リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

リケラボ 全国の大学リポジトリにある学位論文・教授論文を一括検索するならリケラボ論文検索大学・研究所にある論文を検索できる

大学・研究所にある論文を検索できる 「Investigation of the mechanisms of taxane-induced peripheral neuropathy focusing on Schwann cell and search for novel therapies by drug repositioning」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
リケラボ

コピーが完了しました

URLをコピーしました

論文の公開元へ論文の公開元へ
書き出し

Investigation of the mechanisms of taxane-induced peripheral neuropathy focusing on Schwann cell and search for novel therapies by drug repositioning

Koyanagi, Madoka 京都大学 DOI:10.14989/doctor.k23147

2021.03.23

概要

がん化学療法誘発末梢神経障害（CIPN）は四肢末端の痛み、しびれなどの感覚異常が前景に立つ副作用で、タキサン系抗がん薬などの投与を受ける患者の50%以上に発症する。 CIPNが重症化すると抗がん薬の使用継続が困難になり、がん治療の大きな妨げにもなる。しかしながら、CIPN発症機序の全容が解明されていないため、未だに予防/治療法は確立されておらず、アンメットメディカルニーズは高い。本研究では、感覚神経とその機能制御や再生・維持に関与する髄鞘形成シュワン細胞との相互作用の破綻がCIPN発症の一因であるという仮説のもと、シュワン細胞に焦点を当てた研究を行い、以下の新知見を得た。

Chapter 1: Taxane-induced dedifferentiation of mature myelin-forming Schwann cells participates in CIPN development
まず、ラット坐骨神経由来初代培養シュワン細胞を用いて、タキサン系抗がん薬処置による影響を検討した。パクリタキセル（10 nM）をシュワン細胞に48時間処置したところ、髄鞘構成成分myelin basic protein（MBP、分化シュワン細胞マーカー）の発現低下、low-affinity nerve growth factor receptor（p75、未分化シュワン細胞マーカー）およびガレクチン-3（脱分化シュワン細胞マーカー）発現増加で示されるシュワン細胞の脱分化が観察された。同様の変化はドセタキセル（10 nM）の処置後にも観察された。さらに、ラット脊髄後根神経節（DRG）由来初代培養神経細胞とシュワン細胞を共培養し、in vitro条件下で髄鞘様構造を構築させた神経−シュワン細胞共培養系にパクリタキセルを処置し、その影響について検討した。その結果、パクリタキセル（10 nM）を48時間処置しても、神経の数および軸索形態に変化は認められなかったが、MBP陽性シュワン細胞の減少が観察され、脱髄が引き起こされたと考えられた。そこで、CIPNマウスモデルにおいてもシュワン細胞の脱分化が認められるかを検討した。パクリタキセル（4 mg/kg）の反復腹腔内投与により、投与開始4から 7日後において機械過敏応答が惹起され、さらに、投与開始7日後に坐骨神経のシュワン細胞において、p75およびガレクチン-3の一過性の発現増加が認められた。以上の結果から、タキサン系抗がん薬により、感覚神経の障害に先行して神経軸索の成熟シュワン細胞が脱分化すること示され、シュワン細胞と感覚神経の相互作用の破綻がCIPN発症のトリガーとなる可能性を新たに提唱した。

Chapter 2: Schwann cell-derived galectin-3 has pro-nociceptive roles in taxane-induced peripheral neuropathy
Chapter 1の結果に基づき、パクリタキセル処置に応答して脱分化シュワン細胞で発現増加するガレクチン-3の役割について解析した。パクリタキセル（10 nM）あるいはドセタキセル（10 nM）を初代培養シュワン細胞に48時間処置すると、培養上清中へガレクチン-3が分泌された。また、タキサン系抗がん薬の投与によりCIPNを発症した乳癌患者、およびパクリタキセル（20 mg/kg）を反復投与したマウスにおいて、CIPNの発症初期にシュワン細胞由来と考えられるガレクチン-3の血漿中濃度が上昇することを確認した。ガレクチン-3が免疫細胞の遊走因子として知られることから、マクロファージ細胞株RAW 264.7を用いて細胞遊走アッセイを実施した。その結果、RAW 264.7は、パクリタキセル処置後のシュワン細胞の培養上清、およびガレクチン-3（2 pM）含有培地に対する遊走反応を示した。同様に、パクリタキセル反復投与によるCIPNモデルマウスの坐骨神経軸索において、造血幹細胞由来の末梢マクロファージが多数浸潤していることを確認し、クロドロン酸内包リポソーム処置により末梢マクロファージを除去すると、機械過敏応答がほぼ完全に抑制された。また、ガレクチン-3遺伝子欠損マウス、あるいはガレクチン-3阻害剤TD-139（15 mg/kg）を腹腔内投与されたマウスでは、パクリタキセル投与後のマクロファージの浸潤および機械過敏応答が抑制された。以上の結果から、シュワン細胞由来の分泌型ガレクチン-3が、化学誘引分子としてマクロファージの末梢神経への浸潤を誘発し、パクリタキセルによるCIPNの誘導に関与すると考えられた。

Chapter 3: Cilostazol is a causal therapy for preventing taxane-related CIPN by suppression of Schwann cell dedifferentiation
これまでの結果から、タキサン系抗がん薬により脱分化したシュワン細胞の再分化/再髄鞘化を促進する薬物がCIPNの新規予防/治療薬候補となるのではないかと考えられた。そこで、MBPの発現増加を指標とし、医薬品・化合物ライブラリーからスクリーニングを行い、ホスホジエステラーゼ-3阻害薬であるシロスタゾールがシュワン細胞の分化を促進することを見出した。シロスタゾール（30 M）は、パクリタキセル処置による初代培養シュワン細胞の脱分化、および神経−シュワン細胞共培養系における脱髄を抑制した。さらに、0.3%シロスタゾール含有飼料を連日マウスに経口摂取させることで、パクリタキセル（5 mg/kg, i.p.）反復投与により誘導される機械過敏応答とともに、坐骨神経のシュワン細胞の脱分化が有意に抑制された。以上の結果から、シロスタゾールはタキサン系抗がん薬によるシュワン細胞の脱分化を抑制することで、CIPN発症を抑制することが示唆され、メカニズムベースの新規予防/治療薬候補として有用であることが示唆された。

以上、本研究結果から、CIPN患者およびモデルマウスに共通した反応として、脱分化シュワン細胞に由来するガレクチン-3の分泌増加を見出し、マクロファージ浸潤を介してタキサン系抗がん薬のCIPN発症に関わることを示した。さらに、シュワン細胞の分化誘導作用を有するシロスタゾールが、CIPNを抑制することを示した。シロスタゾールは、慢性動脈閉塞症などの治療薬として臨床使用されており、本研究成果はCIPNに対する有効な予防/治療薬の開発に直結すると考える。

論文の公開元へ

関連論文

関連論文をもっと見る

参考文献

1. Seretny M, Currie GL, Sena ES, Ramnarine S, Grant R, MacLeod MR, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis. Pain 2014;155:2461-70

2. Velasco R, Bruna J. Taxane-Induced Peripheral Neurotoxicity. Toxics 2015;3:152-69

3. Wilkes G. Peripheral neuropathy related to chemotherapy. Semin Oncol Nurs 2007;23:162-73

4. Hausheer FH, Schilsky RL, Bain S, Berghorn EJ, Lieberman F. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol 2006;33:15-49

5. Melli G, Jack C, Lambrinos GL, Ringkamp M, Höke A. Erythropoietin protects sensory axons against paclitaxel-induced distal degeneration. Neurobiol Dis 2006;24:525-30

6. Leandro-García LJ, Leskelä S, Jara C, Gréen H, Avall-Lundqvist E, Wheeler HE, et al. Regulatory polymorphisms in β-tubulin IIa are associated with paclitaxel- induced peripheral neuropathy. Clin Cancer Res 2012;18:4441-8

7. LaPointe NE, Morfini G, Brady ST, Feinstein SC, Wilson L, Jordan MA. Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology 2013;37:231-9

8. Dorsey SG, Kleckner IR, Barton D, Mustian K, O'Mara A, St Germain D, et al. The National Cancer Institute Clinical Trials Planning Meeting for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy. J Natl Cancer Inst 2019;111:531-7

9. Hu S, Huang KM, Adams EJ, Loprinzi CL, Lustberg MB. Recent Developments of Novel Pharmacologic Therapeutics for Prevention of Chemotherapy-Induced Peripheral Neuropathy. Clin Cancer Res 2019;25:6295-301

10. Stubblefield MD, Burstein HJ, Burton AW, Custodio CM, Deng GE, Ho M, et al. NCCN task force report: management of neuropathy in cancer. J Natl Compr Cancer Netw 2009;7 Suppl 5:S1-S26; quiz S7-8

11. Röyttä M, Raine CS. Taxol-induced neuropathy: chronic effects of local injection. J Neurocytol 1986;15:483-96

12. Flatters SJ, Bennett GJ. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 2006;122:245-57

13. Polomano RC, Mannes AJ, Clark US, Bennett GJ. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain 2001;94:293-304

14. Siau C, Xiao W, Bennett GJ. Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells. Exp Neurol 2006;201:507-14

15. Jessen KR, Mirsky R. The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci 2005;6:671-82

16. Chen ZL, Yu WM, Strickland S. Peripheral regeneration. Annu Rev Neurosci 2007;30:209-33

17. Rotshenker S. Wallerian degeneration: the innate-immune response to traumatic nerve injury. J Neuroinflammation 2011;8

18. Saitoh F, Araki T. Proteasomal degradation of glutamine synthetase regulates schwann cell differentiation. J Neurosci 2010;30:1204-12

19. Nagai T, Ibata K, Park ES, Kubota M, Mikoshiba K, Miyawaki A. A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nat Biotech 2002;20:87-90

20. Farhadi HF, Lepage P, Forghani R, Friedman HC, Orfali W, Jasmin L, et al. A combinatorial network of evolutionarily conserved myelin basic protein regulatory sequences confers distinct glial-specific phenotypes. J Neurosci 2003;23:10214-23

21. Nishitani N, Nagayasu K, Asaoka N, Yamashiro M, Andoh C, Nagai Y, et al. Manipulation of dorsal raphe serotonergic neurons modulates active coping to inescapable stress and anxiety-related behaviors in mice and rats. Neuropsychopharmacology 2019;44:721-32

22. So K, Haraguchi K, Asakura K, Isami K, Sakimoto S, Shirakawa H, et al. Involvement of TRPM2 in a wide range of inflammatory and neuropathic pain mouse models. J Pharmacol Sci 2015;127:237-43

23. Callahan BL, Gil AS, Levesque A, Mogil JS. Modulation of mechanical and thermal nociceptive sensitivity in the laboratory mouse by behavioral state. J Pain 2008;9:174-84

24. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994;53:55-63

25. Woodhoo A, Sommer L. Development of the Schwann cell lineage: from the neural crest to the myelinated nerve. Glia 2008;56:1481-90

26. Liu Z, Jin Y-Q, Chen L, Wang Y, Yang X, Cheng J, et al. Specific Marker Expression and Cell State of Schwann Cells during Culture In Vitro. PLOS ONE 2015;10:e0123278

27. Niapour A, Karamali F, Karbalaie K, Kiani A, Mardani M, Nasr-Esfahani MH, et al. Novel method to obtain highly enriched cultures of adult rat Schwann cells. Biotechnol Lett 2010;32:781-6

28. Pietrucha-Dutczakv M, Marcol W, Francuz T, Gołka D, Lewin-Kowalik J. A new protocol for cultivation of predegenerated adult rat Schwann cells. Cell Tissue Bank 2014;15:403-11

29. Huizing MT, Giaccone G, van Warmerdam LJ, Rosing H, Bakker PJ, Vermorken JB, et al. Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer. J Clin Oncol 1997;15:317-29

30. Hao W, Tashiro S, Hasegawa T, Sato Y, Kobayashi T, Tando T, et al. Hyperglycemia Promotes Schwann Cell De-differentiation and De-myelination via Sorbitol Accumulation and Igf1 Protein Down-regulation. J Biol Chem 2015;290:17106-15

31. Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain 2000;123 ( Pt 7):1516-27

32. Chentanez V, Sanguanrungsirigul S, Panyasawad N. Effects of ganglioside on paclitaxel (Taxol) induced neuropathy in rats. J Med Assoc Thai 2003;86:449-56

33. Leandri M, Ghignotti M, Emionite L, Leandri S, Cilli M. Electrophysiological features of the mouse tail nerves and their changes in chemotherapy induced peripheral neuropathy (CIPN). J Neurosci Methods 2012;209:403-9

34. Stubblefield MD, Vahdat LT, Balmaceda CM, Troxel AB, Hesdorffer CS, Gooch CL. Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study. Clin Oncol 2005;17:271-6

35. Shin YH, Lee SJ, Jung J. Extracellular ATP inhibits Schwann cell dedifferentiation and proliferation in an ex vivo model of Wallerian degeneration. Biochem Biophys Res Commun 2013;430:852-7

36. Taniuchi M, Clark HB, Schweitzer JB, Johnson EM. Expression of nerve growth factor receptors by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by axonal contact, and binding properties. J Neurosci 1988;8:664

37. Jung J, Cai W, Jang SY, Shin YK, Suh DJ, Kim JK, et al. Transient lysosomal activation is essential for p75 nerve growth factor receptor expression in myelinated Schwann cells during Wallerian degeneration. Anat Cell Biol 2011;44:41-9

38. Reichert F, Saada A, Rotshenker S. Peripheral nerve injury induces Schwann cells to express two macrophage phenotypes: phagocytosis and the galactose-specific lectin MAC-2. J Neurosci 1994;14:3231-45

39. Nobusue H, Onishi N, Shimizu T, Sugihara E, Oki Y, Sumikawa Y, et al. Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation. Nat Commun 2014;5:3368

40. Dumic J, Dabelic S, Flogel M. Galectin-3: an open-ended story. Biochim Biophys Acta 2006;1760:616-35

41. Chen A, Hou W, Zhang Y, Chen Y, He B. Prognostic value of serum galectin-3 in patients with heart failure: a meta-analysis. Int J Cardiol 2015;182:168-70

42. Ghorbani A, Bhambhani V, Christenson RH, Meijers WC, de Boer RA, Levy D, et al. Longitudinal Change in Galectin-3 and Incident Cardiovascular Outcomes. J Am Coll Cardiol 2018;72:3246-54

43. Li S, Li S, Hao X, Zhang Y, Deng W. Perindopril and a Galectin-3 Inhibitor Improve Ischemic Heart Failure in Rabbits by Reducing Gal-3 Expression and Myocardial Fibrosis. Front Physiol 2019;10:267

44. Boza-Serrano A, Ruiz R, Sanchez-Varo R, Garcia-Revilla J, Yang Y, Jimenez- Ferrer I, et al. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease. Acta Neuropathol 2019;138:251-73

45. Ntogwa M, Imai S, Hiraiwa R, Koyanagi M, Matsumoto M, Ogihara T, et al. Schwann cell-derived CXCL1 contributes to human immunodeficiency virus type 1 gp120-induced neuropathic pain by modulating macrophage infiltration in mice. Brain Behav Immun 2020; 88:325-39

46. Isami K, Imai S, Sukeishi A, Nagayasu K, Shirakawa H, Nakagawa T, et al. The impact of mouse strain-specific spatial and temporal immune responses on the progression of neuropathic pain. Brain Behav Immun 2018;74:121-32

47. Langer CJ, Stephenson P, Thor A, Vangel M, Johnson DH. Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598. J Clin Oncol 2004;22:1180-7

48. Krop IE, Modi S, LoRusso PM, Pegram M, Guardino E, Althaus B, et al. Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer. Breast Cancer Res 2016;18:34

49. Zielinski C, Lang I, Inbar M, Kahan Z, Greil R, Beslija S, et al. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2- negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol 2016;17:1230-9

50. van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, et al. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: First results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer 2018;102:40-8

51. Wang L, Guo XL. Molecular regulation of galectin-3 expression and therapeutic implication in cancer progression. Biomedicine Pharmacother 2016;78:165-71

52. Ehrhardt C, Rückle A, Hrincius ER, Haasbach E, Anhlan D, Ahmann K, et al. The NF-κB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance. Cell Microbiol 2013;15:1198-211

53. Sano H, Hsu DK, Yu L, Apgar JR, Kuwabara I, Yamanaka T, et al. Human galectin-3 is a novel chemoattractant for monocytes and macrophages. J Immunol 2000;165:2156-64

54. Lobry T, Miller R, Nevo N, Rocca CJ, Zhang J, Catz SD, et al. Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis. Kidney Int 2019;96:350-62

55. Van Rooijen N, Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods 1994;174:83-93

56. Stegmayr J, Zetterberg F, Carlsson MC, Huang X, Sharma G, Kahl-Knutson B, et al. Extracellular and intracellular small-molecule galectin-3 inhibitors. Sci Rep 2019;9:2186

57. Thijssen VL, Heusschen R, Caers J, Griffioen AW. Galectin expression in cancer diagnosis and prognosis: A systematic review. Biochim Biophys Acta 2015;1855:235-47

58. Tian J, Yang G, Chen HY, Hsu DK, Tomilov A, Olson KA, et al. Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 2016;30:4202-13

59. Piek A, Du W, de Boer RA, Sillje HHW. Novel heart failure biomarkers: why do we fail to exploit their potential? Crit Rev Clin Lab Sci 2018;55:246-63

60. Be'eri H, Reichert F, Saada A, Rotshenker S. The cytokine network of wallerian degeneration: IL-10 and GM-CSF. Eur J Neurosci 1998;10:2707-13

61. Huang ZZ, Li D, Liu CC, Cui Y, Zhu HQ, Zhang WW, et al. CX3CL1-mediated macrophage activation contributed to paclitaxel-induced DRG neuronal apoptosis and painful peripheral neuropathy. Brain Behav Immun 2014;40:155-65

62. Zhang H, Li Y, de Carvalho-Barbosa M, Kavelaars A, Heijnen CJ, Albrecht PJ, et al. Dorsal Root Ganglion Infiltration by Macrophages Contributes to Paclitaxel Chemotherapy-Induced Peripheral Neuropathy. J Pain 2016;17:775-86

63. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 2010;11:889-96

64. Ren K, Dubner R. Interactions between the immune and nervous systems in pain. Nat Med 2010;16:1267-76

65. Lee WJ, Tateya S, Cheng AM, Rizzo-DeLeon N, Wang NF, Handa P, et al. M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling. Diabetes 2015;64:2836-46

66. Peters CM, Jimenez-Andrade JM, Kuskowski MA, Ghilardi JR, Mantyh PW. An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. Brain Res 2007;1168:46-59

67. Abdel-Rahman O. Outcomes of early-stage breast cancer patients treated with sequential anthracyclines-taxanes in relationship to relative dosing intensity: a secondary analysis of a randomized controlled trial. Clin Transl Oncol 2019;21:239-45

68. Olawaiye AB, Java JJ, Krivak TC, Friedlander M, Mutch DG, Glaser G, et al. Does adjuvant chemotherapy dose modification have an impact on the outcome of patients diagnosed with advanced stage ovarian cancer? An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 2018;151:18-23

69. Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2014;32:1941-67

70. Smith EM, Pang H, Cirrincione C, Fleishman S, Paskett ED, Ahles T, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 2013;309:1359-67

71. Franklin RJM, Ffrench-Constant C. Regenerating CNS myelin - from mechanisms to experimental medicines. Nat Rev Neurosci 2017;18:753-69

72. Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, et al. A regenerative approach to the treatment of multiple sclerosis. Nature 2013;502:327-32

73. Mei F, Fancy SPJ, Shen YA, Niu J, Zhao C, Presley B, et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat Med 2014;20:954-60

74. Najm FJ, Madhavan M, Zaremba A, Shick E, Karl RT, Factor DC, et al. Drug- based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 2015;522:216-20

75. Han SH, Yun SH, Shin YK, Park HT, Park JI. Heat Shock Protein 90 is Required for cAMP-Induced Differentiation in Rat Primary Schwann Cells. Neurochem Res 2019;44:2643-57

76. Sohn EJ, Park HT, Shin YK. Exosomes derived from differentiated Schwann cells inhibit Schwann cell migration via microRNAs. Neuroreport 2020;31:515-22

77. Hase Y, Okamoto Y, Fujita Y, Kitamura A, Nakabayashi H, Ito H, et al. Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia. Exp Neurol 2012;233:523-33

78. Oyama N, Yagita Y, Kawamura M, Sugiyama Y, Terasaki Y, Omura-Matsuoka E, et al. Cilostazol, not aspirin, reduces ischemic brain injury via endothelial protection in spontaneously hypertensive rats. Stroke 2011;42:2571-7

79. Muirhead GJ, Wilner K, Colburn W, Haug-Pihale G, Rouviex B. The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil. Br J Clin Pharmacol 2002;53 Suppl 1:21s-30s

80. Balinski AM, Preuss CV. Cilostazol. StatPearls. Treasure Island (FL): StatPearls Publishing; 2020.

81. Cheng X, Ji Z, Tsalkova T, Mei F. Epac and PKA: a tale of two intracellular cAMP receptors. Acta biochimica et biophysica Sinica 2008;40:651-62

82. Shintani S, Toba Y, Suzuki S, Ninomiya S, Umezato M, Hiyama T. General pharmacological properties of cilostazol, a new antithrombotic drug. Part I: Effects on the central nervous system. Arzneimittel-Forschung 1985;35:1157-62

83. Savai R, Pullamsetti SS, Banat GA, Weissmann N, Ghofrani HA, Grimminger F, et al. Targeting cancer with phosphodiesterase inhibitors. Expert Opin Investig Drugs 2010;19:117-31

84. Bacallao K, Monje PV. Opposing roles of PKA and EPAC in the cAMP-dependent regulation of schwann cell proliferation and differentiation [corrected]. PloS one 2013;8:e82354

85. Schalcher C, Schad K, Brunner-La Rocca HP, Schindler R, Oechslin E, Scharf C, et al. Interaction of sildenafil with cAMP-mediated vasodilation in vivo. Hypertension 2002;40:763-7

86. Stief CG, Uckert S, Becker AJ, Harringer W, Truss MC, Forssmann WG, et al. Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. Urology 2000;55:146-50

87. Schrör K. The pharmacology of cilostazol. Diabetes Obes Metab 2002;4 Suppl 2:S14-9

88. Kim SM, Jung JM, Kim BJ, Lee JS, Kwon SU. Cilostazol Mono and Combination Treatments in Ischemic Stroke: An Updated Systematic Review and Meta-Analysis. Stroke 2019;50:3503-11

89. Paronis E, Katsimpoulas M, Kadoglou NPE, Provost C, Stasinopoulou M, Spyropoulos C, et al. Cilostazol Mediates Immune Responses and Affects Angiogenesis During the Acute Phase of Hind Limb Ischemia in a Mouse Model. J Cardiovasc Pharmacol Ther 2020;25:273-85

90. Papanas N, Maltezos E. Cilostazol in diabetic neuropathy: premature farewell or new beginning? Angiology 2011;62:605-8

91. Kihara M, Schmelzer JD, Low PA. Effect of cilostazol on experimental diabetic neuropathy in the rat. Diabetologia 1995;38:914-8

92. Naka K, Sasaki H, Kishi Y, Furuta M, Sanke T, Nanjo K, et al. Effects of cilostazol on development of experimental diabetic neuropathy: functional and structural studies, and Na+ -K+ -ATPase acidity in peripheral nerve in rats with streptozotocin-induced diabetes. Diabetes Res Clin Pract 1995;30:153-62

93. Uehara K, Sugimoto K, Wada R, Yoshikawa T, Marukawa K, Yasuda Y, et al. Effects of cilostazol on the peripheral nerve function and structure in STZ-induced diabetic rats. J Diabetes Complications 1997;11:194-202

94. Yamamoto Y, Yasuda Y, Kimura Y, Komiya Y. Effects of cilostazol, an antiplatelet agent, on axonal regeneration following nerve injury in diabetic rats. Eur J Pharmacol 1998;352:171-8

95. Khing TM, Po WW, Sohn UD. Fluoxetine Enhances Anti-tumor Activity of Paclitaxel in Gastric Adenocarcinoma Cells by Triggering Apoptosis and Necroptosis. Anticancer Res 2019;39:6155-63

参考文献をもっと見る

全国の大学の
卒論・修論・学位論文
を
一発検索！

この論文の関連論文を見る