2. Academic Validation
  3. A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis

  • Acta Pharm Sin B. 2021 Mar;11(3):708-726. doi: 10.1016/j.apsb.2020.11.002.
Tailin He 1,  Jialin Shang 2,  Chenglong Gao 1,  Xin Guan 1,  Yingyi Chen 2,  Liwen Zhu 3,  Luyong Zhang 1,  Cunjin Zhang 3,  Jian Zhang 2,  Tao Pang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Medicinal Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 3 Department of Neurology of Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210008, China.
PMID: 33777677 DOI: 10.1016/j.apsb.2020.11.002
Abstract

Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke, but how to control the overactive neuroinflammation is still a long-standing challenge. Here, we designed a novel SIRT6 Activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia, which were abolished by silencing SIRT6. RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811 stimulation and is required for the anti-inflammatory effects of MDL-811. We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation. Moreover, our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS, but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery. Importantly, MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients, underlying an interesting translational perspective. Taken together, MDL-811 could be an alternative therapeutic candidate for ischemic stroke and Other brain disorders associated with neuroinflammation.

Keywords

Deacetylation; EZH2; FOXC1; Ischemic stroke; Macrophage; Microglia; Neuroinflammation; SIRT6 activator.

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