神经炎症
神经保护
小胶质细胞
药理学
组蛋白脱乙酰基酶
星形胶质细胞
化学
中枢神经系统
炎症
医学
神经科学
免疫学
生物
组蛋白
生物化学
基因
作者
Akihiro Ogasawara,Hideyuki Takeuchi,Hiroyasu Komiya,Yuki Ogawa,Koki Nishimura,S. Kubota,Shunta Hashiguchi,Keita Takahashi,Misako Kunii,Kenichi Tanaka,Mikiko Tada,Hiroshi Doi,Fumiaki Tanaka
标识
DOI:10.1016/j.neures.2022.08.003
摘要
Siponimod, which is approved to treat active secondary progressive multiple sclerosis, acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P1) and an agonist of S1P5. S1P1 antagonization, which inhibits lymphocyte egress from lymphoid tissues and subsequent infiltration into the central nervous system (CNS), is considered the main therapeutic mechanism of siponimod. In addition, siponimod's direct effects on CNS glial cells are another potential neuroprotective mechanism because siponimod can penetrate the blood-brain barrier and CNS glial cells express S1P receptors. However, it remains uncertain whether siponimod directly affects CNS glial cells. In this study, we investigated siponimod's effects on astrocytes using mouse primary cultures. Siponimod suppressed nuclear factor kappa B activation and pro-inflammatory cytokine production. Using antagonists for S1P1 and S1P5, we found that siponimod partially exerts its anti-inflammatory effects via S1P1, but not via S1P5. Moreover, siponimod also inhibited histone deacetylase, suggesting that siponimod exerts broad anti-inflammatory effects via S1P1 antagonization and histone deacetylase inhibition. Siponimod might suppress disease progression in multiple sclerosis in part via direct inhibition of astroglial CNS neuroinflammation.
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