Tetramethylpyrazine promotes axonal remodeling and modulates microglial polarization via JAK2-STAT1/3 and GSK3-NFκB pathways in ischemic stroke

Xuefeng Feng; Mingcong Li; Ziyue Lin; Yun Lu; Yuming Zhuang; Jianfeng Lei; Xiaonan Liu; Hui Zhao

doi:10.1016/j.neuint.2023.105607

Tetramethylpyrazine promotes axonal remodeling and modulates microglial polarization via JAK2-STAT1/3 and GSK3-NFκB pathways in ischemic stroke

Neurochem Int. 2023 Nov:170:105607. doi: 10.1016/j.neuint.2023.105607. Epub 2023 Aug 30.

Authors

Xuefeng Feng¹, Mingcong Li², Ziyue Lin², Yun Lu², Yuming Zhuang², Jianfeng Lei³, Xiaonan Liu⁴, Hui Zhao⁵

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, China; School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China.
² School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China; Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, 100069, China.
³ Medical Imaging Laboratory of Core Facility Center, Capital Medical University, Beijing, 100069, China.
⁴ Department of Laboratory Animal, Capital Medical University, Beijing, 100069, China.
⁵ School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China; Beijing Key Lab of TCM Collateral Disease Theory Research, Beijing, 100069, China. Electronic address: zhaohuishouyi@ccmu.edu.cn.

PMID: 37657766
DOI: 10.1016/j.neuint.2023.105607

Abstract

Ischemic stroke results in demyelination that underlies neurological disfunction. Promoting oligodendrogenesis will rescue the injured axons and accelerate remyelination after stroke. Microglia react to ischemia/hypoxia and polarize to M1/M2 phenotypes influencing myelin injury and repair. Tetramethylpyrazine (TMP) has neuroprotective effects in treating cerebrovascular disorders. This study aims to evaluate whether TMP promotes the renovation of damaged brain tissues especially on remyelination and modulates microglia phenotypes following ischemic stroke. Here magnetic resonance imaging (MRI)-diffusion tensor imaging (DTI) and histopathological evaluation are performed to characterize the process of demyelination and remyelination. Immunofluorescence staining is used to prove oligodendrogenesis and microglial polarization. Western blotting is conducted to examine interleukin (IL)-6, IL-10, transforming growth factor β (TGF-β) and Janus protein tyrosine kinase (JAK) 2-signal transducer and activator of transcription (STAT) 1/3-glycogen synthase kinase (GSK) 3-nuclear transcription factor κB (NFκB) signals. Results show TMP alleviates the injury of axons and myelin sheath, increases NG2⁺, Ki67⁺/NG2⁺, CNPase⁺, Ki67⁺/CNPase⁺, Iba1⁺/Arg-1⁺ cells and decreases Iba1⁺ and Iba1⁺/CD16⁺ cells in periinfarctions of rats. Particularly, TMP downregulates IL-6 and upregulates IL-10 and TGF-β expressions, besides, enhances JAK2-STAT3 and suppresses STAT1-GSK3-NFκB activation in middle cerebral artery occlusion (MCAo) rats. Then we demonstrate that TMP reverses M1/M2 phenotype via JAK2-STAT1/3 and GSK3-NFκB pathways in lipopolysaccharide (LPS) plus interferon-γ (IFN-γ)-stimulated BV2 microglia. Blocking JAK2 with AG490 counteracts TMP's facilitation on M2 polarization of microglia. This study warrants the promising therapy for stroke with TMP treatment.

Keywords: Ischemic stroke; Microglia; Polarization; Remyelination; Tetramethylpyrazine.