Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model

Frontiers in Molecular Neuroscience

Xinya Luo¹  Rong Chen²  Haodi Yang³  Wenxiu Luo³  Juming Yu³  Xing Cao³  Jiaming Luo⁴ 

[1] Department of Anesthesia, North Sichuan Medical College, Nanchong, China;Department of Microbiology and Immunology, North Sichuan Medical College, Nanchong, China;Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China;School of Psychiatry, North Sichuan Medical College, Nanchong, China;

关键词: multiple sclerosis;    experimental autoimmune encephalomyelitis;    dabigatran;    protease-activated receptors;    sphingosine-1-phosphate;    coagulation;   

DOI  :  10.3389/fnmol.2020.00114

来源: DOAJ

【 摘 要 】

Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS) that currently does not have any effective treatment. Experimental autoimmune encephalomyelitis (EAE) is often employed as a model to mimic the clinical manifestations of MS, mainly CNS demyelination. Coagulation is known to participate in crosstalk with inflammation and autoimmunity. We herein explored the correlation between the coagulation cascade and CNS immune diseases in vitro using primary astrocytes isolated from mice and in vivo using a mouse model of EAE. We showed that dabigatran, a clinical oral anti-coagulant drug, suppressed the thrombin-induced activation of astrocytes, and the underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs). Importantly, dabigatran effectively recovered neurological function, reduced inflammation in the spinal cord, and prevented spinal cord demyelination caused by EAE. We suggest that dabigatran, a specific inhibitor of thrombin, antagonized the effect of thrombin in astrocytes by limiting the activation of PAR-1, in turn downregulating SphK1 and disrupting S1P receptor signaling. These findings reveal critical information about the relationship between coagulation mechanisms and CNS immune diseases and will contribute to the clinical translation and development of therapeutic strategies against MS.

【 授权许可】

Unknown