Sanford Burnham Prebys Medical Discovery Institute, United States of America.
Sanford Burnham Prebys Medical Discovery Institute, United States of America.
Pharmacol Ther. 2023 Jun;246:108432. doi: 10.1016/j.pharmthera.2023.108432. Epub 2023 May 4.
Multiple sclerosis (MS) is a neurological, immune-mediated demyelinating disease that affects people in the prime of life. Environmental, infectious, and genetic factors have been implicated in its etiology, although a definitive cause has yet to be determined. Nevertheless, multiple disease-modifying therapies (DMTs: including interferons, glatiramer acetate, fumarates, cladribine, teriflunomide, fingolimod, siponimod, ozanimod, ponesimod, and monoclonal antibodies targeting ITGA4, CD20, and CD52) have been developed and approved for the treatment of MS. All the DMTs approved to date target immunomodulation as their mechanism of action (MOA); however, the direct effects of some DMTs on the central nervous system (CNS), particularly sphingosine 1-phosphate (S1P) receptor (S1PR) modulators, implicate a parallel MOA that may also reduce neurodegenerative sequelae. This review summarizes the currently approved DMTs for the treatment of MS and provides details and recent advances in the molecular pharmacology, immunopharmacology, and neuropharmacology of S1PR modulators, with a special focus on the CNS-oriented, astrocyte-centric MOA of fingolimod.
多发性硬化症（MS）是一种影响青壮年人群的神经免疫介导性脱髓鞘疾病。尽管尚未确定确切的病因，但环境、感染和遗传因素都与该病的发病机制有关。然而，已经开发并批准了多种疾病修正疗法（DMTs：包括干扰素、那他珠单抗、富马酸二甲酯、克拉屈滨、特立氟胺、芬戈莫德、西尼莫德、奥扎尼莫德、派恩莫德和针对 ITGA4、CD20 和 CD52 的单克隆抗体）来治疗 MS。迄今为止，所有批准的 DMT 都将免疫调节作为其作用机制（MOA）；然而，一些 DMTs 对中枢神经系统（CNS）的直接影响，特别是鞘氨醇 1-磷酸（S1P）受体（S1PR）调节剂，暗示了一种可能也能减少神经退行性病变后果的平行 MOA。这篇综述总结了目前批准用于治疗 MS 的 DMTs，并详细介绍了 S1PR 调节剂的分子药理学、免疫药理学和神经药理学的最新进展，特别关注了芬戈莫德以 CNS 为导向、星形胶质细胞为中心的 MOA。
