Treatment Of Multiple Sclerosis Research Articles

YOGA CAN AMELIORATE QUALITY OF LIFE OF PATIENTS WITH MULTIPLE SCLEROSIS: A REVIEW

Multiple sclerosis (MS) is a condition in which the body's immune system mistakenly attacks the central nervous system (CNS). MS is characterised by the presence of inflammation, demyelination, and the formation of scar (sclerosis) in the white matter of the brain and spinal cord. This leads to a wide range of symptoms associated with multiple sclerosis, encompassing physical, emotional, and psychological manifestations such as fatigue, chronic pain, impaired mobility, imbalance, spasticity, cognitive impairment, depression, bladder and bowel dysfunction, visual and speech impairments and sensory disturbances. Currently, the aetiology and treatment for MS are still unidentified, and it impacts over 2.8 million individuals globally. Disease modifying therapy (DMT) for MS, which aids in reducing the development of lesions in the white matter of the central nervous system (CNS), is expensive and has notable side effects. Consequently, individuals diagnosed with MS are increasingly turning to complementary and alternative medicine (CAM) as a means to alleviate or conquer MS symptoms and improve their overall quality of life. Among the many kinds of CAM, yoga has emerged as a particularly popular choice. The present review aims to elucidate the possible influence of yoga on enhancing the quality of life in individuals diagnosed with MS. A comprehensive search was undertaken on Google Scholar, included fourteen publications published between 2004 and February 2024. Based on the available data of low to moderate quality, yoga seems to be useful in enhancing the quality of life for individuals with MS.

A 2-stage model of heterogenous treatment effects for brain atrophy in multiple sclerosis utilizing the MS PATHS research network

BackgroundTwo-stage models of heterogenous treatment effects (HTE) may advance personalized medicine in multiple sclerosis (MS). Brain atrophy is a relatively objective outcome measure that has strong relationships to MS prognosis and treatment effects and is enabled by standardized MRI. ObjectivesTo predict brain atrophy outcomes for patients initiating disease-modifying therapies (DMT) with different efficacies, considering the patients’ baseline brain atrophy risk measured via brain parenchymal fraction (BPF). MethodsAnalyses included patients enrolled in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network who started DMT and had complete baseline data and ≥ 6-month brain MRI follow-up. All brain MRIs were acquired using standardized acquisition sequences on Siemens 3T scanners. BPF change risk was derived by linear mixed effects models using baseline covariates. Model performance was assessed by predicted versus actual BPF change R2. Propensity score (PS) weighting was used to balance covariates between groups defined by DMT efficacy (high: natalizumab, alemtuzumab, ocrelizumab, and rituximab; moderate: dimethyl fumarate, fingolimod, and cladribine; low: teriflunomide, interferons, and glatiramer acetate). HTE models predicting 1 year change in BPF were built using a weighted linear mixed effects model with low-efficacy DMT as the reference. ResultsAnalyses included 581 high-, 183 moderate-, and 106 low-efficacy DMT-treated patients. The mean and median number of brain MRI observations per treatment period were 2.9 and 3.0, respectively. Risk model performance R2=0.55. After PS weighting, covariate standardized mean differences were <10 %, indicating excellent balance across measured variables. Changes in BPF between baseline and follow-up were found to be statistically significant (p < 0.001), suggesting a pathological change. Patients with low brain atrophy risk had a similar outcome regardless of DMT selection. In patients with high brain atrophy risk, high- and moderate-efficacy DMTs performed similarly, while a 2-fold worse BPF change was predicted for patients selecting low-efficacy DMTs (p < 0.001). Similar results were observed in a sensitivity analysis adjusting for pseudoatrophy effects in a sub-population of patients treated with natalizumab. ConclusionsThe relative benefit of selecting higher efficacy treatments may vary depending on patients’ baseline brain atrophy risk. Poor outcomes are predicted in individuals with high baseline risk who are treated with low-efficacy DMTs.

Theoretical Examination of the Usability of Some Benzimidazole Derivatives as Active Pharmaceutical Ingredient in the Treatment of Multiple Sclerosis

Theoretical Examination of the Usability of Some Benzimidazole Derivatives as Active Pharmaceutical Ingredient in the Treatment of Multiple Sclerosis

Multiple sclerosis treatment underutilization predicts high risk for obstructive sleep apnea in patients with multiple sclerosis

BackgroundObstructive sleep apnea (OSA) is more common in patients with multiple sclerosis (MS) than in the general population, which suggests MS may predispose patients to OSA. However, the relationships between MS treatment, disease activity, disease severity, fatigue, and OSA are unknown. ObjectivesTo evaluate the connections between OSA risk, MS fatigue, and MS severity, controlling for well-established risk factors for OSA in the general population. MethodsWe administered OSA and fatigue-related questionnaires to patients with MS and collected relevant demographic and clinical data. Then, we utilized multivariate logistic regression to examine relationships between OSA risk and MS disease severity. ResultsWe identified an inverse correlation between medication possession ratio (MPR) and high OSA risk. Statistical models also demonstrated a positive correlation between fatigue and nonwhite race with high OSA risk, controlling for male sex, younger age, and body mass index (BMI). ConclusionWe identified disease-modifying therapy (DMT) underutilization, fatigue, and nonwhite race as predictors of high OSA risk in patients with MS. These findings support aggressive treatment of MS to avoid risk of comorbid OSA and MS-induced fatigue.

ENTIMOS: Decision Support Tool Highlights Potential Impact of Non-intravenous Therapies for Multiple Sclerosis on Patient Care via Clinical Scenario Simulation.

Administration of intravenous (IV), high-efficacy treatments (HETs) for the treatment of multiple sclerosis (MS) poses a high resourcing and planning burden on infusion centres, resulting in treatment delays that may increase the risk of breakthrough disease activity. Simulation tools can be used to systematically analyse capacity scenarios and identify and better understand constraints, therefore enabling decision-makers to optimise patient care. We have previously applied ENTIMOS, a discrete event simulation model, to assess scenarios of patient flow and care delivery using real-life data inputs from the neurology infusion suite at Charing Cross Hospital London. The model predicted that, given current capacity and projected demand, patients would experience high-risk treatment delays within 30 months. This study aimed to address key healthcare challenges for MS patient care management as seen from a neurologist's perspective. We used ENTIMOS to predict the impact of several distinct and clinically plausible scenarios on patient waiting times at the same MS infusion suite and to quantify mitigation strategies needed to assure continuity of care. We used real-world experience of an expert neurologist to identify five clinical scenarios: (1) switching patients to a subcutaneous (SC) MS treatment of the same therapeutic agent, in the same hospital setting; (2) extending opening times to the weekend; (3) reducing the number of infusion chairs (to simulate social distancing measures applied during the coronavirus disease 2019 [COVID-19] pandemic); (4) increasing demand for infusions; and (5) increasing the scheduling approval time. Patient waiting time for next due infusion and time to high-risk treatment delays (≥ 30 days) were the main analysed model outputs. Previously published base case results were used as reference. All hypothetical scenarios were run over a 3-year horizon (with the exception of scenario 1, which was run over a 3- and 5-year horizon). Strategies to mitigate treatment delays were analysed and discussed. Switching 50% of patients to SC treatment of the same therapeutic agent administered in hospital postponed the predicted high-risk treatment delays to shortly beyond the 3-year simulation timeframe (month 38). Weekend opening reduced waiting times from 20 days to 4 days and prevented treatment delays, however, at elevated labour costs. Reducing the infusion chairs increased waiting time to 53 days on average and 86 days at the end of the simulation, leading to high-risk treatment delays within 6 months. An increased demand for infusions increased waiting time to 26 days on average and 47 days at the end of the simulation, leading to high-risk treatment delays within 22 months. Prolonged scheduling approval time did not reduce the waiting time, nor postpone the high-risk treatment delays. Decision makers need transparency on capacity constraints to better plan resourcing at infusion suites and MS treatments. Our results showed that various mitigation measures, such as increasing capacity by additional infusion chairs per year and transferring patients to other infusion suites, may help prevent treatment delays. Switching patients from IV to an SC version of the same therapeutic agent reduced the waiting time moderately and postponed high-risk treatment delays. It was insufficient to prevent high-risk treatment delays in the long term.

Liquid chromatography-tandem mass spectrometry for determination of fingolimod and its active metabolite fingolimod phosphate in whole blood of patients with multiple sclerosis.

Fingolimod is an oral drug for the escalation of treatment of relapsing-remitting multiple sclerosis in patients with persistent disease activity on first-line drugs or in patients with rapidly progressive severe relapsing-remitting multiple sclerosis. An ultra-high-performance liquid chromatography-tandem mass spectrometry method for determining the concentrations of fingolimod and its active metabolite fingolimod phosphate in whole blood has been developed and validated. The advantages of this method are the easy, fast and cheap sample preparation using protein precipitation from blood with a mixture of acetonitrile-methanol (40:60, v/v). Chromatographic separation was performed on a ultra-high performance liquid chromatography BEH C18 1.7 μm (100 × 2.1mm) column. Two modes of ionization, electrospray ionization and atmospheric pressure chemical ionization, were tested and compared. For validation, the electrospray ionization mode was chosen. As internal standard, isotopically labeled fingolimod-D4 was used to quantify the analytes. The method was validated according to the rules of the European Medicines Agency. The coefficients of variation for fingolimod were in the range of 1.13-11.88%, and the recovery was 98.80-106.00%. The coefficients of variation for fingolimod phosphate were in the range of 2.73-9.31%, and the recovery was 90.08-107.00%. The method is quite easy and fast and can be used for routine analysis.

The role of vitamin D in multiple sclerosis and its mechanisms of action

Introduction and Purpose: Multiple sclerosis (MS) is a prevalent autoimmune disease affecting the central nervous system, particularly in young people. Characterized by neurodegenerative and demyelinating processes, MS is influenced by genetic and environmental factors. Research indicates that sufficient levels of vitamin D can reduce the risk of developing MS. Studies show that higher sun exposure and dietary vitamin D intake are associated with a lower incidence of MS. Moreover, vitamin D supplementation may benefit those already diagnosed by alleviating symptoms and improving their quality of life. This review explores the potential benefits of vitamin D and its neuroprotective mechanisms in MS. State of Knowledge: MS research and treatments have focused on immunomodulation, with less emphasis on neuroprotection, including the role of vitamin D. It is well-established that vitamin D has anti-inflammatory effects on the immune system in MS. It influences the proliferation and differentiation of neural stem cells and oligodendrocytes, enhances neurotrophin expression, reduces reactive astrogliosis, decreases oxidative stress, and stabilizes the blood-brain barrier. Research suggests that adequate vitamin D levels and supplementation might improve MS outcomes. Conclusion: New diagnostic tools and therapeutic strategies are urgently needed to address the complex nature of MS, which includes inflammation, neuronal death, demyelination, and oxidative stress. Promoting vitamin D sufficiency and supplementation, alongside developing new neuroprotective agents, remains a valuable approach in combating MS. Understanding the mechanisms of MS and the effects of vitamin D could lead to better management strategies and enhanced quality of life for patients.

Bruton Tyrosine Kinase Inhibition Decreases Inflammation and Differentially Impacts Phagocytosis and Cellular Metabolism in Mouse- and Human-derived Myeloid Cells.

Bruton tyrosine kinase (BTK) is a kinase expressed by various immune cells and is often activated under proinflammatory states. Although the majority of BTK-related research has historically focused on B cells, understanding the role of BTK in non-B cell populations is critical given myeloid cells also express BTK at comparable levels. In this study, we investigated and compared how BTK inhibition in human and murine myeloid cells alters cell phenotype and function. All experiments were performed using two BTK inhibitors (evobrutinib and tolebrutinib) that are currently in late-stage clinical trials for the treatment of multiple sclerosis. Assays were performed to assess the impact of BTK inhibition on cytokine and microRNA expression, phagocytic capacity, and cellular metabolism. In all cells, both evobrutinib and tolebrutinib significantly decreased phosphorylated BTK and LPS-induced cytokine release. BTK inhibition also significantly decreased the oxygen consumption rate and extracellular acidification rate in myeloid cells, and significantly decreased phagocytosis in murine-derived cells, but not human macrophages. To further elucidate the mechanism, we also investigated the expression of microRNAs known to impact the function of myeloid cells. BTK inhibition resulted in an altered microRNA expression profile (i.e., decreased miR-155-5p and increased miR-223-3p), which is consistent with a decreased proinflammatory myeloid cell phenotype. In summary, these results provide further insights into the mechanism of action of BTK inhibitors in the context of immune-related diseases, while also highlighting important species-specific and cell-specific differences that should be considered when interpreting and comparing results between preclinical and human studies.

Clinicians' Preferences for Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis Based on Clinical Management Considerations: A Choice Experiment.

Four sphingosine-1-phosphate receptor (S1PR) modulators are currently available in the USA for treating relapsing forms of multiple sclerosis (MS). These S1PR modulators have similar efficacy. Clinicians may therefore consider other factors, such as clinical management considerations, when distinguishing among treatments. This study estimated which S1PR modulator clinicians would choose on the basis of a treatment's clinical management and quantified how individual aspects of clinical management might drive this choice. A multi-criteria decision analysis (MCDA) was conducted on the basis of clinical management preferences elicited in a discrete choice experiment (DCE) and real-world clinical management profiles of the S1PR modulators currently available to treat relapsing forms of MS (fingolimod, ozanimod, ponesimod, siponimod). The DCE was completed by neurologists in the USA experienced in treating MS and included eight clinical management attributes: first-dose observations, genotyping, liver function tests, eye exams, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Attribute levels were selected on the basis of S1PR modulator product labels. In the MCDA, partial MCDA scores were created for each attribute and summed to produce an overall MCDA score for each S1PR modulator. The DCE was completed by 200 neurologists. The overall MCDA score was highest for ponesimod (4.78 points), followed by siponimod (4.10 points), fingolimod (3.61 points), and ozanimod (2.38 points). Having fewer drug-drug interactions contributed most to the overall scores (up to 1.56 points), followed by having no first-dose observations (0.95 points), the shortest immune system recovery time (0.94 points), and not interacting with foods high in tyramine (0.86 points). When considering clinical management convenience, the average US-based neurologist treating MS is likely to choose ponesimod over siponimod, fingolimod, or ozanimod. The strongest driver of preferences was the number of drug-drug interactions. This information can help inform recommendations for the treatment of MS and facilitate shared decision-making between clinicians and patients.

Technological prospection study of the development of S1P1 modulator drugs for the multiple sclerosis treatment

Technological prospection study of the development of S1P1 modulator drugs for the multiple sclerosis treatment

Enhanced and cross-reactive in vitro memory B cell response against Epstein-Barr virus nuclear antigen 1 in multiple sclerosis.

Multiple sclerosis (MS) is a prototypical autoimmune disease of the central nervous system (CNS). In addition to CD4+ T cells, memory B cells are now recognized as a critical cell type in the disease. This is underlined by the fact that the best-characterized environmental risk factor for MS is the Epstein-Barr virus (EBV), which can infect and persist in memory B cells throughout life. Several studies have identified changes in anti-EBV immunity in patients with MS. Examples include elevated titers of anti-EBV nuclear antigen 1 (EBNA1) antibodies, interactions of these with the MS-associated HLA-DR15 haplotype, and molecular mimicry with MS autoantigens like myelin basic protein (MBP), anoctamin-2 (ANO2), glial cell adhesion molecule (GlialCAM), and alpha-crystallin B (CRYAB). In this study, we employ a simple in vitro assay to examine the memory B cell antibody repertoire in MS patients and healthy controls. We replicate previous serological data from MS patients demonstrating an increased secretion of anti-EBNA1380-641 IgG in cell culture supernatants, as well as a positive correlation of these levels with autoantibodies against GlialCAM262-416 and ANO21-275. For EBNA1380-641 and ANO21-275, we provide additional evidence suggesting antibody cross-reactivity between the two targets. Further, we show that two efficacious MS treatments - natalizumab (NAT) and autologous hematopoietic stem cell transplantation (aHSCT) - are associated with distinct changes in the EBNA1-directed B cell response and that these alterations can be attributed to the unique mechanisms of action of these therapies. Using an in vitro system, our study confirms MS-associated changes in the anti-EBNA1 memory B cell response, EBNA1380-641 antibody cross-reactivity with ANO21-275, and reveals treatment-associated changes in the immunoglobulin repertoire in MS.

Nanocarriers' repartitioning of drugs between blood subcompartments as a mechanism of improving pharmacokinetics, safety, and efficacy

For medical emergencies, such as acute ischemic stroke, rapid drug delivery to the target site is essential. For many small molecule drugs, this goal is unachievable due to poor solubility that prevents intravenous administration, and less obviously, by extensive partitioning to plasma proteins and red blood cells (RBCs), which greatly slows delivery to the target. Here we study these effects and how they can be solved by loading into nanoscale drug carriers. We focus on fingolimod, a small molecule drug that is FDA-approved for treatment of multiple sclerosis, which has also shown promise in the treatment of stroke. Unfortunately, fingolimod has poor solubility and very extensive partitioning to plasma proteins and RBCs (in whole blood, 86% partitions to RBCs, 13.96% to plasma proteins, and 0.04% is free). We develop a liposomal formulation that slows the partitioning of fingolimod to RBCs and plasma proteins, enables intravenous delivery, and additionally prevents fingolimod toxicity to RBCs. The liposomal formulation nearly completely prevented fingolimod adsorption to plasma proteins (association with plasma proteins was 98.4 ± 0.4% for the free drug vs. 5.6 ± 0.4% for liposome-loaded drug). When incubated with whole blood in vitro, the liposomal formulation greatly slowed partitioning of fingolimod to RBCs and also eliminated deleterious effects of fingolimod on RBC rigidity, morphology, and hemolysis. In vivo, the liposomal formulation delayed fingolimod partitioning to RBCs for over 30 min, a critical time window for stroke. Fingolimod-loaded liposomes showed improved efficacy in a mouse model of post-stroke neuroinflammation, completely sealing the leaky blood-brain barrier (114 ± 11.5% reduction in albumin leak into the brain for targeted liposomes vs. 38 ± 16.5% reduction for free drug). This effect was only seen for liposomes modified with antibodies to enable targeted delivery to the site of action, and not in unmodified, long-circulating liposomes. Thus, loading fingolimod into liposomes prevented partitioning to RBCs and associated toxicities and enabled targeted delivery. This paradigm can be used for tuning the blood distribution of small molecule drugs for the treatment of acute illnesses requiring rapid pharmacologic intervention.

A thermosensitive chitosan hydrogel: An attempt for the nasal delivery of dimethyl fumarate

Dimethyl fumarate (DMF) is a drug that is orally administered for the treatment of relapsing-remitting multiple sclerosis. However, DMF causes gastrointestinal side effects and flushing in 43 % of patients, which significantly contributes to treatment discontinuation. To reduce side effects and increase patient compliance, the aim of this study was to develop a thermosensitive chitosan/glycerophosphate hydrogel for the nasal administration of DMF. A binary system of DMF with hydroxypropyl-β-cyclodextrin (HP-β-CD) was made and included in the hydrogel precursor solution. The precursor solution (drug content, DMF stability, thermogelling properties, viscosity), and the resulting thermosensitive hydrogel (mucoadhesion, in vitro DMF permeation) were characterized. HP-β-CD was able to interact with DMF and improve its water solubility. The leader thermosensitive nasal solution, G1 solution, was loaded with approximately 92 % DMF, which remained stable for 21 days. The G1 solution formed a hydrogel in approximately 2–1 min; it had a pH of 6.8 ± 0.06 and caused no significant change in the osmolality of the simulated nasal medium. The G1 hydrogel showed good mucoadhesive properties and released DMF that permeated in vitro in a controlled manner. As a result, G1 is a potential new approach to exploit the intranasal administration of DMF for treating multiple sclerosis.

Pediatric-onset Multiple Sclerosis treatment: a multicentre observational study comparing natalizumab with fingolimod.

Pediatric-onset Multiple Sclerosis (POMS) patients show more inflammatory disease compared with adult-onset MS. However, highly effective treatments are limited with only fingolimod being approved in Italy and natalizumab prescribed as off-label treatment. to compare the efficacy of natalizumab versus fingolimod in POMS. This is an observational longitudinal multicentre study including natalizumab- and fingolimod-treated POMS patients (N-POMS and F-POMS, respectively). We collected Annual Relapse Rate (ARR), Expanded Disability Status Scale (EDSS), Symbol Digit Modality Test (SDMT), and MRI activity at baseline (T0), 12-18months (T1), and last available observation (T2). We enrolled 57 N-POMS and 27 F-POMS patients from six Italian MS Centres. At T0, N-POMS patients showed higher ARR (p = 0.03), higher EDSS (p = 0.003) and lower SDMT (p = 0.04) at baseline compared with F-POMS. Between T0 and T1 ARR improved for both N-POMS and F-POMS (p < 0.001), while EDSS (p < 0.001) and SDMT (p = 0.03) improved only for N-POMS. At T2 (66.1 ± 55.4months) we collected data from 42 out of 57 N-POMS patients showing no further ARR decrease. Both natalizumab and fingolimod showed high and sustained efficacy in controlling relapses and natalizumab also associated to a disability decrease in POMS. This latter effect might be partly mediated by the high inflammatory activity at baseline in N-POMS.

Ofatumumab in the treatment of multiple sclerosis - A summary of preclinical and clinical data

B-cell targeted therapies are highly effective in multiple sclerosis (MS). Most of these therapies are administered intravenously at long intervals. Ofatumumab, an anti-CD20 antibody that is administered subcutaneously at low doses on a monthly basis due to its high affinity to the target structure, became available for the treatment of MS in 2021. An overview of practice-relevant immunological and clinical data on ofatumumab is provided. The high affinity of ofatumumab to the target structure allows low dose and low volume administration, with the release and absorption profile after subcutaneous application allowing for high concentrations in the lymph nodes and gradual depletion of B-cells. Rapid onset of action is achieved as well as B-cell repletion within a few months in case of discontinuation of therapy. Long-term data show stable IgG levels over up to four years and high efficacy with respect to relapse rate, progression, and cognition. According to current study data, the effect compared to teriflunomide is greater the earlier therapy is initiated. Ofatumumab has a specific B-cell depletion pattern. CD20 expressing B-cell progenitor cells in the bone marrow are preserved and therefore also the inducibility and differentiation of plasma cells. The formation of a humoral immunological memory is therefore possible. Four-year study data showed no abnormalities in the rate of severe infections or malignancies. Ofatumumab is an innovative B-cell targeted therapy. It is highly effective with a good safety and tolerability profile, well controllable and maintains immunocompetence against pathogens.

The Role of Glucagon-Like Peptide-1 Agonists in the Treatment of Multiple Sclerosis: A Narrative Review

The Role of Glucagon-Like Peptide-1 Agonists in the Treatment of Multiple Sclerosis: A Narrative Review

Features of depressive disorders in patients with multiple sclerosis

Depressive disorders are the most common manifestations of multiple sclerosis. The severity of depressive symptoms depends on many factors: fear of a disabling disease, dependence on loved ones, the frequency of exacerbations. Early diagnosis of affective conditions helps to prescribe therapy in a timely manner, thereby improving the quality of life of patients with multiple sclerosis. The purpose of this study is to investigate the features and manifestations of depressive disorders in patients with multiple sclerosis. Patients and methods: The study involved patients with relapsing-remitting multiple sclerosis who were diagnosed with depressive disorders — the study group, and patients with depressive disorders — the comparison group. At the time of examination, the age of the patients in the study group (113 participants) ranged from 15 to 60 years, with the mean age of 39.7±10.91 years. The duration of the disease was 9.84±0.73 years, while the disability rate by the EDSS was 2.89±0.16 points. The comparison group was represented by patients with disorders of the depressive spectrum (70 patients). The mean age of the patients was 32.81±13.57 years. The age of onset of the disease in patients with depressive disorders was within 22.09±2.09 years, and the duration of the disease with depression was 4.6±3.86 years. Results and discussion: In the study group patients with depressive disorders, the initial manifestations are not pronounced and are within the limits of the average degree of depression. The analysis revealed the dynamics of symptoms depending on the level of depression: with mild depression p&lt;0.001, «loss of appetite» appears more often, with moderate depression p&lt;0.001, the symptoms of «dissatisfaction», «feelings of guilt», and «preoccupation with bodily sensations» appeared, and with severe depression p&lt;0.001, «ideas of self-blame», increased «tearfulness», and changes in «body image» became significant. Meanwhile, in the patients in the comparison group, symptoms of low mood and dissatisfaction, which were often accompanied by feelings of guilt and ideas of self-blame, came to the fore. Conclusion: The symptoms of depressive manifestations in patients with multiple sclerosis differ from those in patients with depressive disorders. When selecting the basic therapy for the treatment of multiple sclerosis with disease modifying drugs, it is necessary to take into account the emotional background of patients, since interferons affect the emotional sphere of multiple sclerosis patients and can cause or intensify depressive experiences.

Disclosing the Novel Protective Mechanisms of Ocrelizumab in Multiple Sclerosis: The Role of PKC Beta and Its Down-Stream Targets.

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for both Relapsing and Primary Progressive forms of Multiple Sclerosis (MS) treatment. OCR is postulated to act via rapid B cell depletion; however, by analogy with other anti-CD20 agents, additional effects can be envisaged, such as on Protein Kinase C (PKC). Hence, this work aims to explore novel potential mechanisms of action of OCR in peripheral blood mononuclear cells from MS patients before and after 12 months of OCR treatment. We first assessed, up-stream, PKCβII and subsequently explored two down-stream pathways: hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF), and human antigen R (HuR)/manganese-dependent superoxide dismutase (MnSOD) and heat shock proteins 70 (HSP70). At baseline, higher levels of PKCβII, HIF-1α, and VEGF were found in MS patients compared to healthy controls (HC); interestingly, the overexpression of this inflammatory cascade was counteracted by OCR treatment. Conversely, at baseline, the content of HuR, MnSOD, and HSP70 was significantly lower in MS patients compared to HC, while OCR administration induced the up-regulation of these neuroprotective pathways. These results enable us to disclose the dual positive action of OCR: anti-inflammatory and neuroprotective. Therefore, in addition to B cell depletion, the effect of OCR on these molecular cascades can contribute to counteracting disease progression.

Primary Progressive Multiple Sclerosis-A Key to Understanding and Managing Disease Progression.

Primary progressive multiple sclerosis (PPMS), the least frequent type of multiple sclerosis (MS), is characterized by a specific course and clinical symptoms, and it is associated with a poor prognosis. It requires extensive differential diagnosis and often a long-term follow-up before its correct recognition. Despite recent progress in research into and treatment for progressive MS, the diagnosis and management of this type of disease still poses a challenge. Considering the modern concept of progression "smoldering" throughout all the stages of disease, a thorough exploration of PPMS may provide a better insight into mechanisms of progression in MS, with potential clinical implications. The goal of this study was to review the current evidence from investigations of PPMS, including its background, clinical characteristics, potential biomarkers and therapeutic opportunities. Processes underlying CNS damage in PPMS are discussed, including chronic immune-mediated inflammation, neurodegeneration, and remyelination failure. A review of potential clinical, biochemical and radiological biomarkers is presented, which is useful in monitoring and predicting the progression of PPMS. Therapeutic options for PPMS are summarized, with approved therapies, ongoing clinical trials and future directions of investigations. The clinical implications of findings from PPMS research would be associated with reliable assessments of disease outcomes, improvements in individualized therapeutic approaches and, hopefully, novel therapeutic targets, relevant for the management of progression.

Hybrid derivatives containing dimethyl fumarate and benzothiazole scaffolds for the potential treatment of multiple sclerosis; in silico & in vivo study.

Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways. Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment. Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivoevaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model. The proposed derivatives were recognized to be potent enough based on docking studies (ΔGbind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based onin vivostudies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently,D4 and D6derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders.