2000 Fiscal Year Final Research Report Summary
Radicicol potentiates neurotrophin-mediated neurite outgrowth and survival of cultured sensory neurons from chick embryo.
| Project/Area Number |
10680735
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Kyoto Prefectural University of Medicine |
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Principal Investigator |
SANO Mamoru Kyoto Prefectural University of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (60090429)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Radicicol / Neurotrophin / Dorsal root ganglion / Anti-cancer drug / Geldanamycin |
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| Research Abstract |
The low concentration of radicicol enhanced the survival and neurite outgrowth of the embryonic sensory and sympathetic neurons from chick embryos. The cultured dorsal root ganglion (DRG) neurons were extremely susceptible to the antineoplastic drugs, cisplatin, vincristine and taxol even in the presence of saturating levels of the neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). The neurotoxic effects of these anti-cancer drugs were completely prevented by the addition of radicicol (20 nM) to the cultures. Recent studies showed that the major intracellular target of radicicol and geldanamycin is the heat shock protein 90 (HSP90) chaperone, interfering with its function. Geldanamycin at low doses (about 2 nM) appeared to also be neurotrophic on DRG neurons in the presence or absence of neurotrophins, but higher doses of geldanamycin (>5 nM) had severe cytotoxic effects on neurons. Geldanamycin at low doses was also found to be neuroprotective against anti-cancer drugs as radicicol. Higher doses of radicicol (500 nM), however, still induced neurites and prevented apoptosis of the isolated DRG neurons in the absence of neurotrophins. Treatment of neurons with optimal doses of geldanamycin and radicicol together was cytotoxic instead of neurotrophic. These two antibiotics may share a common target and provide trophic and toxic effect to the cultured neurons. While different cellular effects between two antibiotics were not well explicable. It is presumed that the novel activity might be mediated via suppression of HSP90 function, although I can not rule out the possibility that limited doses of these antibiotics interact with specicfic target molecule (s) other than HSP90 and suppress apoptosis. These results indicated that radicicol has therapeutic potential for neurodegenerative diseases, especially for anti-cancer drug-induced sensory neuropathy.
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[Publications] Sakuma, K., Watanabe, K., Sano, M., Uramoto, I., Sakamoto, K., and Totsuka, T.: "The adaptive response of Myo D family proteins in overloaded, regenerating and denervated rat muscles."Biol.Biophys.Acta. 1428. 284-292 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Sakuma, K., Watanabe, K., Sano, M., Uramoto, and Totsuka, T.: "Differential adaptation of growth and differentiation factor 8/myostatin, fibroblast growth factor 6 and leukemia inhibitory factor it overloaded, regenerating and denervated rat muscles."Biol.Biophys.Acta. 1497. 77-88 (2000)
Description
「研究成果報告書概要(欧文)」より
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