Abstract
Multiple sclerosis (MS) is an autoimmune disease targeting the central nervous system, characterized by an unpredictable disease course and a wide range of symptoms. Emotional and cognitive deficits are now recognized as primary disease manifestations and not simply the consequence of living with a chronic condition, raising questions regarding the efficacy of current therapeutics for these specific symptoms. Mechanisms underlying psychiatric sequelae in MS are believed to be similar to those underlying pathogenesis, that is mediated by cytokines and other inflammatory mediators. To gain insight into the pathogenesis of MS depression, we performed behavioral assays in the murine experimental autoimmune encephalomyelitis (EAE) MS model, in the presence or absence of immunomodulation using the drug FTY720, an analogue of the lipid signaling molecule sphingosine-1-phosphate (S1P). Specifically, mice were challenged with the elevated plus maze (EPM) test, a validated experimental paradigm for rodent-specific anxiety-like behavior. FTY720 treatment failed to ameliorate anxiety-like symptoms, irrespective of dosage. On the other hand, it was effective in reducing inflammatory infiltration, microglial reactivity and levels of pro-inflammatory molecules in the hippocampus, confirming the anti-inflammatory capacity of treatment. To explore the absence of FTY720 effect on behavior, we confirmed expression of S1P receptors (S1PR) S1PR1, S1PR3 and S1PR5 in the hippocampus and mapped the dynamics of these receptors in response to drug treatment alone, or in combination with EAE induction. We identified a complex pattern of responses, differing between (1) receptors, (2) dosage and (3) hippocampal sub-field. FTY720 treatment in the absence of EAE resulted in overall downregulation of S1PR1 and S1PR3, while S1PR5 exhibited a dose-dependent upregulation. EAE induction alone resulted in overall downregulation of all three receptors. On the other hand, combined FTY720 and EAE showed generally no effect on S1PR1 and S1PR3 expression except for the fimbrium region, but strong upregulation of S1PR5 over the range of doses examined. These data illustrate a hitherto undescribed complexity of S1PR response to FTY720 in the hippocampus, independent of drug effect on effector immune cells, but simultaneously emphasize the need to explore novel treatment strategies to specifically address mood disorders in MS.
Highlights
Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) of unknown cause, manifesting most commonly in young adults [1]
The human equivalent dose for FTY720 is 0.3mg/kg/day [19], but under experimental conditions in this study this dose resulted in incomplete restoration of lymphocyte counts to normal levels (Supplementary Figure 3)
No meningeal inflammatory cell accumulation was detected in both EAE+FTY720 treated groups (FTY720-L, Figures 1F, G, and FTY720-H, Figures 1I, J), nor were any lesions found within the hippocampus itself
Summary
Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) of unknown cause, manifesting most commonly in young adults [1]. It is characterized by a very complex pathophysiology, which underscores the unpredictable course of the disease and implicates a wide range of CNS regions, resulting in an array of symptoms [2]. The pathology of the hippocampus in EAE recapitulates that of MS, by exhibiting severe white matter lesions, but microglial reactivity in the absence of major lymphocytic infiltration in grey matter
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