Fingolimod: Direct CNS Effects of Sphingosine 1-Phosphate (S1P) Receptor Modulation and Implications in Multiple Sclerosis Therapy
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Journal of the Neurological Sciences 328 (2013) 9–18 Contents lists available at SciVerse ScienceDirect Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns Fingolimod: Direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy Aran Groves, Yasuyuki Kihara, Jerold Chun ⁎ The Scripps Research Institute, Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, 10550 N. Torrey Pines Rd, DNC-118, La Jolla, CA 92037, USA article info abstract Article history: Fingolimod is the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis Received 19 October 2012 (MS). Following phosphorylation in vivo, the active agent, fingolimod phosphate (fingolimod-P), acts as a Received in revised form 14 February 2013 sphingosine 1-phosphate (S1P) receptor modulator, binding with high affinity to four of the five known Accepted 15 February 2013 S1P receptors (S1P , S1P , S1P and S1P ). The mechanism of action of fingolimod in MS has primarily Available online 19 March 2013 1 3 4 5 been considered as immunomodulatory, whereby fingolimod-P modulates S1P1 on lymphocytes, selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous Keywords: fi S1P system (CNS). However, emerging evidence indicates that ngolimod has direct effects in the CNS in MS. For Fingolimod example, in the MS animal model of experimental autoimmune encephalomyelitis (EAE), fingolimod is highly Experimental autoimmune encephalitis efficacious in both a prophylactic and therapeutic setting, yet becomes ineffective in animals selectively defi- Multiple sclerosis cient for S1P1 on astrocytes, despite maintained normal immunologic receptor expression and functions, and Neuroprotection S1P-mediated immune activities. Here we review S1P signaling effects relevant to MS in neural cell types Sphingosine 1-phosphate receptor modulator expressing S1P receptors, including astrocytes, oligodendrocytes, neurons, microglia and dendritic cells. The Lysophospholipids direct effects of fingolimod on these CNS cells observed in preclinical studies are discussed in view of the func- tional consequences of reducing neurodegenerative processes and promoting myelin preservation and repair. The therapeutic implications of S1P modulation in the CNS are considered in terms of the clinical outcomes of MS, such as reducing MS-related brain atrophy, and other CNS disorders. Additionally, we briefly outline other existing and investigational MS therapies that may also have effects in the CNS. © 2013 Elsevier B.V. All rights reserved. Contents 1. Introduction ............................................................... 10 2. S1P signaling in MS ........................................................... 11 3. S1P signaling in CNS cells and effects of fingolimod ............................................ 11 3.1. Astrocytes ............................................................ 11 3.2. Oligodendrocytes ......................................................... 11 3.3. Neurons ............................................................. 12 3.4. Microglia ............................................................. 12 3.5. Dendritic cells .......................................................... 12 3.6. Functional effects of S1P signaling and fingolimod .......................................... 12 3.6.1. Blood–brain barrier .................................................... 12 4. Preservation of CNS tissue integrity and functional recovery in animal models and organotypic cultures .................... 13 5. Clinical effects of S1P signaling altered by fingolimod in the CNS ...................................... 14 6. Other current or potential MS therapies .................................................. 14 7. Conclusions ............................................................... 15 Conflict of interest .............................................................. 15 Acknowledgments .............................................................. 15 References .................................................................. 15 ⁎ Corresponding author. Tel.: +1 858 784 8410. E-mail addresses: [email protected] (A. Groves), [email protected] (Y. Kihara), [email protected] (J. Chun). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.02.011 10 A. Groves et al. / Journal of the Neurological Sciences 328 (2013) 9–18 1. Introduction survival and cell death [10,16–36]. Neurological disorders may also be impacted by LPA receptor signaling, as reported for neuropathic pain Sphingosine 1-phosphate (S1P), a naturally occurring lipid mediator [30,37],hypoxicinsults[38] and hydrocephalus [39]. Evidence has fur- and part of the larger family of lysophospholipids, can act as a regulator ther highlighted S1P receptors as a potential target for the treatment of of diverse physiological and pathophysiological processes, including pain [40] and stroke via neuroprotection [41]. Furthermore, S1P recep- those involved in the pathogenesis of multiple sclerosis (MS) [1–3].S1P tor modulation has been shown to decrease vascular permeability and is produced from sphingolipids present in the cell membrane, which are astrocyte accumulation in spinal cord injury [42]. in part defined by the constituent presence of the amino alcohol sphin- These examples underscore the likelihood that S1P signaling, as gosine. A prominent sphingolipid is sphingomyelin, from which sphin- part of the larger field of lysophospholipid signaling, will have func- gosine is liberated through a series of reactions catalyzed by metabolic tions through direct CNS activities as is known to occur for the signal- enzymes, including sphingomyelinase and ceramidase [4,5]. Sphingo- ing activities of LPA. sine can then be phosphorylated to produce S1P by sphingosine kinase Fig. 1 provides a composite picture of S1P receptor gene expres- 1 (SphK1) or 2 (SphK2). Both of these enzymes have fairly broad tissue sion reported in the literature for neurons and glia [8,43,44]. Binding distribution, with SphK1 predominating in the lungs and spleen, and of S1P to each of the S1P receptor subtypes activates a range of different SphK2 predominating in the heart, brain and liver [6,7]. Extracellular intracellular signaling pathways mediated by distinct heterotrimeric G S1P acts in both autocrine and paracrine fashions by binding to five proteins [3,45–49]. Fingolimod (FTY720; GILENYA™, Novartis Pharma cell-surface S1P receptor subtypes named S1P1, S1P2, S1P3,S1P4, and AG, Basel, Switzerland) is a modulator of S1P receptors and is the first S1P5 [8], which belong to the G protein-coupled receptor (GPCR) super oral disease-modifying therapy to be approved for relapsing forms of family [3,9].S1P1,S1P2 and S1P3 show broad tissue gene expression, MS. Fingolimod is phosphorylated in vivo by sphingosine kinase, partic- while S1P4 shows gene expression primarily in immune system cells, ularly SphK2, to produce the active metabolite fingolimod phosphate and S1P5 is primarily expressed in the spleen (on natural killer cells and (fingolimod-P). Fingolimod and fingolimod-P are structural analogs of other lymphocytes) and central nervous system (CNS; mainly on oligo- sphingosine and S1P, respectively. Being a structural analog of S1P en- dendrocytes) [3]. These receptors can, therefore,functioninmultiple ables fingolimod-P to bind to and activate four of the five S1P receptor organ systems, such as the immune, cardiovascular, and respiratory sys- subtypes. Receptor studies have shown that fingolimod-P activates tems, as well as in the CNS. Precedence for CNS functions of S1P receptors S1P1,S1P4,S1P5 (half maximal effective concentration [EC50] values of can be seen through their relationships to known activities of the close- ~0.3–0.6 nM) and S1P3 (EC50 values of ~3 nM), but has shown essen- ly related lysophospholipid receptors for lysophosphatidic acid (LPA). tially no activity at S1P2 (EC50 values of >10 μM) [50,51]. The first lysophospholipid receptor, now known as LPA1,wasidentified Modulation of S1P1 on lymphocytes by fingolimod is thought to through studies of the CNS [10]. This led to the deorphanization of retain circulating pathogenic lymphocytes in the lymph nodes, there- homologous putative receptors in genomic databases resulting in the by preventing their infiltration into the CNS where they would pro- discovery of new receptors for LPA and S1P that shared homology de- mote pathological damage [52–54]. Fingolimod-P initially acts as an spite recognizing distinct ligands [11–13]. Indeed, early studies identified S1P1 agonist [50,51]; however, chronic exposure to fingolimod-P the S1P receptor known as S1P1, which plays a key role in the actions of leads to irreversible receptor internalization resulting in ‘functional fingolimod, as a receptor for LPA [14,15]. The neurobiological effects antagonism’ of S1P1-mediated S1P signaling [55–57]. Circulating T of LPA receptors have a remarkable range of activities that affect most cells express S1P1 and lower levels of S1P4 and S1P3 [56,58], and the CNS cell types at some time during their developmental history, cover- interaction of extracellular S1P with S1P1 is thought to initiate lym- ing the gamut of processes from neurogenesis and differentiation to phocyte egress from lymph nodes by overcoming retention signals Astrocyte • S1P1, S1P2, S1P3 and S1P5 • Proliferation, migration, gap junction