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Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2023-12-13 , DOI: 10.1038/s41392-023-01713-z
Jun Wei 1 , Min Li 1 , Zhi Ye 1 , Xinqian Hu 1 , Xiaoyan He 1 , Jia Wang 1 , Gaofeng Chen 1 , Chengyu Zou 2 , Daichao Xu 2 , Hongbing Zhang 3 , Junying Yuan 2 , Yunhong Zha 1
Affiliation  

Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1G93A mice and ALS patients. SOD1G93A mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).



中文翻译:


受体相互作用蛋白激酶 1 (RIPK1) 和 IL-8 的外周水平升高作为人类肌萎缩侧索硬化症的生物标志物



肌萎缩侧索硬化症(ALS)是一种毁灭性的致命神经退行性疾病,无法治愈。受体相互作用蛋白激酶 1 (RIPK1) 被认为可以介导 ALS 的发病机制。普米酮已被认定为老药,也能抑制RIPK1激酶。我们使用 SOD1 G93A小鼠和 ALS 患者进行了扑米酮作为 RIPK1 抑制剂的药物再利用生物标志物研究。用扑米酮治疗的 SOD1 G93A小鼠表现出明显延迟症状发作并改善运动表现。每日服用扑米酮(62.5 毫克)的 162 名 ALS 参与者完成了 24 周的随访。 ALS 患者血清 RIPK1 和 IL-8 水平显着降低,且显着高于健康对照( P < 0.0001)。血清 RIPK1 水平与延髓症状严重程度呈正相关( P < 0.05)。我们的研究表明,外周血中 RIPK1 和 IL-8 的水平可作为人类 ALS 患者中枢神经系统 RIPK1 激活的临床生物标志物。扑米酮的重新利用可能为 ALS 提供一种有前景的治疗策略。还可以考虑扑米酮治疗其他炎症性疾病的作用,因为 RIPK1 的激活与介导多种炎症性疾病有关,包括 COVID-19 相关细胞因子释放综合征 (CRS)。 (ChiCTR2200060149)。

更新日期:2023-12-14
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