Mechanism of Siponimod: Anti-Inflammatory and Neuroprotective Mode of Action

Abstract

Multiple sclerosis (MS) is a neuroinflammatory disorder of the central nervous system (CNS), and represents one of the main causes of disability in young adults. On the histopathological level, the disease is characterized by inflammatory demyelination and diffuse neurodegeneration. Although on the surface the development of new inflammatory CNS lesions in MS may appear consistent with a primary recruitment of peripheral immune cells, questions have been raised as to whether lymphocyte and/or monocyte invasion into the brain are really at the root of inflammatory lesion development. In this review article, we discuss a less appreciated inflammation-neurodegeneration interplay, that is: Neurodegeneration can trigger the formation of new, focal inflammatory lesions. We summarize old and recent findings suggesting that new inflammatory lesions develop at sites of focal or diffuse degenerative processes within the CNS. Such a concept is discussed in the context of the EXPAND trial, showing that siponimod exerts anti-inflammatory and neuroprotective activities in secondary progressive MS patients. The verification or rejection of such a concept is vital for the development of new therapeutic strategies for progressive MS.

COVID-19 pandemic and the risk of infection in multiple sclerosis patients on disease modifying therapies: “what the bleep do we know?”

“…Rituximab Selectively targets the B lymphocytes that express the CD20 antigen triggers cell death [13] Significant risk Siponimod Inhibits the migration of the lymphocytes to the location of the inflammation by binding to sphingosine-1-phosphate receptor [14] Could pose a significant risk Ofatumumab Antibody to anti-CD20 that inhibits early-stage B lymphocyte activation (https://www.centerwatch.com/directories/1067-fdaapproved-drugs/listing/3172-arzerra-ofatumumab)]…”

Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis

“…Furthermore, CNS neurons and glia express S1PRs, S1P modulators are neuroprotective in various preclinical models (39,40), and siponimod is CNS penetrant (41). Although clear evidence for neuroprotective activity within MS patients has not yet been established, it was proposed that an S1PR-mediated reduction in glial activation may synergize with the peripheral immune modulation to prevent disease-associated inflammatory activity in the CNS (42). Notwithstanding these potential additional dimensions of the effects of siponimod, our study shows that siponimod reduces the inflammatory profile in the peripheral blood through enhancement of regulatory cell populations.…”

New possibilities for the therapy of secondary progressive multiple sclerosis

“…Несомненно, важным свойством сипонимода, помимо снижения количества циркулирующих лимфоцитов, является высокая аффинность к SIP-рецепторам 1-го и 5-го типов, которые встречаются на поверхности астроцитов, олигодендроцитов и микроглии, непросредственно участвующих в нейровоспалении в ЦНС и индуцирующих нейродегенерацию при РС. Возможно, что нейропротективное действие и соответствующее снижение скорости прогрессирования инвалидизации при приеме сипонимода связано с его центральными эффектами в отношении неиммунных механизмов прогрессирующих форм РС при модуляции SIP-рецепторов 5-го типа, которые расположены на глиальных клетках [27].…”