysfunction by striatal transplantation of mouse embroyonic stem cells. (2006)
  • Author(s): Yanagisawa, D., Qi, M., Kim, D., Kitamura, Y., Inden, M., Tsuchiya, D., Takata, K., Taniguchi, T., Yoshimoto, K., Shimohama, S., Akaike, A., Sumi, S., Inoue, K.
  • Journal Title: Neurosci. Lett. 407 Pages: 74-79
  • Description: 「研究成果報告書概要(和文)」より
• [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, A.
  • Journal Title: J. Neurochem. 97 Pages: 1232-1242
  • NAID: 120002468470
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Amyloid b-peptide preconditioning reduces glutamate-induced neurotoxicity by pormoting endocytosis of NMDA receptor. (2006)
  • Author(s): Goto, Y., Niidome, T., Akaike, A.Kihara, T., Sugimoto, H
  • Journal Title: Biochem. Biophys. Res. Commun. 351 Pages: 259-265
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mechanisms of cell death of neural progenitor cells caused by trophic support deprivation. (2006)
  • Author(s): Niidome, T., Morimoto, N., Iijima, S., Akaike, A., Kihara, T., Sugimoto, H.
  • Journal Title: Eur. J. Pharmacol. 548 Pages: 1-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] c-jun N-terminal kinase inhibition and a-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, A.
  • Journal Title: J. Neruosci. Res. 83 Pages: 102-109
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nitric oxide-mediated effect of nipradilol, a- and b-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
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Amyloid β-peptide preconditioning reduces glutamate-induced neurotoxicity by pormoting endocytosis of NMDA (2006)
  • Author(s): Goto, Y., Niidome, T., Akaike, A., Kihara, T., Sugimoto, H.
  • Journal Title: Biochem. Biophys. Res. Commun. 351 Pages: 259-265
• [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] 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] Effects of selegiline on antioxidant systems in the nigrostriatum in rat. (2006)
  • Author(s): Takahata, K., Shimazu, S., Katsuki, H., Yoneda, F.
  • Journal Title: J. Neural Transm. 113 Pages: 151-158
• [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., Sumimoto.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] Effects of R-(-)-BPAP on the expressions of neurotrophins and their receptors in mesencephalic slices. (2005)
  • Author(s): Hirami, C., Takahata, K., Shimazu, S., Yoneda, F., Hayashi, K., Katsuki, H., Akaike, A.
  • Journal Title: Biol. Pharm. Bull. 28 Pages: 1524-1526
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] p-Quinone mediates 6-hydroxydopomine-induced dopaminergic neuronal death and ferrous iron accelerates the conversion of p-quinone into melanin extracellularly. (2005)
  • Author(s): Izumi, Y., Sawada, H., Sakka, N., Yamamoto, N., Kume, T., Katsuki, H., Shimohama, S., Akaike, A.
  • Journal Title: J. Neurosci. Res. 79 Pages: 849-860
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells. (2005)
  • Author(s): Izumi, Y., Sawada, H., Yamamoto, N., Kume, T., Katsuki, H., Shimohama, S., Akaike, A.
  • Journal Title: J. Neurosci. Res. 82 Pages: 126-137
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Quinolinic acid toxicity on orexin neurons blocked by gamma aminobutyric acid type A receptor stimulation. (2005)
  • Author(s): Katsuki, H., Akaike, A.
  • Journal Title: Neuroreport 16 Pages: 1157-1161
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Tetraethylammonium exacerbates ischemic neuronal injury in rat cerebrocortical slice cultures. (2005)
  • Author(s): Katsuki, H., Shinohara, A., Fujimoto, S., Kume, T., Akaike, A.
  • Journal Title: Eur. J. Pharmacol. 508 Pages: 85-91
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Protective effect of serofendic acid on glutamate-induced neurotoxicity in rat cultured motor neurons. (2005)
  • Author(s): Kume, T., Kawai, Y., Yoshida, K., Nakamizo, T., Kanki, R., Sawada, H., Katsuki, H., Shimohama, S., Sugimoto, H., Akaike, A.
  • Journal Title: Neurosci. Lett. 383 Pages: 199-202
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons. (2005)
  • Author(s): Kume, T., Sugimoto, M., Takada, Y., Yamaguchi, T., Yonezawa, A., Katsuki, H., Sugimoto, H., Akaike, A.
  • Journal Title: Eur. J. Pharmacol. 527 Pages: 77-85
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pregnenolone sulphate attenuates AMPA cytotoxicity on rat cortical neurons. (2005)
  • Author(s): Shirakawa, H., Katsuki, H., Kume, T., Kaneko, S., Akaike, A.
  • Journal Title: Eur. J. Neurosci. 21 Pages: 2329-2335
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Serofendic acid prevents 6-hydroxydopamine-induced nigral neurodegeneration and drug-induced rotational asymmetry in hemi-parkinsonian rats. (2005)
  • Author(s): Inden, M., Kitamura, Y., Kondo, J., Hayashi, K., Yanagida, T., Takata, K., Tsuchiya, D., Yanagisawa, D., Nishimura, K., Taniguchi, T., Shimohama, S., Sugimoto.H., Akaike.A.
  • Journal Title: J. Neurochem. 95 Pages: 950-961
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Serofendic acid promotes survival of auditory hair cells and neurons of mice. (2005)
  • Author(s): Kita, T., Nakagawa, T., Kim, T., Iwai, K., Takebayashi, S., Akaike, A., Ito, J.
  • Journal Title: NeuroReport 16 Pages: 689-692
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Stimulation of nicotinic acetylcholine receptors protects motor neurons. (2005)
  • Author(s): Nakamizo, T., Kawamata, J., Yamashita, H., Kanki, R., Kihara, T., Sawada, H., Akaike, A., Shimohama, S.
  • Journal Title: Biochem. Biophys. Res. Com. 330 Pages: 1285-1289
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons. (2005)
  • Author(s): Kume, T., Sugimoto, M., Takada, Y., Yamaguchi, T., Yonezawa, A.Katsuki, H., Sugimoto, H., Akaike, A.
  • Journal Title: Eur. J. Pharmacol. 527 Pages: 77-85
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serofendic acid prevents 6-hydroxydopamine-induced nigral neurodegeneration and drug-induced rotational asymmetry in hemi-parkinsonian rats. (2005)
  • Author(s): Inden, M., Kitamura, Y., Kondo, J., Hayashi, K., Yanagida, T., Takata, K., Tsuchiya, D., Yanagisawa, D., Nishimura, K., Taniguchi, T., Shimohama, S., Sugimoto, H., Akaike, A.
  • Journal Title: J. Neurochem. 95 Pages: 950-961
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons. (2005)
  • Author(s): Kume T.et al.
  • Journal Title: European Journal of Pharmacology 527・1-3 Pages: 77-85
• [Journal Article] Serofendic acid prevents 6-hydroxydopamine-induced nigral neurodegeneration and drug-induced rotational asymmetry in hemi-parkinsonian rats. (2005)
  • Author(s): Inden M. et al.
  • Journal Title: Journal of Neurochemistry 95・4 Pages: 950-961
• [Journal Article] Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells. (2005)
  • Author(s): Izumi Y.et al.
  • Journal Title: Journal of Neuroscience Research 82・1 Pages: 126-137
• [Journal Article] Effects of R-(-)-BPAP on the expressions of neurotrophins and their receptors in mesencephalic slices. (2005)
  • Author(s): Hirami C. et al.
  • Journal Title: Biological and Pharmaceutical Bulletin 28・8 Pages: 1524-1526
• [Journal Article] Quinolinic acid toxicity on orexin neurons blocked by gamma aminobutyric acid type A receptor stimulation. (2005)
  • Author(s): Katsuki H., Akaike A.
  • Journal Title: Neuroreport 16・11 Pages: 1157-1161
• [Journal Article] Protective effect of serofendic acid on glutamate-induced neurotoxicity in rat cultured motor neurons. (2005)
  • Author(s): Kume T.et al.
  • Journal Title: Neuroscience Letters 383・3 Pages: 199-202
• [Journal Article] Pregnenolone sulphate attenuates AMPA cytotoxicity on rat cortical neurons. (2005)
  • Author(s): Shirakawa H. et al.
  • Journal Title: European Journal of Neuroscience 21・9 Pages: 2329-2335
• [Journal Article] Serofendic acid promotes survival of auditory hair cells and neurons of mice. (2005)
  • Author(s): Kita T.et al.
  • Journal Title: Neuroreport 16・7 Pages: 689-692
• [Journal Article] Stimulation of nicotinic acetylcholine receptors protects motor neurons. (2005)
  • Author(s): Nakamizo T. et al.
  • Journal Title: Biochemical and Biophysical Research Communications 330・4 Pages: 1285-1289
• [Journal Article] p-Quinone mediates 6-hydroxydopamine-induced dopaminergic neuronal death and ferrous iron accelerates the conversion of p-quinone into melanin. (2005)
  • Author(s): Izumi Y. et al.
  • Journal Title: Journal of Neuroscience Research 79・6 Pages: 849-860
• [Journal Article] Tetraethylammonium exacerbates ischemic neuronal injury in rat cerebrocortical slice cultures. (2005)
  • Author(s): Katsuki H. et al.
  • Journal Title: European Journal of Pharmacology 508・1-3 Pages: 85-91
• [Journal Article] ニューロンのアポトーシスを制御する内在性保護因子 (2005)
  • Author(s): 赤池昭紀, 香月博志, 久米利明
  • Journal Title: 日本神経精神薬理学雑誌 25・5 Pages: 245-250
  • NAID: 10016851917