Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis

作者：Wei, Jun; Li, Min; Ye, Zhi; Hu, Xinqian; He, Xiaoyan; Wang, Jia; Chen, Gaofeng; Zou, Chengyu; Xu, Daichao; Zhang, Hongbing; Yuan, Junying^*; Zha, Yunhong^*

来源：Signal Transduction and Targeted Therapy, 2023, 8(1): 451.

DOI：10.1038/s41392-023-01713-z

• NECROPTOSIS
• DEGENERATION
• INFLAMMATION
• MECHANISMS

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 SOD1(G93A) mice and ALS patients. SOD1(G93A) 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).

• 单位
  中国科学院; 中国医学科学院; 中国医学科学院北京协和医院; 1