PMID- 32424774
OWN - NLM
STAT- MEDLINE
DCOM- 20211006
LR  - 20240226
IS  - 1573-6830 (Electronic)
IS  - 0272-4340 (Linking)
VI  - 41
IP  - 4
DP  - 2021 May
TI  - Tetramethylpyrazine Protects Blood-Spinal Cord Barrier Integrity by Modulating 
      Microglia Polarization Through Activation of STAT3/SOCS3 and Inhibition of NF-small ka, CyrillicB 
      Signaling Pathways in Experimental Autoimmune Encephalomyelitis Mice.
PG  - 717-731
LID - 10.1007/s10571-020-00878-3 [doi]
AB  - We previously reported that tetramethylpyrazine (TMP) alleviates experimental 
      autoimmune encephalomyelitis (EAE) by decreasing glia activation. Activated 
      microglia has been shown to mediate blood-spinal cord barrier (BSCB) disruption, 
      which is a primary and continuous pathological characteristic of multiple 
      sclerosis (MS). Therefore, in this study, we further investigated whether TMP 
      protects the BSCB integrity by inhibition of glia activation to alleviate EAE. 
      Extravasation of evans blue was used to detect the BSCB disruption. Tumor 
      necrosis factor-alpha (TNF-alpha)/interlukine-1beta (IL-1beta) and interlukine-4 
      (IL-4)/interlukine-10 (IL-10) were determined by enzyme-linked immunosorbent 
      assay. BV2 glial cells stimulated by interferon-gamma (IFN-gamma) were co-cultured with 
      human brain microvascular endothelial cells to investigate the effect of TMP on 
      the BSCB disruption. Flow cytometry was used to analyze the microglia phenotype. 
      Western blot was performed to reveal the signaling pathways involved in the 
      microglia activation. In this study, most importantly, we found that TMP protects 
      the BSCB integrity by modulating microglia polarization from M1 phenotype to M2 
      phenotype through activation of STAT3/SOCS3 and inhibition of NF-small ka, CyrillicB signaling 
      pathways. Moreover, TMP significantly preserves the tight junction proteins, 
      reduces the secretion of pro-inflammatory cytokines (TNF-alpha, IL-1beta) and increases 
      the secretion of anti-inflammatory cytokines (IL-4, IL-10) from IFN-gamma-stimulated 
      BV2 microglia cells. Consequently, protection of the BSCB integrity leads to 
      alleviation of clinical symptoms and demyelination in EAE mice. Therefore, TMP 
      might be an effective therapeutic agent for cerebral disorders with BBB or BSCB 
      disruption, such as ischemic stroke, MS, and traumatic brain injury.
FAU - Zhang, Lianshuang
AU  - Zhang L
AD  - Department of Histology and Embryology, Binzhou Medical University, Yantai, 
      264003, People's Republic of China.
FAU - Lu, Xueyan
AU  - Lu X
AD  - Department of Histology and Embryology, Binzhou Medical University, Yantai, 
      264003, People's Republic of China.
FAU - Gong, Lihua
AU  - Gong L
AD  - Department of Histology and Embryology, Binzhou Medical University, Yantai, 
      264003, People's Republic of China.
FAU - Cui, Linlu
AU  - Cui L
AD  - Department of Histology and Embryology, Binzhou Medical University, Yantai, 
      264003, People's Republic of China.
FAU - Zhang, Hongqin
AU  - Zhang H
AD  - Department of Histology and Embryology, Binzhou Medical University, Yantai, 
      264003, People's Republic of China.
FAU - Zhao, Wei
AU  - Zhao W
AD  - Department of Histology and Embryology, Binzhou Medical University, Yantai, 
      264003, People's Republic of China.
FAU - Jiang, Pengyu
AU  - Jiang P
AD  - Department of Histology and Embryology, Binzhou Medical University, Yantai, 
      264003, People's Republic of China.
FAU - Hou, GuiGe
AU  - Hou G
AD  - The Key Laboratory of Prescription Effect and Clinical Evaluation of State 
      Administration of Traditional Chinese Medicine of China, Binzhou Medical 
      University, Yantai, 264003, People's Republic of China. guigehou@163.com.
FAU - Hou, Yun
AU  - Hou Y
AUID- ORCID: 0000-0001-8440-8035
AD  - Department of Histology and Embryology, Binzhou Medical University, Yantai, 
      264003, People's Republic of China. houyun820424@163.com.
LA  - eng
GR  - 81601049/The National Natural Science Foundation of China/
GR  - 21402010/The National Natural Science Foundation of China/
GR  - ZR2019MB032/Nature Science Foundation of Shandong Province/
GR  - 2018GSF118129/Key Research and Development Program of Shandong Province/
PT  - Journal Article
DEP - 20200518
PL  - United States
TA  - Cell Mol Neurobiol
JT  - Cellular and molecular neurobiology
JID - 8200709
RN  - 0 (Cytokines)
RN  - 0 (NF-kappa B)
RN  - 0 (Pyrazines)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Socs3 protein, mouse)
RN  - 0 (Suppressor of Cytokine Signaling 3 Protein)
RN  - 82115-62-6 (Interferon-gamma)
RN  - V80F4IA5XG (tetramethylpyrazine)
SB  - IM
MH  - Animals
MH  - Brain/blood supply
MH  - *Cell Polarity/drug effects
MH  - Cytokines/metabolism
MH  - Encephalomyelitis, Autoimmune, Experimental/blood/*metabolism/pathology
MH  - Endothelial Cells/metabolism
MH  - Female
MH  - Humans
MH  - Inflammation/pathology
MH  - Interferon-gamma/pharmacology
MH  - Mice, Inbred C57BL
MH  - Microglia/drug effects/metabolism/*pathology
MH  - Microvessels/pathology
MH  - NF-kappa B/*metabolism
MH  - Neuroprotection/drug effects
MH  - Phenotype
MH  - Pyrazines/*pharmacology
MH  - STAT3 Transcription Factor/*metabolism
MH  - Signal Transduction/drug effects
MH  - Spinal Cord/drug effects/*pathology
MH  - Suppressor of Cytokine Signaling 3 Protein/*metabolism
MH  - Mice
OTO - NOTNLM
OT  - Blood-spinal cord barrier
OT  - Experimental autoimmune encephalomyelitis
OT  - Microglia activation
OT  - Multiple sclerosis
OT  - Tetramethylpyrazine
OT  - Tight junctions
EDAT- 2020/05/20 06:00
MHDA- 2021/10/07 06:00
CRDT- 2020/05/20 06:00
PHST- 2020/02/05 00:00 [received]
PHST- 2020/05/12 00:00 [accepted]
PHST- 2020/05/20 06:00 [pubmed]
PHST- 2021/10/07 06:00 [medline]
PHST- 2020/05/20 06:00 [entrez]
AID - 10.1007/s10571-020-00878-3 [pii]
AID - 10.1007/s10571-020-00878-3 [doi]
PST - ppublish
SO  - Cell Mol Neurobiol. 2021 May;41(4):717-731. doi: 10.1007/s10571-020-00878-3. Epub 
      2020 May 18.