S100A11通过抑制MAPK信号通路介导依达拉奉dexborneol对多西他赛诱导的大鼠认知损伤的保护作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-08-06 DOI:10.1016/j.taap.2025.117504

Ping Liu , Jiantao Jia , Yinliang Lu , Hanmin Tang , Chengyi Gao , Suxia Han

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引用次数: 0

摘要

认知障碍是多西紫杉醇化疗的常见副作用。发现新型神经保护剂依达拉奉右冰片（ED）可减轻DTX引起的不良表型。然而，潜在的机制仍未被探索。通过分析mrna测序数据，我们注意到，在dtx治疗的认知损伤大鼠中，神经系统保护者S100钙结合蛋白A11 （S100A11）的表达降低，但ED治疗逆转了这一趋势。因此，我们推测S100A11可能参与ED对dtx诱导的认知损伤的保护作用。Sprague-Dawley大鼠腹腔注射DTX诱导认知功能障碍，DTX诱导后腹腔注射ED。结果表明，ED治疗减轻了DTX引起的认知障碍。接下来，将携带编码S100A11序列的腺病毒给予接受DTX治疗的大鼠。S100A11过表达减轻了dtx治疗大鼠的认知功能障碍，表现为逃避潜伏期缩短、游泳距离缩短、过平台次数增加。机制上，S100A11过表达通过失活MAPK信号通路抑制神经元凋亡。进一步的抢救实验表明，S100A11敲低逆转了ED在dtx诱导的神经元损伤中的防御作用。综上所述，ED通过上调S100A11的表达，进而使MAPK信号通路失活，从而改善DTX引起的认知功能障碍。

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S100A11 mediates the protective effects of edaravone dexborneol on docetaxel-induced cognitive impairment in rats by inhibiting the MAPK signaling pathway

Cognitive impairment is a common side effect of docetaxel (DTX)-based chemotherapy. The novel neuroprotective agent edaravone dexborneol (ED) was found to alleviate the adverse phenotype caused by DTX. However, the underlying mechanism remains unexplored. By analyzing mRNA-sequencing data, we noticed that the expression of S100 calcium-binding protein A11 (S100A11), a protector of the nervous system, was decreased in DTX-treated rats with cognitive damage, but ED administration reversed the trend. Therefore, we speculated that S100A11 might be involved in the protective effects of ED on DTX-induced cognitive impairment. Sprague-Dawley rats were intraperitoneally injected with DTX to induce cognitive impairment, followed by intraperitoneal injection of ED after DTX induction. The results showed that ED treatment mitigated cognitive impairment caused by DTX. Next, adenoviruses carrying sequences encoding S100A11 were given to rats receiving DTX treatment. S100A11 overexpression alleviated cognitive dysfunction of DTX-treated rats, as evidenced by the decreased escape latency and swimming distance, and the increased number of platform crossings. Mechanically, S100A11 overexpression inhibited neuronal apoptosis by inactivating the MAPK signaling pathway. Further rescue experiments showed that S100A11 knockdown reversed the defensive role of ED in DTX-induced neuronal damage. In conclusion, ED ameliorates cognitive dysfunction caused by DTX by upregulating the S100A11 expression and subsequently inactivating the MAPK signaling pathway.

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.