Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates a variety of physiological processes including lymphocyte recirculation and cardiac function. Most S1P effects are mediated via five G-protein-coupled S1P receptor subtypes referred to as S1P1–5 (originally termed EDG-1, 3, 5, 6, and 8)
[1][7]. These receptors are differentially expressed on various cell types, including lymphocytes
[2][3][8,9], cardiomyocytes
[4][5][10,11] and brain cells. In 2000, Kuppermann showed that S1P receptors regulate cell migration during vertebrate heart development
[6][12], and two years later a similar pro-migratory effect of S1P receptors was demonstrated for CD4
+ T cells
[7][13]. Two years after, in 2004, Matloubian for the first time showed that the egress of lymphocytes from the thymus and the peripheral lymphoid organs is dependent on S1P1
[8][14]. Due to these observations, the anti-inflammatory potency of S1P-receptor modulators have been intensively investigated.
The S1P-receptor modulator fingolimod, also called FTY720, induces a rapid and drastic deletion of T cells from the peripheral blood by inhibiting the egress of T cells from the thymus
[9][15] and lymph nodes. By this mechanism, fingolimod prevents the entry of lymphocytes into the blood, and thus T cell infiltration into the CNS
[10][11][12][16,17,18]. It has additionally been demonstrated that fingolimod can trigger lymphocyte apoptosis
[10][13][14][16,19,20]. Consequently, preclinical studies show that fingolimod ameliorates pathology in several models of autoimmune diseases, including type 1 diabetes
[15][21], adjuvant-induced arthritis
[16][22], systemic lupus erythematosus
[17][23] and, most importantly in the context of MS research, in different models of experimental autoimmune encephalomyelitis (EAE)
[18][19][24,25]. In a number of clinical trials, it has been shown that fingolimod is well tolerated and associated with low relapse rates and lesion activity in relapsing-remitting MS patients
[20][21][22][23][26,27,28,29]. Consequently, fingolimod was the first oral disease-modifying therapeutic agent to be approved for the treatment of MS. This pro-drug is rapidly converted in vivo into the active S-fingolimod-phosphate (FTY720-P) which is a potent agonist on S1P1, S1P3, S1P4 and S1P5 receptors. Since S1P-receptors are ubiquitinated and subsequently degraded when exposed to FTY720-P
[24][30], the experimental and clinical efficacy of FTY720-P is thought to involve functional antagonism by persistent internalization and enhanced degradation of the S1P-receptor. Of note, its efficacy in MS and related animal models may in part be due to additional, direct effects within the brain. For example, a strong increase in S1P1 and S1P3 expression on reactive astrocytes was detected in active and chronic inactive MS lesions
[25][31], whereas another study has suggested S1P5 expression in oligodendrocytes
[26][27][32,33].
In general, fingolimod has a favorable benefit-risk profile
[28][56]. However, a critical challenge of fingolimod therapy still remains in the initiation phases due to the risk of cardiac events. The first dose of fingolimod is associated with a decrease in heart rate and slowing of atrioventricular conduction
[22][23][29][28,29,57]. The discovery of the S1P3 receptor mediating bradycardia in mice
[30][58] prompted the search for S1P-receptor modulators devoid of S1P3 signaling. This effort led to the discovery of siponimod (also called BAF312), which is a selective modulator of S1P1 and S1P5 receptors. Siponimod was furthermore designed to have a relatively short elimination half-life that provides a rapid recovery of blood lymphocyte counts on stopping treatment, but would allow once-daily oral dosing
[31][59].