FTY720 Rescue Therapy in the Dark Agouti Rat Model of Experimental Autoimmune Encephalomyelitis: Expression of Central Nervous System Genes and Reversal of Blood‐Brain‐Barrier Damage

Abstract

FTY720 (fingolimod) is an oral sphingosine-1 phosphate (S1P) receptor modulator in phase III development for the treatment of multiple sclerosis. To further investigate its mode of action, we analyzed gene expression in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). FTY720 downregulated inflammatory genes in addition to vascular adhesion molecules. It decreased the matrix metalloproteinase gene MMP-9 and increased its counterregulator--tissue inhibitor of metalloproteinase, TIMP-1--resulting in a proteolytic balance that favors preservation of blood-brain-barrier (BBB) integrity. Furthermore, FTY720 reduced S1P lyase that increases the S1P concentration in the brain, in line with a marked reversal of neurological deficits and raising the possibility for enhanced triggering of S1P receptors on resident brain cells. This is accompanied by an increase in S1P(1) and S1P(5) in contrast with the attenuation of S1P(3) and S1P(4). Late-stage rescue therapy with FTY720, even up to 1 month after EAE onset, reversed BBB leakiness and reduced demyelination, along with normalization of neurologic function. Our results indicate rapid blockade of ongoing disease processes by FTY720, and structural restoration of the CNS parenchyma, which is likely caused by the inhibition of autoimmune T cell infiltration and direct modulation of microvascular and/or glial cells.

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

“…The selective adhesion molecule inhibitor Natalizumab, which binds integrin-α4 on endothelial cells and blocks the VCAM-1 driven transmigration of immune cells sensitized against myelin antigen from the vessel lumen to the neuropil across the BBB, precludes VEGF-induced angiogenesis [208,209]. Fingolimod (FTY720), an immunomodulator that acts on sphingosine 1-phosphate (S1P) receptors, is the first oral drug approved for the treatment of RR-MS. Downmodulation of S1P receptor type 1 (S1P1) prevents the release of lymphocytes from lymph nodes into the lymphatic vessels and vascular recirculation to the CNS, reduces astrogliosis, restores BBB function, and inhibits angiogenesis during chronic neuroinflammation, also via inhibiting PDGF-B-induced migration of vascular smooth muscle cells [210][211][212]. Alemtuzumab, recently licensed for the treatment of MS, is a humanized monoclonal antibody directed against CD52, a protein that is widely distributed on the surface of lymphocytes and monocytes and is also an anti-angiogenic molecule [213].…”

“…In a stroke model, exogenous VEGF administration increases neurogenesis of the SVZ, only after 28 days, without concomitant angiogenesis, demonstrating that a specific VEGF isoform could protect neurons independently of the endothelial cell influence [231]. In the EAE model, despite several reports of an improved clinical score after early VEGF inhibition, one study [232] demonstrated that pertussis toxin stimulated VEGF expression and that VEGF neuroprotection could Fingolimod Gilenya [210][211][212] Glatiramer acetate Copaxone [206,207] Interferon β-1a Avonex, Rebif [84,204,205] Interferon β-1b Betaferon, Extavia Mitoxantrone Novantrone [216] Natalizumab Tysabri [208,209] Teriflunomide Aubagio Only indirect evidence derived from antilymphocytes activity be responsible for milder disease. VEGF may have different effects in different cell types depending on different splice variants [233].…”

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

“…Indeed, animal studies using acute models of RRMS suggest that FTY720 modulates the activity of CNS-resident cell populations (28)(29)(30)(31). However, limited information is available on the effects of S1PR modulation on SPMS and its experimental models of CNS chronic inflammation and progressive neurodegeneration.…”

Metalloproteinases and their inhibitors as therapeutic targets for multiple sclerosis: current evidence and future perspectives

“…4,5 Several studies have shown that both anti-MS-specific therapies [6][7][8][9] and some antioxidant and anti-inflammatory compounds have the ability to downregulate MMPs, suggesting that inhibition of MMPs may represent an additional mechanism by which these agents decrease the development of new CNS lesions in the course of MS. [10][11][12] In this review, we summarize the general characteristics of the different MMPs and their regulatory mechanisms. The pathogenic role of MMPs in the development and progression …”

“…91 Only one study has investigated the effect of this drug on MMP production. In this study, to investigate the possible pathways by which FTY720 exerts its efficacy, Foster et al 8 analyzed a broad spectrum of inflammatory and immune-response genes in the CNS of EAE animals under FTY720 treatment. The authors demonstrated the ability of FTY720 to downregulate the MMP9 gene and upregulate TIMP-1 gene, resulting in a proteolytic balance that preserved the BBB integrity.…”