Possible regenerative effects of fingolimod (FTY720) in multiple sclerosis disease: An overview on remyelination process

Abstract

Fingolimod (FTY720) is a sphingosine 1‐phosphate (S1P) receptor analog, which has been approved as an oral immunomodulator for treating relapsing–remitting multiple sclerosis. This drug prevents lymphocyte egression from lymph nodes and reduces the infiltration of inflammatory mediators into the central nervous system. Based on its lipophilic nature, FTY720 passes through the blood–brain barrier and can directly affect neural cells. A notably different subtype of S1P receptors expresses in neural cells, which suggests FTY720 is a drug capable of affecting neural cells. Oligodendrocytes (OLs) are considered as the primary target cells in MS. Remyelination is a process including the proliferation of neural progenitors and oligodendrocyte precursor cells, their migration to the lesion site and their differentiation to mature oligodendrocytes. Experimental and clinical studies have described the impact of FTY720 on endogenous remyelination elements. In this review, we will explain the current clinical and experimental evidence that exists on the effects of FTY720 on remyelination and the underlying mechanisms.

Diffusion basis spectrum imaging measures anti-inflammatory and neuroprotective effects of fingolimod on murine optic neuritis

“…Following increased λ ⊥ (demyelination) in optic nerves of EAE mice with ON, we noted the subsequent reduction of DBSI λ ⊥ after 10 weeks of fingolimod but not placebo treatment, suggesting remyelination could have occurred in those mice treated with fingolimod. There is no direct histological data to validate in this study, but the profile of DBSI-derived λ ⊥ was consistent with other reports ( Yazdi et al, 2020 , Zhang et al, 2015 ).…”

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…Both the prominent S1P expression in neural cells [38], and its widespread effects on the proliferation, differentiation and the migration of neural cells [40] together with the fact that FTY720 is proven to be lipophilic and thus capable of crossing the BBB [41], make this drug an attractive treatment for diseases with neural pathology. The clear effect of FTY720 treatment on remyelination in the CNS has already been reviewed elsewhere [22,23]. In the next sections, we discuss the molecular effects of FTY720 specifically on microglia, astrocytes, neurons and oligodendrocytes (for details, see Supplementary Table S1; for article search terms, see Supplementary Information).…”

“…Molecular effects on cell types in the CNS have been reviewed for a number of FDA-approved MS drugs, such as Fingolimod (FTY720; Gilenya), Dimethyl Fumarate (DMF; Tecfidera), Glatiramer Acetate (GA; Copaxone), Interferon-beta (IFN-β; Rebif, Avonex, Betaseron, Extavia, Plegridy) and Teriflunomide (TF; Aubagio) [17][18][19][20][21][22][23][24][25][26][27][28]. The CNS-directed molecular effects of more recently approved drugs, such as Laquinimod (LQ; Nerventra), Natalizumab (NZ; Tysabri), Alemtuzumab (AZ; Lemtrada) and Orcelizumab (OCR; Ocrevus), have been less well described, except for the neuroprotective effects of LQ and NZ [29][30][31].…”

“…The CNS-directed molecular effects of more recently approved drugs, such as Laquinimod (LQ; Nerventra), Natalizumab (NZ; Tysabri), Alemtuzumab (AZ; Lemtrada) and Orcelizumab (OCR; Ocrevus), have been less well described, except for the neuroprotective effects of LQ and NZ [29][30][31]. In general, each of these previous studies has reported the (molecular) effects of only one or two MS drugs (e.g., [28,29,31]) on one or two CNS cell types (e.g., [22]). Moreover, the protective effects of MS drugs on neurons and oligodendrocytes have often been attributed to indirect effects caused by the actions of MS drugs on peripheral immune cells (e.g., [28]).…”

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

“…Fingolimod crosses the BBB and interacts with the sphingosine-1-phosphate (S1P) glial receptors in vivo. The preventive treatment with fingolimod was demonstrated to ameliorate remyelination in several models of MS including the EAE, but its direct effects on remyelination is still debated [30,31].…”