Central nervous system-directed effects of FTY720 (fingolimod)

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Abstract

FTY720, also known as fingolimod, is an orally administered sphingosine-1-phosphate (S1P) analogue that is under investigation as a therapy for both relapsing–remitting (RR) and progressive forms of multiple sclerosis (MS). The demonstrated beneficial effect of FTY720 on disease activity in RR–MS patients and in the animal model experimental autoimmune encephalomyelitis (EAE) is largely attributed to effects on the systemic immune system. In addition, unlike other current systemic immuno-modulators used in MS, the lipophilic nature of FTY720 allows it to cross the blood-brain barrier (BBB). Since S1P receptors are expressed on all cell types, FTY720 has the potential to exert effects directly on the BBB and on resident cells of the CNS. The latter include cells implicated in regulating immune reactivity within the CNS (astrocytes, microglia), those that are targeted by the disease process (oligodendrocytes, neurons), and those involved in repair (oligodendrocyte progenitor cells). In vitro studies document the dose-dependent effects of FTY720 on neural cell survival, differentiation, and cytoskeletal dynamics. Animal model studies, specifically EAE, indicate an overall neuroprotective effect of FTY720 mediated at least in part by its actions within the CNS. Ongoing studies will need to define the direct and indirect (via immune-modulation) effects of FTY720 on the CNS across the broad clinical spectrum of MS.

Introduction

FTY720 (fingolimod) is a sphingosine-1-phosphate (S1P) analogue shown to reduce the frequency of clinical relapses and magnetic resonance (MR)-defined disease activity in multiple sclerosis (MS) patients [1]. These effects have mainly been attributed to the ability of FTY720 to restrict immune cell entry into the CNS via sequestration of T- and B-lymphocytes in secondary lymph nodes [2]. However, unlike other immuno-modulatory agents currently approved as therapies for relapsing forms of MS, FTY720 readily accesses the CNS by virtue of its lipophilicity [3]. S1P receptors are expressed on all cell types found within the CNS under physiologic and pathologic conditions [4]. This combination of drug entry into the brain parenchyma and presence of its receptors within this compartment highlights the importance of evaluating its effects on the CNS both via a direct neurobiological mechanism and an indirect mechanism consequent to its immuno-modulatory effects. Both the direct and indirect mechanisms could have significant impacts on the extent of tissue injury and repair that occur in MS. We will discuss ongoing in vitro and experimental model-based studies targeted at showing how the direct neurobiological and indirect immuno-modulatory actions of FTY720 can impact tissue injury and repair. Such studies should provide guidance on how to use and monitor this agent across the broad clinical spectrum of MS.

Section snippets

Pharmacology of S1P receptors, their endogenous ligand, and FTY720

There are 5 known S1P G protein coupled receptor isoforms that belong to the endothelial differentiation gene-related (EDG) receptor family. The endogenous ligand for the S1P receptors, S1P, is a bioactive lysosphingolipid present in the circulation in micromolar concentrations [5] and in the CNS. S1P is produced by cells of the innate immune system [6] and by endothelial cells, neurons, and astrocytes in the CNS [7], [8], [9], [10]. S1P can act in an autocrine or paracrine manner on immune and

Effects on FTY720 on the blood-brain barrier (BBB)

The BBB is composed of endothelial cells and serves as a tightly regulated semi-permeable barrier between the blood and underlying tissue. In MS, the disruption of the BBB likely contributes to entry of activated blood-derived lymphocytes, and resulting injury to the brain parenchyma [23]. Extensive studies have been conducted on the effects of S1P and FTY720 on an array of endothelial cells. Human-derived endothelial cells express high levels of S1P1 and S1P3 [24], and can also produce S1P

In vivo studies

Orally administered FTY720 readily accesses the CNS [3] where neural cells have endogenous sphingosine kinase activity to contribute to generating the active form of the drug [17], [29]. Levels of both the parent drug and active metabolite are found in higher concentrations in the brain parenchyma versus the blood in treated animals. While blood levels reach a plateau by 7 days of treatment, brain concentrations of FTY720 further increase between 7 and 13 days of treatment. After this, the

Effects of FTY720 in an animal model of MS (EAE)

Many studies have shown that FTY720 is highly effective in different EAE models, both prophylactically and therapeutically [65], [66], [67], [68], [69]. In both mouse and rat models, treatment with FTY720 is associated with a pronounced reduction in inflammatory infiltrates (T cells, B cells and macrophages), demyelination and axonal loss. A reduction of macrophage recruitment into the brain is also observed by MRI-based in vivo tracking using USPIOs [67]. This is paralleled by reduced levels

Conclusion

Together, the above outlined studies indicate the importance of S1P receptor signaling cascades in regulating neural cell functions. Fully understanding the net effect of FTY720 on the CNS is a daunting task given the complexity of S1P receptor-associated signaling and regulation, and the ubiquitous expression of these receptors on most cell types. The impact of FTY720 on neural cells in the MS brain will depend on the relative S1P receptor levels of a given cell type, modulation of these

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