Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (10): 2229-2239.doi: 10.4103/1673-5374.392890

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Association of DNA methylation/demethylation with the functional outcome of stroke in a hyperinflammatory state

Yubo Wang1, 2, #, Ling Zhang1, #, Tianjie Lyu1, 2, #, Lu Cui2, Shunying Zhao2, Xuechun Wang1, 2, Meng Wang2, 3, Yongjun Wang1, 2, 3, 4, 5, 6, *, Zixiao Li1, 2, 3, 4, 5, 6, *   

  1. 1Vascular Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 2China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 3National Center for Healthcare Quality Management in Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 4Chinese Institute for Brain Research, Beijing, China; 5Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, China; 6Beijing Engineering Research Center of Digital Healthcare for Neurological Diseases, Beijing, China
  • Online:2024-10-15 Published:2024-01-29
  • Contact: Yongjun Wang, PhD, MD, yongjunwang@ncrcnd.org.cn; Zixiao Li, PhD, MD, lizixiao2008@hotmail.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 82171270 (to ZL); Public Service Platform for Artificial Intelligence Screening and Auxiliary Diagnosis for the Medical and Health Industry, Ministry of Industry and Information Technology of the People’s Republic of China, No. 2020-0103-3-1 (to ZL); the Natural Science Foundation of Beijing, No. Z200016 (to ZL); Beijing Talents Project, No. 2018000021223ZK03 (to ZL); Beijing Municipal Committee of Science and Technology, No. Z201100005620010 (to ZL); CAMS Innovation Fund for Medical Sciences, No. 2019-I2M-5-029 (to YongW).

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Abstract: Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke and has an important role in the functional outcome of hyperinflammatory stroke.

Key words: DNA demethylation, DNA methylation, DNMT3A, functional outcome, hyperinflammatory state, interleukin, neuroinflammation, stroke, TET2