Molecular and neuroimmune pharmacology of S1P receptor modulators and other disease-modifying therapies for multiple sclerosis

by Selleckchem | Jul 07 2023

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.

Comments:

Multiple sclerosis (MS) is a complex neurological disease characterized by immune-mediated damage to the myelin sheath, the protective covering of nerve fibers in the central nervous system (CNS). The exact cause of MS is not yet fully understood, but it is believed to involve a combination of environmental, infectious, and genetic factors. Despite the lack of a definitive cause, significant progress has been made in the development of disease-modifying therapies (DMTs) for MS.

Various DMTs have been approved for the treatment of MS, and they primarily target immunomodulation as their mechanism of action. These therapies aim to modulate the immune system to reduce the frequency and severity of relapses and slow down the progression of disability. Some of the commonly used DMTs include interferons, glatiramer acetate, fumarates, cladribine, teriflunomide, fingolimod, siponimod, ozanimod, ponesimod, and monoclonal antibodies targeting proteins such as ITGA4, CD20, and CD52.

While the primary mode of action of these DMTs is immunomodulation, some of them, especially the sphingosine 1-phosphate receptor (S1PR) modulators, have been found to have direct effects on the CNS. Fingolimod, in particular, has been extensively studied for its neuropharmacological effects. Fingolimod acts as an agonist for S1PRs, which are widely expressed in the CNS, including on astrocytes, a type of glial cell.

Astrocytes play crucial roles in maintaining the health and function of neurons in the CNS. Fingolimod has been shown to directly affect astrocyte function, leading to various neuroprotective effects. It can reduce the production of pro-inflammatory molecules and enhance the production of neurotrophic factors, which promote the survival and growth of neurons. Fingolimod's effects on astrocytes also involve modulating calcium signaling, which is important for neuronal communication.

Additionally, fingolimod has been found to impact other cell types in the CNS, including neurons, microglia, and oligodendrocytes. It can influence neuronal excitability, regulate microglial activation and migration, and promote remyelination by enhancing the differentiation of oligodendrocyte precursor cells.

The ability of fingolimod and other S1PR modulators to target both the immune system and the CNS suggests a potential dual mechanism of action. By reducing immune cell infiltration into the CNS, these drugs can limit the inflammatory damage to myelin. Simultaneously, their effects on CNS cells, particularly astrocytes, may contribute to neuroprotection and repair processes, potentially mitigating neurodegenerative aspects of the disease.

In summary, the approved DMTs for MS primarily target immunomodulation, but some, such as fingolimod, have additional effects on the CNS. Fingolimod's ability to modulate astrocyte function and impact multiple cell types in the CNS highlights its potential to reduce neurodegenerative sequelae associated with MS. Further research into the molecular pharmacology and neuropharmacology of S1PR modulators, including their effects on different cell types in the CNS, may provide valuable insights for the development of future therapies for MS.