Immunomodulation Eliminates Inflammation in the Hippocampus in Experimental Autoimmune Encephalomyelitis, but Does Not Ameliorate Anxiety-Like Behavior.

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.

Platelet Depletion is Effective in Ameliorating Anxiety-Like Behavior and Reducing the Pro-Inflammatory Environment in the Hippocampus in Murine Experimental Autoimmune Encephalomyelitis.

The neuropsychiatric symptoms of multiple sclerosis (MS), such as anxiety and depression, can result from disease activity itself as well as psychological reaction to an unfavorable diagnosis. Accordingly, the literature reports evidence of increased anxiety-like behavior in experimental autoimmune encephalomyelitis (EAE), an accepted MS model. Due to the recently described critical role of platelets in inflammation and autoimmune disease, we examined the relationship between platelets, inflammation, and anxiety-like behavior in EAE. In the elevated plus maze, EAE-induced C57BL/6J mice showed decreased time spent in the open arms relative to vehicle-only controls, demonstrating an increase in anxiety-like behavior. This effect occurred in the presence of platelet⁻neuron association, but absence of lymphocytic infiltration, in the hippocampal parenchyma. Platelet depletion at the pre-clinical disease stage, using antibody-mediated lysis prevented the EAE-induced increase in anxiety-like behavior, while no significant difference in distance moved was recorded. Furthermore, platelet depletion was also associated with reduction of the pro-inflammatory environment to control levels in the hippocampus and prevention of EAE disease symptomology. These studies demonstrate the high efficacy of a platelet-targeting approach in preventing anxiety-like symptoms and clinical manifestations of EAE and have implications for the treatment of neuropsychiatric symptoms in MS.

Differential anxiety-like responses in NOD/ShiLtJ and C57BL/6J mice following experimental autoimmune encephalomyelitis induction and oral gavage.

Oral gavage is commonly used in pre-clinical drug evaluation, but is potentially aversive and may induce behavioral effects independent of compounds under investigation. This study examined the combined effects of repeated oral gavage and disease induction on anxiety-like behavior in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. The C57BL/6J and NOD/ShiLtJ EAE variants were exposed to sham-EAE induction or untreated control conditions, and either daily oral gavage or home cage conditions. Anxiety-like behavior was subsequently assessed in the elevated plus maze. C57BL/6J mice exhibited increased anxiety-like behavior, relative to NOD/ShiLtJ mice, in response to repeated gavage, whereas sham-EAE induction and repeated gavage were associated with increased anxiety-like behavior in NOD/ShiLtJ mice. Thus, exposure to the induction procedure and repeated gavage differentially altered subsequent anxiety-like behavior in the two EAE variants. Future pre-clinical studies should rely on prior evaluation of parameters of the experimental design using sham-EAE mice. Additionally, less aversive administration routes should be utilized wherever possible to ensure that procedures do not distort effects of the therapeutic under investigation.

Multiple pathological mechanisms contribute to hippocampal damage in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

Emotional and cognitive deficits and associated hippocampal damage observed in multiple sclerosis (MS) are now recognized as primary disease manifestations. However, the pathological substrate of these dysfunctions is unclear. In the experimental autoimmune encephalomyelitis (EAE) MS model, impaired hippocampal-dependent functions are concomitant with severe microglial reactivity and neurodegeneration, but reports vary with respect to evidence of lymphocytic infiltration, raising questions as to the nature of the underlying neurodegenerative mechanisms. Our investigations of EAE-induced inflammation across the hippocampal formation showed CD3 infiltration only in regions adjacent to inflamed meningeal membranes interposed between the ventral aspect of the hippocampus and the dorsal aspect of the mid-brain, but widespread microglial reactivity across the structure. Regions that contact the lateral ventricles do not show inflammation, but CD3 cells are observed in the adjacent ventricular space and choroid plexus, suggesting that microglial reactivity in these regions results from exposure to proinflammatory mediators released into the ventricles. These data indicate that multiple pathophysiological mechanisms underlie hippocampal damage during EAE. Treatment with the immunomodulator FTY720 eliminates microglial reactivity across the whole structure, suggesting potential benefit for neuropsychological symptoms in MS.

Health Equity Talk: Understandings of Health Equity among Health Leaders.

INTRODUCTION: Reducing health inequities is a stated goal of health systems worldwide. There is widespread commitment to health equity among public health leaders and calls for reorientation of health systems towards health equity. As part of the Equity Lens in Public Health (ELPH) program of research, public health decision makers and researchers in British Columbia collaborated to study the application of a health equity lens in a time of health system renewal. We drew on intersectionality, complexity and critical social justice theories to understand how participants construct health equity and apply a health equity lens as part of public health renewal. METHODS: 15 focus groups and 16 individual semi-structured qualitative interviews were conducted with 55 health system leaders. Data were analyzed using constant comparative analysis to explore how health equity was constructed in relation to understandings and actions. RESULTS: Four main themes were identified in terms of how health care leaders construct health equity and actions to reduce health inequities: (1) population health, (2) determinants of health, and (3) accessibility and (4) challenges of health equity talk. The first three aspects of health equity talk reflect different understandings of health equity rooted in vulnerability (individual versus structural), determinants of health (material versus social determinants), and appropriate health system responses (targeted versus universal responses). Participants identified that talking about health equity in the health care system, either inside or outside of public health, is a 'challenging conversation' because health equity is understood in diverse ways and there is little guidance available to apply a health equity lens. CONCLUSIONS: These findings reflect the importance of creating a shared understanding of health equity within public health systems, and providing guidance and clarity as to the meaning and application of a health equity lens. A health equity lens for public health should capture both the production and distribution of health inequities and link to social justice to inform action.

Modelling MS: Chronic-Relapsing EAE in the NOD/Lt Mouse Strain.

Modelling complex disorders presents considerable challenges, and multiple sclerosis (MS) is no exception to this rule. The aetiology of MS is unknown, and its pathophysiology is poorly understood. Moreover, the last two decades have witnessed a dramatic revision of the long-held view of MS as an inflammatory demyelinating white matter disease. Instead, it is now regarded as a global central nervous system (CNS) disorder with a neurodegenerative component. Currently, there is no animal model recapitulating MS immunopathogenesis. Available models are based on autoimmune-mediated demyelination, denoted experimental autoimmune encephalomyelitis (EAE) or virally or chemically induced demyelination. Of these, the EAE model has been the most commonly used. It has been extensively improved since its first description and now exists as a number of variants, including genetically modified and humanized versions. Nonetheless, EAE is a distinct disease, and each variant models only certain facets of MS. Whilst the search for more refined MS models must continue, it is important to further explore where mechanisms underlying EAE provide proof-of-principle for those driving MS pathogenesis. EAE variants generated with the myelin component myelin oligodendrocyte glycoprotein (MOG) have emerged as the preferred ones, because in this particular variant disease is associated with both T- and B-cell effector mechanisms, together with demyelination. MOG-induced EAE in the non-obese diabetic (NOD) mouse strain exhibits a chronic-relapsing EAE clinical profile and high disease incidence. We describe the generation of this variant, its contribution to the understanding of MS immune and pathogenetic mechanisms and potential for evaluation of candidate therapies.