Neuroprotective effect of adenine on purkinje cell survival

• Project/Area Number: 18590107
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Tokyo University of Science
• Principal Investigator: IKEKITA Masahiko Tokyo University of Science, Faculty of Sciences and Technology, Professor (70138981)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,260,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥360,000); Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: adenine / purine / Purkinje cell / neuronal cell death / purinergic / target molecule / phagocyte / micro glia / 細胞・組織 / 生体分子 / 神経科学 / 核酸 / 細胞死 / シグナル伝達 / degenerate PCR

Research Abstract

We recently reported that adenine acts as a neurotrophic factor independent of adenosine or P2 receptors in cultured Purkinje cells [Watanabe S., et. al. (2003) J. Neurosci. Res. 74, 754-759], suggesting the presence of specific receptors for adenine in the brain. In this study, the characterization of adenine-binding activity in the rat brain was performed to further characterize the receptor-like adenine-binding sites. Specific binding sites for [3H] adenine were detected in membrane fractions prepared from rat brains. The kinetics of [3H] adenine binding to membranes was described by the association and dissociation rate constants, 8. 6 x 10^5 /M/min and 0.118±0. 045 min-1, respectively. A single binding site for [3H] adenine with a K D of 157. 1±20. 8 nM and a B max of 16. 3 ± 1. 1 pmol/mg protein (n = 6) was demonstrated in saturation experiments. A displacement study involving various related compounds showed that the [3H] adenine binding was highly specific for adenine. It was a lso found that [3H] adenine-binding activity was inhibited by adenosine, although other adenosine receptor ligands were ineffective as to [3H] adenine binding. The brain, especially the cerebellum and spinal cord, showed the highest [3H] adenine-binding activity of the tissues examined. These results are consistent with the presence of a novel adenine receptor in rat brain membranes. We examined the effects of various purines on survival in the cerebellar cortex of Purkinje cells with large cell bodies and highly branched dendrites, and it was found that some purine and pyrimidine derivatives influence Purkinje cell survival. Treatment with adenine, guanine, guanosine, guanine nucleotides, and uracil nucleotides protected Purkinje cells from cell death in the cerebellar primary cultures. Among the effective compounds, adenine had the most potent survival activities on Purkinje cells. These results suggest that adenine is involved in the control of Purkinje cell survival in cerebellar primary cultures via a novel adenine-dependent mechanism.

Research Products

• [Journal Article] Syntheses and applications of fluorescent and biotinylated epolactaene derivatives:Epolactaene and its derivative induce disulfide formation (2008)
  • Author(s): Kuramochi K, Yukizawa S, Ikeda S, Sunoki T, Arai S, Matsui R, Morita A, Mizushina Y, Sakaguchi K, Sugawara F, Ikekita M, Kobayashi S.
  • Journal Title: Bioorg.Med.Chem. 16 Pages: 5039-5049
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] BODIPY-Based Fluorescent Redox Potential Sensors that Utilize Reversible Redox Properties of Flavin (2008)
  • Author(s): Yamada Y, Tomiyama Y, Morita A, Ikekita M, Aoki s.
  • Journal Title: Chembiochem 2008Mar1(印刷中)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Synthesis and pharmacological evaluation of the novel pseudo-symmetrical tamoxifen derivatives as anti-tumor agents (2008)
  • Author(s): Shiina I, Sano Y, Nakata K, Kikuchi T, Sasaki A, Ikekita M, Nagahara Y, Hasome Y, Yamori T, Yamazaki K.
  • Journal Title: Biochem Pharmacol 75 Pages: 1014-1026
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Syntheses and applications of fluorescent and biotinylated epolactaene derivatives : Epolactaene and its derivative induce disulfide formation (2008)
  • Author(s): Kuramochi, K., Yukizawa, S., Ikeda, S., Sunoki, T., Arai, S., Matsui, R., Morita, A., Mizushina, Y., Sakaguchi, K., Sugawara, F., Ikekita, M., Kobayashi, S
  • Journal Title: Bioorg Med Chem 1 ; 16(9) Pages: 5039-49
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] BODIPY-Based Fluorescent Redox Potential Sensors that Utilize Reversible Redox Properties of Flavin (2008)
  • Author(s): Yamada, Y., Tomiyama, Y., Morita, A., Ikekita, M., Aoki, S
  • Journal Title: Chembiochem
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Binding parameters and thermodynamics of the interaction of imino sugars with a recombinant human acid alpha-glucosidase (alglucosidase alfa) : Insight into the complex formation mechanism (2008)
  • Author(s): Yoshimizu, M., Tajima, Y., Matswawa, F., Aikawa, SI, Iwamoto, K., Kobayashi, T., Edmunds, T., Fujishima, K., Tsuji, D., Itoh, K., Ikekita, M., Kawashima, I, Sugawara, K., Ohyanagi, N., Suzuki, T., Togawa, T., Ohno, K., Salcuraba, H
  • Journal Title: Clin Chim Acta
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis and pharmacological evaluation of the novel pseudo-symmetrical tamoxifen derivatives as anti-tumor agents (2008)
  • Author(s): Shiina, I., Sano, Y., Nakata, K., Kikuchi, T., Sasaki, A., Ikekita, M., Nagahara, Y., Hasome, Y., Yamori, T., Yamazaki, K
  • Journal Title: Biochem Pharmacol 1 ; 75(5) Pages: 1014-26
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induction of mitochondria-involved apoptosis in estrogen receptor-negative cells by a novel tamoxifen derivative, ridaifen-B (2008)
  • Author(s): Nagahara, Y., Shiina, I., Nakata, K., Sasaki, A., Miyamoto, T., Ikekita, M
  • Journal Title: Cancer Sci 99(3) Pages: 608-14
  • NAID: 10024004105
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] BODIPY-Based Fluorescent Redox Potential Sensors that Utilize Reversible Redox Properties of Flavin. (2008)
  • Author(s): Yamada Y, Tomiyama Y, Morita A, Ikekita M, Aoki S.
  • Journal Title: Chembiochem. (In press)
  • Peer Reviewed
• [Journal Article] Binding parameters and thermodynamics of the interaction of imino sugars with a recombinant human acid alpha-glucosidase (alglucosidase alfa): Insight into the complex formation mechanism. (2008)
  • Author(s): Yoshimizu M, Tajima Y, Matsuzawa F, Aikawa SI, Iwamoto K, Kobayashi T, Edmunds T, Fujishima K, Tsuji D, Itoh K, Ikekita, et. al.
  • Journal Title: Clin Chim Acta. (In Press)
  • Peer Reviewed
• [Journal Article] Synthesis and pharmacological evaluation of the novel pseudo-symmetrical tamoxifen derivatives as anti-tumor agents. (2008)
  • Author(s): Shiina I, Sano Y, Nakata K, Kikuchi T, Sasaki A, Ikekita M, Nagahara Y, Hasome Y, Yamori T, Yamazaki K.
  • Journal Title: Biochem Pharmacol. 75(5) Pages: 14-26
  • Peer Reviewed
• [Journal Article] An expeditious synthesis of tamoxiten, a representative SERM (selective estrogen receptor modulator), via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and beta-chlorophenetole (2007)
  • Author(s): Shiina, I., Sano, Y., Nakata, K., Suzuki, M., Yokoyama, T., Sasaki, A., Orikasa, T., Miyamoto, T., Ikekita, M., Nagahara, Y., Hasome, Y
  • Journal Title: Bioorg Med Chem
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of the new pseudo-symmetrical tamoxifen derivatives and their anti-tumor activity (2007)
  • Author(s): Shiina, I., Sano, Y., Nakata, K., Kikuchi, T., Sasaki, A., Ikekita, M., Hasome, Y
  • Journal Title: Bioorg Med Chem Lett 1 ; 17(9) Pages: 2421-4
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Structural and biochemical studies on Pompe disease and a "pseudodeficiency of acid alpha-glucosiciase (2007)
  • Author(s): Tajima, Y., Matswawa, F., Aikawa, SI., Okumiya, T., Yoshimizu, M., Tsukimura, T., Ikekita, M, Tsujino, S., Tsuji, A., Edmunds, T., Sakuraba, H
  • Journal Title: J Hum Genet
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Synthesis of the new pseudo-symmetrical tamoxifen derivatives and their anti-tumor activity. (2007)
  • Author(s): Shiina I, Sano Y, Nakata K, Kikuchi T, Sasaki A, Ikekita M, Hasome Y.
  • Journal Title: Bioorg Med Chem Lett. 17(9) Pages: 2421-4
• [Journal Article] Auxiliary liver organ formation by implantation of spleen-encapsulated hepatocytes. (2006)
  • Author(s): Nishio R, Nakayama M, Ikekita M, Watanabe Y.
  • Journal Title: Tissue Eng. 12(9)
• [Journal Article] Preferential reduction of the alpha-2-6-sialylation from cell surface N-glycans of human diploid fibroblastic cells by in vitro aging. (2006)
  • Author(s): Tadokoro T, Yamamoto K, Kuwahara I, Fujisawa H, Ikekita M, Taniguchi A, Sato T, Furukawa K.
  • Journal Title: Glycoconj J. 23(5-6) Pages: 443-52
• [Journal Article] Apoptosis-inducing effect of epolactaene derivatives on BALL-1 cells. (2006)
  • Author(s): Kuramochi K, Matsui R, Matsubara Y, Nakai J, Sunoki T, Arai S, Nagata S, Nagahara Y, Mizushina Y, Ikekita M, Kobayashi S.
  • Journal Title: Bioorg Med Chem. 14(7) Pages: 2151-61
• [Presentation] 受容体結合実験によるアデニン結合分子の性状解析 (2006)
  • Author(s): 渡辺 俊、池北 雅彦、中田 裕康
  • Organizer: 日本薬学会第126年会
  • Place of Presentation: 横浜
  • Year and Date: 2006-03-30
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Characterization of adenine binding protein (2006)
  • Author(s): S. Watanabe, M. Ikekita, Y. Nakata
  • Organizer: 126th The Conference of Pharmaceutical Society of Japan
  • Year and Date: 2006-03-30
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 生物を知るための生化学 (2007)
  • Author(s): 池北 雅彦、榎並 勲、辻 勉
  • Total Pages: 224
  • Publisher: 丸善出版(株)
  • Description: 「研究成果報告書概要(和文)」より