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Radicicol potentiates neurotrophin-mediated neurite outgrowth and survival of cultured sensory neurons from chick embryo.

根赤考可增强神经营养素介导的神经突生长和鸡胚培养感觉神经元的存活。

基本信息

批准号：
10680735
负责人：
SANO Mamoru
金额：
$ 1.98万
依托单位：
Kyoto Prefectural University of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10680735/
关键词：
Radicicol Neurotrophin Dorsal root ganglion Anti-cancer drug Geldanamycin Goldanamycin apoptosis Neive Growth Factor

项目摘要

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.

低浓度的根赤霉素能促进鸡胚感觉神经元和交感神经元的存活和突起生长。培养的背根神经节（DRG）神经元对顺铂、长春新碱和紫杉醇等化疗药物非常敏感，即使在神经营养因子、神经生长因子（NGF）、脑源性神经营养因子（BDNF）和神经营养因子-3（NT-3）达到饱和水平的情况下也是如此。这些抗癌药物的神经毒性作用通过向培养物中添加根赤霉素（20 nM）而被完全阻止。最近的研究表明，根赤霉素和格尔德霉素的主要细胞内靶点是热休克蛋白90（HSP 90）伴侣，干扰其功能。在存在或不存在神经营养因子的情况下，低剂量（约2 nM）的格尔德霉素似乎也对DRG神经元具有神经营养作用，但较高剂量（>5 nM）的格尔德霉素对神经元具有严重的细胞毒性作用。低剂量的格尔德霉素也被发现对抗癌药物如根赤霉素具有神经保护作用。然而，在没有神经营养因子的情况下，较高剂量的根赤霉素（500 nM）仍然诱导神经突并阻止分离的DRG神经元的凋亡。用最佳剂量的格尔德霉素和根赤霉素一起处理神经元是细胞毒性的，而不是神经营养的。这两种抗生素可能具有共同的靶点，对培养的神经元具有营养和毒性作用。而两种抗生素之间的不同细胞效应尚不能很好地解释。推测这种新的活性可能是通过抑制HSP 90功能介导的，尽管我不能排除有限剂量的这些抗生素与HSP 90以外的特异性靶分子相互作用并抑制凋亡的可能性。这些结果表明，根赤霉素对神经退行性疾病，特别是抗癌药物引起的感觉神经病变具有治疗潜力。