中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (9): 2047-2055.doi: 10.4103/1673-5374.367929

• 原著:退行性病与再生 • 上一篇    下一篇

5-羟色胺：肌萎缩侧索硬化的潜在干预靶点

  

  • 出版日期:2023-09-15 发布日期:2023-03-07
  • 基金资助:
    国家自然科学基金项目（30560042，81160161，81360198，82160255）；江西省教育厅项目（GJJ13198，GJJ170021）；江西省科技厅项目（20142BBG70062，20171BAB215022，20192BAB205043）；江西省卫计委项目（20181019）

5-Hydroxytryptamine: a potential therapeutic target in amyotrophic lateral sclerosis

Shi-Shi Jiang1, #, Meng-Ni Gong2, #, Wei Rao1, #, Wen Chai1, Wen-Zhi Chen1, Xiong Zhang3, *, Hong-Bing Nie1, *, Ren-Shi Xu1, *   

  1. 1Medical College of Nanchang University, Department of Neurology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Clinical College of Nanchang Medical College, Nanchang, Jiangxi Province, China; 2Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; 3Department of Neurology, Maoming People’s Hospital, Maoming, Guangdong Province, China
  • Online:2023-09-15 Published:2023-03-07
  • Contact: Xiong Zhang, MD, PhD, xiong715@163.com; Hong-Bing Nie, MD, Mrniehongbing@163.com; Ren-Shi Xu, MD, PhD, xurenshi@ncu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 30560042, 81160161, 81360198, and 82160255; Education Department of Jiangxi Province, Nos. GJJ13198 and GJJ170021; Jiangxi Provincial Department of Science and Technology, Nos. 20142BBG70062, 20171BAB215022, and 20192BAB205043; and Health and Family Planning Commission of Jiangxi Province, No. 20181019 (all to RSX). 

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摘要：

既往研究发现，肌萎缩侧索硬化的发病机制与5-羟色胺密切相关，为了解其具体的作用机制，实验对肌萎缩侧索硬化SOD1*G93A转基因小鼠分别腹腔注射三种5-羟色胺受体拮抗剂格拉司琼、哌波色罗和利坦色林。结果可见，与野生型小鼠相比，肌萎缩侧索硬化转基因模型小鼠脊髓中5-羟色胺阳性细胞明显减少，而格拉司琼可减少转基因小鼠的体质量，哌波色罗和利坦色林则能缩短转基因小鼠悬挂实验的潜伏期，但3种拮抗剂都对肌萎缩侧索硬化疾病进展没有影响。转基因小鼠经这3种拮抗剂干预后，其TDP-43和SOD1-G93A的分布或/和表达以及TDP-43的细胞质离域均显著增加，且存在星形胶质细胞和小胶质细胞数量增加以及神经元数量减少的现象。提示5-羟色胺缺乏可能通过诱导TDP-43和SOD1-G93A的异常表达和/或分布，激活胶质细胞，参与肌萎缩侧索硬化的发病。因此5-羟色胺可能是肌萎缩侧索硬化的潜在干预靶点。

https://orcid.org/0000-0002-0478-4039 (Xiong Zhang); https://orcid.org/0000-0002-6370-7244 (Hong-Bing Nie); https://orcid.org/0000-0003-0313-3434 (Ren-Shi Xu)

关键词: 肌萎缩侧索硬化, 血清素, 5-羟色胺, 格拉司琼, 哌波色罗, 利坦色林, TDP-43, SOD1-G93A, 星形胶质细胞, 小胶质细胞, 神经元

Abstract: Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis (ALS) is closely linked to 5-hydroxytryptamine (5-HT). To investigate this further, we administered 5-HT receptor antagonists to SOD1*G93A transgenic (ALS mouse model) and wide-type mice. This involved intraperitoneal injections of either granisetron, piboserod, or ritanserin, which inhibit the 5-HT3, 5-HT4, and 5-HT2 receptors, respectively. The transgenic mice were found to have fewer 5-HT-positive cells in the spinal cord compared with wide-type mice. We found that the administration of granisetron reduced the body weight of the transgenic mice, while piboserod and ritanserin worsened the motor functioning, as assessed using a hanging wire test. However, none of the 5-HT receptor antagonists affected the disease progression. We analyzed the distribution and/or expression of TAR DNA binding protein 43 (TDP-43) and superoxide dismutase 1 G93A (SOD1-G93A), which form abnormal aggregates in ALS. We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists. In addition, the disease-related mislocalization of TDP-43 to the cytoplasm increased markedly for all three drugs. In certain anatomical regions, the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons. These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells. 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis.

Key words: 5-hydroxytryptamine, amyotrophic lateral sclerosis, astrocytes, granisetron, microglia, neuron, piboserod, ritanserin, SOD1-G93A, TAR DNA-binding protein 43