The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

Abstract

The immunomodulator 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720) has promising therapeutic effects in multiple sclerosis (MS), a degenerative disease in which demyelination of the central nervous system is accompanied by death of oligodendrocytes (OLGs), the myelin-producing cells. In vivo phosphorylation of FTY720 generates an agonist for G protein-coupled receptors for sphingosine-1-phosphate, a lipid mediator that plays a crucial role in the stimulation of OLG survival by neurotrophin-3 (NT-3). The mechanisms underlying the action of FTY720 in MS are not clearly understood, although the effects of this drug in autoimmune diseases are thought to stem from its ability to reduce lymphocyte infiltration and inflammation. Interestingly, we now found that FTY720 also has a direct effect on OLG progenitors. Treatment of these cells with FTY720 causes activation of extracellular signal-regulated kinase 1/2 and Akt, accompanied by protection from apoptosis. However, FTY720 also arrested OLG differentiation. Importantly, this effect was counteracted by NT-3, which not only enhanced the survival of OLG progenitors induced by FTY720 but also stimulated their maturation. Altogether, these observations suggest that in addition to its immunosuppressive functions, FTY720 could also have a beneficial effect in MS by direct action on OLG progenitors. However, the finding that FTY720 blocks the differentiation of these cells raises the question of whether MS therapies with FTY720 should include the use of differentiation-enhancing factors such as NT-3. This approach would ensure both protection of existing OLG progenitor pools against immune-mediated insults as well as stimulation of remyelination by enhancing the maturation of these cells.Multiple sclerosis (MS) is a chronic degenerative and debilitating disease of the central nervous system (CNS) characterized by inflammation and demyelination (McQualter and Bernard, 2007). The pathological hallmarks of MS also include axonal degeneration (Trapp et al., 1999) and death of oligodendrocytes (OLGs) (Barnett and Prineas, 2004;Lucchinetti et al., 2004), the cells that make the myelin membrane in the CNS. Although the cause of MS remains unknown, the presence of serum antibodies against different myelin constituents and the existence of multiple inflammatory foci in brain and spinal cord support the idea of a predominant autoimmune component. For this reason, most therapeutic approaches involve the use of anti-inflammatory drugs and immunosuppressants.2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720, also known as Fingolimod), is among the latest immunomodulatory agents under evaluation for the treatment of MS. This synthetic drug was developed by chemical modification of ISP-I (myriocin), a sphingosine-like metabolite produced by the fungus Isaria sinclairii. FTY720 has been shown to prolong allograft survival in different animal models of transplantation (Chiba et al., 1996) and exert a protective effect in animal models of autoimmune diseases (Ma...

Activation of Sphingosine-1-Phosphate 1 Receptor in the Proximal Tubule Protects Against Ischemia-Reperfusion Injury

“…The S1P 1 R agonist FTY720 has been demonstrated to have direct cytoprotective effects in oligodendrocyte progenitor cells. 44 Treatment of these cells blocks apoptosis, an effect that is due to S1PR-induced activation of downstream ERK and Akt signaling pathways. 44 Activation of the Akt pathway is cytoprotective, whereas blocking this pathway leads to apoptosis.…”

“…44 Treatment of these cells blocks apoptosis, an effect that is due to S1PR-induced activation of downstream ERK and Akt signaling pathways. 44 Activation of the Akt pathway is cytoprotective, whereas blocking this pathway leads to apoptosis. Our results support these observations and demonstrate that Akt/ERK pathways are likely mediators of tissue protection after S1P 1 R activation.…”

“…FTY720-P-treated cultured oligodendrocyte progenitor cells are protected from apoptotic cell death through activation of mitogen-activated protein kinase/extracellular regulated kinase (MEK/ERK) and phosphatidylinositol-3-kinase (PI3K)/Akt signaling. 17 The downstream MEK/ERK and PI3K/Akt signaling pathways, which are activated by various GPCRs, have been implicated in promoting cell survival under various conditions along with pertussis toxinsensitive coupling of S1P 1 R activation. 18,19 We and others have demonstrated that selective activation of the S1P 1 Rs with S1P 1 R agonists reduces kidney IRI 20 -22 ; however, it is not known whether the tissue-protective effects of these S1P 1 R agonists are mediated by the canonical effect of S1P 1 R agonists to induce lymphopenia or by stimulating S1P 1 Rs on other target tissues or both.…”

Sphingosine 1-Phosphate Receptor-1 Enhances Mitochondrial Function and Reduces Cisplatin-Induced Tubule Injury

“…19 S1PR activation promotes cell survival. 20,21 In various disease models, FTY720 causes reversible redistribution of lymphocytes from the circulation to secondary lymph tissue leading to its anti-inflammatory and tissue-protective effects. 17,22 FTY720 protects kidneys from IRI through PT-S1P1 activation.…”

Remyelination Therapy for Multiple Sclerosis

“…Because S1P receptors are found on a variety of cell types, and fingolimod has been shown to readily cross the blood-brain-barrier, considerable research both in vitro and in vivo has assessed the outcome of this medication directly on cells in the CNS. In isolation, fingolimod protects OPC survival, but inhibits their differentiation, the latter of which can be counteracted with growth factors [68,69]. With longer treatment in culture, initial process retraction mediated through S1P 5 is overcome with process extension mediated through S1P 1 [70,71].…”