The Antidepressant- and Anxiolytic-Like Effects of the Phosphodiesterase Type-5 Inhibitor Tadalafil are Associated with the Modulation of the Gut-Brain Axis During CNS Autoimmunity.

Multiple Sclerosis (MS) is a debilitating disease that severely affects the central nervous system (CNS). Apart from neurological symptoms, it is also characterized by neuropsychiatric comorbidities, such as anxiety and depression. Phosphodiesterase-5 inhibitors (PDE5Is) such as Sildenafil and Tadalafil have been shown to possess antidepressant-like effects, but the mechanisms underpinning such effects are not fully characterized. To address this question, we used the EAE model of MS, behavioral tests, immunofluorescence, immunohistochemistry, western blot, and 16 S rRNA sequencing. Here, we showed that depressive-like behavior in Experimental Autoimmune Encephalomyelitis (EAE) mice is due to neuroinflammation, reduced synaptic plasticity, dysfunction in glutamatergic neurotransmission, glucocorticoid receptor (GR) resistance, increased blood-brain barrier (BBB) permeability, and immune cell infiltration to the CNS, as well as inflammation, increased intestinal permeability, and immune cell infiltration in the distal colon. Furthermore, 16 S rRNA sequencing revealed that behavioral dysfunction in EAE mice is associated with changes in the gut microbiota, such as an increased abundance of Firmicutes and Saccharibacteria and a reduction in Proteobacteria, Parabacteroides, and Desulfovibrio. Moreover, we detected an increased abundance of Erysipelotrichaceae and Desulfovibrionaceae and a reduced abundance of Lactobacillus johnsonii. Surprisingly, we showed that Tadalafil likely exerts antidepressant-like effects by targeting all aforementioned disease aspects. In conclusion, our work demonstrated that anxiety- and depressive-like behavior in EAE is associated with a plethora of neuroimmune and gut microbiota-mediated mechanisms and that Tadalafil exerts antidepressant-like effects probably by targeting these mechanisms. Harnessing the knowledge of these mechanisms of action of Tadalafil is important to pave the way for future clinical trials with depressed patients.

Global DNA Methylation and Hydroxymethylation Levels in PBMCs Are Altered in RRMS Patients Treated with IFN-ß and GA-A Preliminary Study.

Multiple sclerosis (MS) is a chronic disease affecting the central nervous system (CNS) due to an autoimmune attack on axonal myelin sheaths. Epigenetics is an open research topic on MS, which has been investigated in search of biomarkers and treatment targets for this heterogeneous disease. In this study, we quantified global levels of epigenetic marks using an ELISA-like approach in Peripheral Blood Mononuclear Cells (PBMCs) from 52 patients with MS, treated with Interferon beta (IFN-ß) and Glatiramer Acetate (GA) or untreated, and 30 healthy controls. We performed media comparisons and correlation analyses of these epigenetic markers with clinical variables in subgroups of patients and controls. We observed that DNA methylation (5-mC) decreased in treated patients compared with untreated and healthy controls. Moreover, 5-mC and hydroxymethylation (5-hmC) correlated with clinical variables. In contrast, histone H3 and H4 acetylation did not correlate with the disease variables considered. Globally quantified epigenetic DNA marks 5-mC and 5-hmC correlate with disease and were altered with treatment. However, to date, no biomarker has been identified that can predict the potential response to therapy before treatment initiation.

The role of iron metabolism in the pathogenesis and treatment of multiple sclerosis.

Multiple sclerosis is a severe demyelinating disease mediated by cells of the innate and adaptive immune system, especially pathogenic T lymphocytes that produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). Although the factors and molecules that drive the genesis of these cells are not completely known, some were discovered and shown to promote the development of such cells, such as dietary factors. In this regard, iron, the most abundant chemical element on Earth, has been implicated in the development of pathogenic T lymphocytes and in MS development via its effects on neurons and glia. Therefore, the aim of this paper is to revise the state-of-art regarding the role of iron metabolism in cells of key importance to MS pathophysiology, such as pathogenic CD4+ T cells and CNS resident cells. Harnessing the knowledge of iron metabolism may aid in the discovery of new molecular targets and in the development of new drugs that tackle MS and other diseases that share similar pathophysiology.

Quality of life and mental health in multiple sclerosis patients during the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic had a profound impact on mental health symptoms and quality of life (QoL) in the general population due to necessary public health restrictions such as social distancing. The psychosocial effect of the pandemic on vulnerable groups such as people living with Multiple Sclerosis (PwMS) has been scarcely explored in countries with additional socioeconomical burdens such as access to healthcare disparities METHODS: A questionnaire exploring sociodemographic variables, quality of life, mental health determinants and sleep quality was applied to 92 PwMS to explore changes prior and during the pandemic regarding these domains RESULTS: 58.8% of the subjects were female, median age was 37.1 (± 8.5) years and relapsing-remitting MS was the predominant clinical subtype (83.5%). Unemployment rate significantly increased during the pandemic (12.3% vs 27.8%; p= 0.001). Only 46.4% received medical follow-up care during the pandemic. QoL was affected predominantly due to limitations in instrumented activities of daily life (IADL). Neuropsychiatric symptoms, requiring healthcare during the pandemic, anxiety prior to the pandemic and restricted IADL were predictors of MS-related physical impact worsening, while decreased physical/emotional wellbeing selfcare, neuropsychiatric symptoms, bad sleep quality, anxiety prior to the pandemic and restricted non-instrumental ADL predicted aggravation of MS-related psychological impact measured by the MSIS-29. Curiously, specific items regarding anxiety were more prevalent prior to the pandemic (anxious mood; p=0.02, helplessness; p=0.01), sleep problems; p=0.001 and cardiovascular symptoms; p=0.001, nevertheless, stability was observed for most items. Importantly, 77.3% of PwMS reported at least one neuropsychiatric symptom CONCLUSION: The deleterious effects of the COVID-19 pandemic on psychosocial wellbeing in PwMS, QoL and mental health outcomes are frequently overseen in vulnerable populations such as PwMS. Albeit the limitations of this study, our results may help implement policies that prevent negative outcomes on psychosocial wellbeing due to public health measures (e.g., social distancing) in MS and other neurological diseases that inexorably need constant follow-up.

Is there a role for herpes simplex virus type 1 in multiple sclerosis?

Numerous studies relate the onset and severity of multiple sclerosis (MS) with viral infections. Herpes simplex virus type 1 (HSV-1), which is neurotropic and highly prevalent in the brain of healthy individuals, has been proposed to relate to MS. Here, we review and discuss the reported connections between HSV-1 and MS.

The adenosinergic signaling in the pathogenesis and treatment of multiple sclerosis.

Multiple sclerosis (MS) is a highly disabling, progressive neurodegenerative disease with no curative treatment available. Although significant progress has been made in understanding how MS develops, there remain aspects of disease pathogenesis that are yet to be fully elucidated. In this regard, studies have shown that dysfunctional adenosinergic signaling plays a pivotal role, as patients with MS have altered levels adenosine (ADO), adenosine receptors and proteins involved in the generation and termination of ADO signaling, such as CD39 and adenosine deaminase (ADA). We have therefore performed a literature review regarding the involvement of the adenosinergic system in the development of MS and propose mechanisms by which the modulation of this system can support drug development and repurposing.

Microbial Metabolites in Multiple Sclerosis: Implications for Pathogenesis and Treatment.

Metabolites produced by the gut microbiota have been shown to play an important role in numerous inflammatory, neuropsychiatric, and neurodegenerative diseases. Specifically, microbial metabolites have been implicated in the modulation of innate and adaptive immunity, especially in the generation of regulatory T cells (Tregs), which are key regulators of multiple sclerosis (MS) pathogenesis. Furthermore, they affect processes relevant to MS pathophysiology, such as inflammation and demyelination, which makes them attractive molecules to be explored as therapeutics in MS. In this review, we discuss the importance of these metabolites as factors contributing to disease pathogenesis and as therapeutic targets in MS. Establishing an improved understanding of these gut-microbiota derived metabolites may provide new avenues for the treatment of MS.

Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases.

Programmed Cell Death 1 (PD-1) receptor and its ligands (PD-Ls) are essential to maintain peripheral immune tolerance and to avoid tissue damage. Consequently, altered gene or protein expression of this system of co-inhibitory molecules has been involved in the development of cancer and autoimmunity. Substantial progress has been achieved in the study of the PD-1/PD-Ls system in terms of regulatory mechanisms and therapy. However, the role of the PD-1/PD-Ls pathway in neuroinflammation has been less explored despite being a potential target of treatment for neurodegenerative diseases. Multiple Sclerosis (MS) is the most prevalent, chronic, inflammatory, and autoimmune disease of the central nervous system that leads to demyelination and axonal damage in young adults. Recent studies have highlighted the key role of the PD-1/PD-Ls pathway in inducing a neuroprotective response and restraining T cell activation and neurodegeneration in MS. In this review, we outline the molecular and cellular mechanisms regulating gene expression, protein synthesis and traffic of PD-1/PD-Ls as well as relevant processes that control PD-1/PD-Ls engagement in the immunological synapse between antigen-presenting cells and T cells. Also, we highlight the most recent findings regarding the role of the PD-1/PD-Ls pathway in MS and its murine model, experimental autoimmune encephalomyelitis (EAE), including the contribution of PD-1 expressing follicular helper T (TFH) cells in the pathogenesis of these diseases. In addition, we compare and contrast results found in MS and EAE with evidence reported in other autoimmune diseases and their experimental models, and review PD-1/PD-Ls-targeting therapeutic approaches.

SARS-CoV-2 Infection and Risk Management in Multiple Sclerosis.

The novel coronavirus can cause a severe respiratory disease with impact on the central nervous system, as has been reported by several medical health services. In the COVID-19 pandemic caused by the SARS-CoV-2 neurotrophic virus, neurologists have focused their attention on the early identification of suggestive manifestations of the neurological impact of the disease. In this context, they are exploring related chronic disease and the possibility of achieving a more effective understanding of symptoms derived from COVID-19 infection and those derived from the course of preexisting neurological disease. The present review summarizes evidence from the infection with SARS-CoV-2 and the management of the risks of multiple sclerosis and how it is related to the risks of general comorbidities associated with COVID-19. In addition, we reviewed other factors characteristic of MS, such as relapses, and the maximum tolerated dose of treatment medications from clinical and experimental evidence.

Acute Disseminated Encephalomyelitis: Current Perspectives.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated central nervous system (CNS) disorder, characterized by polyfocal symptoms, encephalopathy and typical magnetic resonance imaging (MRI) findings, that especially affects young children. Advances in understanding CNS neuroimmune disorders as well as the association of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) with both monophasic and recurrent forms of ADEM have led to new insights into its definition, management and outcome. In this review, we aim to provide an update based on current epidemiologic, clinical, radiological and immunopathological aspects and clinical outcome of ADEM.

Neuritis óptica recurrente posterior a encefalomielitis diseminada aguda en pediatría. Reporte de un caso / Recurrent optic neuritis after acute disseminated encephalomyelitis in pediatrics. A case report

Abstract: Optic Neuritis (ON) is a condition caused by the inflammation of the optic nerve, causing diminished visual acuity and ocular pain. It is tightly related to Multiple Sclerosis (MS), often being the first demyelinating event. There is a 31% risk of recurrence during the first 10 years after the diagnosis, and 48% of the patients end up being diagnosed with Multiple Sclerosis1. Imaging studies like brain MRI (Magnetic Resonance Imaging) have a critical role in the diagnosis and prognosis of ON, as well as in the recognition of MS.2 The patient is a 11-year-old girl with recurrent ON and past medical history of Acute Disseminated Encephalomyelitis (ADEM) when she was 5 years old. ON diagnosis was based on clinical findings as well as on ophtalmologic, electrophysiologic and imaging studies. The recurrent episodes of ON improved after the use of high dose steroids. Recurrences were observed after titration of the dose, but remission was achieved after adjustment of treatment. During one of the recurrent episodes, blood work was performed to evaluate possible underlying infectious, demyelinating or autoinmmune process. Anti-MOG antibodies were found positive. The patient at the moment is not presenting with any other criteria suggesting MS or Optic Neuromyelitis, but long term follow up is adviced. Key words: Optic neuritis (ON), multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), right eye (RE); visual acuity (VA), optic neuromyelitis (ONM)

Impact, Frequency, and Severity of Restless Legs Syndrome in Patients with Multiple Sclerosis in Argentina.

BACKGROUND: Restless legs syndrome (RLS) frequency, and its association with depression, anxiety, sleep disorders, and fatigue, has not been previously studied in Latin American patients with multiple sclerosis (MS). We aimed to assess RLS frequency in patients with MS living in Argentina and to examine potential associations with depression, anxiety, and sleep disorders. METHODS: A cross-sectional study (n = 427) was conducted using a self-administered questionnaire, including International RLS Study Group criteria, to compare RLS frequency in patients with MS versus controls. The Hospital Anxiety and Depression Scale and the Fatigue Severity Scale were administered to all participants. Insomnia, excessive daytime somnolence, and other risk factors in patients with MS with RLS were analyzed using logistic regression. RESULTS: We included 189 patients with definite MS and 238 controls. The RLS frequency was 29.1% in patients with MS versus 13.0% in controls (odds ratio [OR] = 2.74, P = .00005). Moreover, clinically significant RLS (csRLS; ie, symptoms present ≥2 days per week) frequency was 19.4% in patients with MS versus 4.2% in controls (OR = 5.37, P < .00001). Longer MS duration and presence of anxiety, depression, insomnia, and smoking cigarettes were all significantly associated with RLS. Multivariate analysis showed that anxiety and fatigue were significantly associated with MS with RLS and MS with csRLS. CONCLUSIONS: Both RLS and csRLS showed strong association with MS, supporting the need to screen for anxiety/depression, sleep quality, and fatigue in this patient population. We believe that identifying the presence and severity of these conditions would contribute to better MS management and treatment.

Neuromyelitis Optica (NMO IgG+) and Genetic Susceptibility, Potential Ethnic Influences.

INTRODUCTION: Neuromyelitis optica (NMO) and Multiple Sclerosis (MS) have been reported in different populations. NMO is more frequent in non-Caucasians, and clinical phenotype differences between populations are likely influenced by genetic susceptibility. In Brazil, it has been reported that NMO patients have a mainly European ancestry background. Like other autoimmune diseases, NMO has a multifactorial origin (i.e., genetics, environmental and infectious factors). Regarding the genetics of NMO, epidemiological findings suggest that a polygenic background has an important role in the development of this type of disease. In this context, various genes have been studied, such as those involved in the synthesis of the T cell beta chain receptor, the VH2-5 gene, myelin basic protein, the CTLA-4 gene, and the interleukin-1 gene. MATERIALS AND METHODS: We performed a study with the main objective of identifying candidate genes involved in the susceptibility to develop NMO in a Mexican population. RESULT: We included 35 patients with an NMO diagnosis according to the Wingerchuk 2006 criteria. The mean age of the patients was 43.3 years old (20-67), and 80 percent of the patients were women. The presence of HLA-DRB1*03 and HLA-DRB1*10 alleles were more frequent in NMO patients than in controls (n=198; p=0.03 and 0.005, respectively). CONCLUSION: There were no differences in the other alleles that have been described in MS subjects, such as HLA-DRB1*04, HLA-DRB1*08 and HLA-DRB1*13. These findings may support the hypothesis that implicated immune-genetics as a key factor in development of this type of disease.