Elsevier

Brain Research Bulletin

Volume 74, Issue 5, 19 October 2007, Pages 307-316
Brain Research Bulletin

Research report
FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis

https://doi.org/10.1016/j.brainresbull.2007.06.023Get rights and content

Abstract

FTY720 (fingolimod) is an oral sphingosine 1-phosphate (S1P) receptor modulator under development for the treatment of multiple sclerosis (MS). To elucidate its effects in the central nervous system (CNS), we compared functional parameters of nerve conductance in the DA rat model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) after preventive and therapeutic treatment. We demonstrate that prophylactic therapy protected against the emergence of EAE symptoms, neuropathology, and disturbances to visual and somatosensory evoked potentials (VEP, SEP). Moreover, therapeutic treatment from day 25 to 45 markedly reversed paralysis in established EAE and normalized the electrophysiological responses, correlating with decreased demyelination in the brain and spinal cord. The effectiveness of FTY720 in this model is likely due to several contributing factors. Evidence thus far supports its role in the reduction of inflammation and preservation of blood-brain-barrier integrity. FTY720 may also act via S1P receptors in glial cells to promote endogenous repair mechanisms that complement its immunomodulatory action.

Introduction

Classical concepts of multiple sclerosis (MS) view relapses as the clinical expression of acute inflammatory demyelination, whereas progression reflects neurodegenerative aspects involving chronic demyelination, gliosis, and axonal loss [16]. Emerging evidence suggest that these pathogenic processes must not occur sequentially but rather can proceed simultaneously, based on the detection of cortical atrophy early in disease and axon transection in inflammatory lesions [9], [30]. Furthermore, neuropathology does not support the concept that neurodegenerative components develop independently from inflammation, yet the nature of the inflammatory response does differ between the acute and progressive stages of MS [32]. Brain, spinal cord and optic tract nerves in the central nervous system (CNS) are all vulnerable to demyelination, resulting in conduction deficits that reflect overt functional loss or underlying disease in clinically silent lesions. Impaired nerve impulses can be quantified by the amplitude and latency of evoked potential (EP) responses to sensory stimuli [3]. Visual evoked potential (VEP) analyses, for example, suggest that delayed latency is more indicative of focal demyelination in the optic nerve, whereas a decrease in amplitude indicates the extent of axonal damage [12], [54]. Changes in electrophysiological parameters and disability measures in MS patients underscore the potential of multimodal EP in monitoring disease evolution, as well as surrogate end points in clinical trials [33]. Investigations of experimental autoimmune encephalomyelitis (EAE), the primary model for MS, have likewise helped to elucidate the pathogenic events involving demyelination and axonal loss, especially applying electrophysiology techniques coupled with clinical evaluation and histopathology.

FTY720 (fingolimod) is an oral sphingosine 1-phosphate (S1P) receptor modulator that is highly effective in EAE [7], [17], [27], [44], [57] and is currently in Phase 3 development for MS [26]. The in vivo efficacy of FTY720 is mainly reliant on its phosphate ester metabolite (FTY720-P), which acts as a high-affinity ligand for the G-protein-coupled receptors S1P1 and S1P3–5[7], [35]. The signature feature of FTY720 is a reduction in blood lymphocyte counts as a consequence of S1P1-mediated retention in the peripheral lymph nodes [8], [37], thereby preventing the migration of autoreactive T cells into sites such as the CNS [21]. On the other hand, its mode of action in MS and EAE may be related to additional, direct effects in the CNS since FTY720 and FTY720-P are both present in the brain (C.A.F. and Andreas Billich, submitted for publication), which contains glial cells that express S1P receptors and respond to FTY720-P [23], [25].

Starting FTY720 treatment at the time of EAE immunization or at the peak of established disease prevents further development of neurological deficits [7], [17], [27], [44], [57]. However, less is known about the disease-modifying potential of FTY720 during later phases of ongoing neurodegeneration. Because visual and sensory abnormalities are common manifestations of MS, our aim was to evaluate EP responses of the somatosensory and optic pathways in the Dark Agouti (DA) rat model of EAE following immunization with myelin oligodendrocyte glycoprotein (MOG). We demonstrate for the first time that FTY720 can prevent electrophysiological disturbances and restore nerve conductance patterns in an established demyelinating disease which shows striking similarities to MS.

Section snippets

Animals and antigens

Female DA/OlaHsd rats from Harlan Winkelmann (Borchen, Germany) were used at 8–10 weeks of age and kept under standardized light- and climate-controlled conditions with free access to food and water. All procedures were approved by the Austrian health authorities in compliance with international animal welfare standards according to the European Communities Council Directive and the guidelines set forth in the NIH Guide for the Care and Use of Laboratory Animals.

Recombinant rat MOG,

Results

DA rats given a single injection of MOG develop an ascending and chronic paralytic disease beginning 8–12 days post-immunization, accompanied by weight loss. The kinetics and severity of MOG-induced EAE are known to be dependent on the rat MHC haplotype and immunization protocol [50], [58]. In agreement with such reports, our studies showed that higher concentrations of MOG invoked a sustained and often fatal disease course while lower protein levels induced a more protracted or relapsing EAE

Discussion

To more efficiently manage progressive disability in MS patients, it will be necessary to identify therapeutic strategies that prevent and curtail ongoing pathogenesis as well as repair the residual damage that has already occurred. While considerable progress has been made with the former through the development of anti-inflammatory and immunomodulatory agents, there are currently no effective repair therapies that are routinely used in MS patients [13], [34]. Various MOG-EAE studies have

Acknowledgements

We thank Hans Lassmann for reviewing this manuscript, Chris Linington for kindly providing the MOG plasmid, Marijke Nefzger for statistical consultation, Sam C. Wilkerson III for IT assistance, and Franz Hammerschmid for protein analysis. All experiments were supported by Novartis Pharma AG.

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