西尼莫德改善实验性自身免疫性神经炎。
Siponimod ameliorates experimental autoimmune neuritis.
机构信息
Division of Neurology, Department of Internal Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.
Department of Neurology, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro-Ku, Tokyo, 153-8515, Japan.
出版信息
J Neuroinflammation. 2023 Feb 14;20(1):35. doi: 10.1186/s12974-023-02706-z.
BACKGROUND
Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are human autoimmune peripheral neuropathy. Besides humoral immunity, cellular immunity is also believed to contribute to these pathologies, especially CIDP. Sphingosine-1-phosphate receptor 1 (S1PR1) regulates the maturation, migration, and trafficking of lymphocytes. As of date, the therapeutic effect of sphingosine-1-phosphate receptor (S1PR) agonists on patients with GBS or CIDP remains unclear.
METHODS
To evaluate the effect of siponimod, an agonist of S1PR1 and S1PR5, on experimental autoimmune neuritis (EAN), an animal model of autoimmune peripheral neuropathy, was used. Lewis rats were immunized with 125 μg of synthetic peptide from bovine P2 protein. Rats in the siponimod group were orally administered 1.0 mg/kg siponimod and those in the EAN group were administrated the vehicle on days 5-27 post-immunization (p.i.) daily. The symptom severity was recorded daily. The changes in the expression of cytokines and transcription factors in the lymph nodes and cauda equina (CE) which correlate with the pathogenesis of EAN and recovery of injured nerve were measured using reverse transcription quantitative PCR. Histological study of CE was also performed.
RESULTS
Flaccid paralysis developed on day 11 p.i. in both groups. Siponimod relieved the symptom severity and decreased the expression of interferon-gamma and IL-10 mRNAs in lymph nodes and CE compared with that in the EAN group. The expression of Jun proto-oncogene (c-Jun) mRNA increased from the peak to the recovery phase and that of Sonic hedgehog signaling molecule (Shh) and Glial cell line-derived neurotrophic factor (Gdnf) increased prior to increase in c-Jun with no difference observed between the two groups. Histologically, siponimod also reduced demyelinating lesions and inflammatory cell invasion in CE.
CONCLUSIONS
Siponimod has a potential to ameliorate EAN. Shh and Gdnf, as well as C-Jun played a significant role during the recovery of injured nerves.
背景
吉兰-巴雷综合征（GBS）和慢性炎症性脱髓鞘性多发性神经病（CIDP）是人类自身免疫性周围神经病。除了体液免疫外，细胞免疫也被认为与这些病理有关，尤其是 CIDP。鞘氨醇-1-磷酸受体 1（S1PR1）调节淋巴细胞的成熟、迁移和运输。迄今为止，鞘氨醇-1-磷酸受体（S1PR）激动剂对 GBS 或 CIDP 患者的治疗效果尚不清楚。
方法
使用实验性自身免疫性神经炎（EAN），即自身免疫性周围神经病的动物模型，评估 S1PR1 和 S1PR5 激动剂西尼莫德对其的影响。用 125μg 牛 P2 蛋白合成肽免疫 Lewis 大鼠。西尼莫德组大鼠在免疫后第 5-27 天（p.i.）每日口服 1.0mg/kg 西尼莫德，EAN 组大鼠给予载体。每天记录症状严重程度。采用逆转录定量 PCR 检测与 EAN 发病机制和受损神经恢复相关的淋巴结和马尾（CE）中细胞因子和转录因子的表达变化。还进行了 CE 的组织学研究。
结果
两组大鼠均于第 11 天 p.i.出现弛缓性瘫痪。与 EAN 组相比，西尼莫德缓解了症状严重程度，并降低了淋巴结和 CE 中干扰素-γ和 IL-10 mRNA 的表达。原癌基因 Jun（c-Jun）mRNA 的表达从峰值到恢复阶段增加，而 Sonic hedgehog 信号分子（Shh）和胶质细胞源性神经营养因子（Gdnf）的表达在 c-Jun 增加之前增加，两组之间无差异。组织学上，西尼莫德还减轻了 CE 中的脱髓鞘病变和炎症细胞浸润。
结论
西尼莫德有可能改善 EAN。Shh 和 Gdnf 以及 C-Jun 在受损神经的恢复中发挥了重要作用。
Zotero 插件