Mitochondria are energy-producing organelles, and neurons are high energy consumption cells. Therefore, mitochondrial dysfunction is a critical factor in neurodegenerative processes. Mitochondrial division inhibitor-1 (Mdivi-1) is a small chemical inhibitor of mitochondrial division dynamin, which plays multiple roles in mitochondrial dynamics, mitochondrial autophagy, ATP production, the immune response, and Ca2+ homeostasis. Mdivi-1 inhibition of excessive mitochondrial fission exerted cytoprotective effects in neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Mdivi-1 changed the mRNA expression of the electron transport chain (ETC) and reduced Ca2+ overload against neuronal injury. Elucidation of the molecular mechanism of Mdivi-1 in neurodegenerative diseases will help evaluate its therapeutic potential and promote its application in clinical studies. The present article focused on the multiple effects of Mdivi-1 on mitochondrial function and its potential therapeutic effects in neurodegenerative diseases.

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelination and axonal degeneration in the central nervous system (CNS). Bacterial and fungal infections have been associated with the development of MS; microbial components that are present in several microbes could contribute to MS pathogenesis. Among such components, curdlan is a microbial 1,3-β-glucan that can stimulate dendritic cells, and enhances T helper (Th) 17 responses. We determined whether curdlan administration could affect two animal models for MS: an autoimmune model, experimental autoimmune encephalomyelitis (EAE), and a viral model, Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD). We induced relapsing-remitting EAE by sensitizing SJL/J mice with the myelin proteolipid protein (PLP)_139-151 peptide and found that curdlan treatment prior to PLP sensitization converted the clinical course of EAE into hyperacute EAE, in which the mice developed a progressive motor paralysis and died within 2 weeks. Curdlan-treated EAE mice had massive infiltration of T cells and neutrophils in the CNS with higher levels of Th17 and Th1 responses, compared with the control EAE mice. On the other hand, in TMEV-IDD, we found that curdlan treatment reduced the clinical scores and axonal degeneration without changes in inflammation or viral persistence in the CNS. In summary, although curdlan administration exacerbated the autoimmune MS model by enhancing inflammatory demyelination, it suppressed the viral MS model with reduced axonal degeneration. Therefore, microbial infections may play contrasting roles in MS depending on its etiology: autoimmunity versus viral infection.

Keywords: CNS demyelinating diseases; Picornaviridae infections; animal models; bioinformatics; fungal infections; neuropathology; persistent virus infections; principal component analysis.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Keywords: COVID-19; DMT-associated infections; Multiple sclerosis; SARS-CoV-2; coronavirus disease 2019; disease-modifying treatment; neuromyelitis optica spectrum disorder; progressive multifocal leukoencephalopathy; risk mitigation strategies.

In patients with multiple sclerosis (MS), a typical pattern of muscle tone alteration, known as spasticity, is frequently observed in combination with other signs or symptoms such as spasms, cramps, pain, bladder dysfunction, sleep disturbances, fatigue, and tremor. Recently, the concept of spasticity-plus syndrome (SPS) has been proposed to take into account the frequent coexistence of all these complaints in patients with MS and a common pathophysiological basis for this putative new clinical entity has been proposed. Muscle tone, sleep, bladder function, and the pain pathway are controlled by cannabinoid CB1 (CB1R) and CB2 receptors (CB2R) that are particularly enriched in the brainstem. Axons with smaller diameters are particularly susceptible to conduction block and the irritative, ephaptic, consequences of demyelination and their involvement in the demyelination process caused by MS in the brainstem might underlie the various clinical manifestations of SPS. The adoption of SPS in clinical practice could be useful to improve symptomatic treatments in a significant proportion of patients with MS, possibly limiting the adverse events produced by polypharmacotherapy.

Keywords: axonal transmission; cannabinoid; multiple sclerosis; spasticity; symptoms therapy.

Astrocytes utilize both glycolytic and mitochondrial pathways to power cellular processes that are vital to maintaining normal CNS functions. These cells also mount inflammatory and acute phase reactive programs in response to diverse stimuli. While the metabolic functions of astrocytes under homeostatic conditions are well-studied, the role of cellular bioenergetics in astrocyte reactivity is poorly understood. Teriflunomide exerts immunomodulatory effects in diseases such as multiple sclerosis by metabolically reprogramming lymphocytes and myeloid cells. We hypothesized that teriflunomide would constrain astrocytic inflammatory responses. Purified murine astrocytes were grown under serum-free conditions to prevent acquisition of a spontaneous reactive state. Stimulation with TNFα activated NFκB and increased secretion of Lcn2. TNFα stimulation increased basal respiration, maximal respiration, and ATP production in astrocytes, as assessed by oxygen consumption rate. TNFα also increased glycolytic reserve and glycolytic capacity of astrocytes but did not change the basal glycolytic rate, as assessed by measuring the extracellular acidification rate. TNFα specifically increased mitochondrial ATP production and secretion of Lcn2 required ATP generated by oxidative phosphorylation. Inhibition of dihydroorotate dehydrogenase via teriflunomide transiently increased both oxidative phosphorylation and glycolysis in quiescent astrocytes, but only the increased glycolytic ATP production was sustained over time, resulting in a bias away from mitochondrial ATP production even at doses down to 1 μM. Preconditioning with teriflunomide prevented the TNFα-induced skew toward oxidative phosphorylation, reduced mitochondrial ATP production, and reduced astrocytic inflammatory responses, suggesting that this drug may limit neuroinflammation by acting as a metabolomodulator.

Background: Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis.

Objective: To investigate whether CD19⁺ B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8⁺ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients.

Methods: In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses.

Results: RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8⁺GzmB⁺ T lymphocytes when compared to healthy volunteers. An increase in circulating CD19⁺GzmB⁺ B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-β (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8⁺ T lymphocytes, the expression of GzmB was significantly higher in CD19⁺Runx3⁺-expressing B cells when compared to CD19⁺Runx3^- counterparts in RRMS patients.

Conclusions: CD19⁺ B cells may exhibit cytotoxic behavior resembling CD8⁺ T lymphocytes in MS patients during different treatments. In the future, monitoring "cytotoxic" subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.

Keywords: MS treatment; cytotoxicity; granzyme B; neurodegeneration; neuroinflammation.

Background: Myalgic encephalitis or chronic fatigue syndrome (ME/CFS) has again come into focus as a result of coronavirus disease 2019 (COVID-19). Fundamentally problematic is the fact that ME/CFS is considered a separate entity; however, extreme fatigue is also a common symptom of an underlying disease. Our article aims to increase the acceptance of ME/CFS and extreme fatigue facing a symptomatology that is not fully understood, and to highlight the need for research, orientation for physicians, and counselling services for patients.

Materials and methods: Orientative research by focused information gathering.

Results: In various research projects, the hypothesis of post-infectious ME/CFS as an autoimmune disease could be confirmed. In general, the heterogeneity of diagnostic criteria as well as the variety of formulations to describe the symptomatology and different coding options make it difficult to clearly assign symptoms to a clinical picture. Exertion intolerance has been identified as a severe symptom of post-COVID-19 disorder. For this reason, recommendations in international guidelines are currently being revised, especially with regard to pacing. The implications for recommendations in tumor-related fatigue or due to multiple sclerosis are unclear.

Conclusion: Against the background of a decreasing burden of disease due to increasing vaccination rates, research on fatigue should not only include viral diseases.

Keywords: Chronic fatigue syndrome; ME/CFS; Myalgic encephalitis; PEM; Pacing; Post-exertional malaise; Stress intolerance.

Antecedentes: Programas de exercícios físicos são recomendados para pacientes com esclerose múltipla. No entanto, são limitados os estudos que envolvem o treinamento aquático de força para a melhoria das capacidades funcionais.

Objetivo: Investigar o efeito de um programa de treinamento aquático de força nas capacidades funcionais e nos níveis de força e fadiga de pessoas diagnosticadas com esclerose múltipla.

Métodos: Foram selecionados 29 voluntários com esclerose múltipla. Todos os participantes realizaram uma bateria de testes, incluindo os de capacidades funcionais, nível de força e níveis de fadiga em dois momentos distintos: pré-intervenção e pós-intervenção. O programa de treinamento de força foi realizado durante 12 semanas. Foram utilizados exercícios de força localizados, com controle específico de carga de trabalho, que variou entre 50 e 90% do máximo, de acordo com a semana de treinamento. Para a análise estatística, optou-se por utilizar o teste t de Student na comparação ente os momentos pré- e pós-intervenção.

Resultados: Os resultados demonstraram melhora significativa em todas as variáveis investigadas: teste de 6 min de caminhada (p=0,00); força mão dominante (p=0,02); força mão não dominante (p=0,00); levantar (p=0,00); sentar e levantar-se (p=0,00); subir 15 degraus (p=0,00); descer 15 degraus (p=0,00); calçar meias (p=0,00); gravidade da fadiga (p=0,01); impacto da fadiga (p=0,01).

Conclusão: O treinamento aquático de força foi eficiente para melhorar as capacidades funcionais relacionadas à qualidade de vida de pacientes com esclerose múltipla.

Background: Vaccination has proven to be effective in preventing SARS-CoV-2 transmission and severe disease courses. However, immunocompromised patients have not been included in clinical trials and real-world clinical data point to an attenuated immune response to SARS-CoV-2 vaccines among patients with multiple sclerosis (MS) receiving immunomodulatory therapies.

Methods: We performed a retrospective study including 59 ocrelizumab (OCR)-treated patients with MS who received SARS-CoV-2 vaccination. Anti-SARS-CoV-2-antibody titres, routine blood parameters and peripheral immune cell profiles were measured prior to the first (baseline) and at a median of 4 weeks after the second vaccine dose (follow-up). Moreover, the SARS-CoV-2-specific T cell response and peripheral B cell subsets were analysed at follow-up. Finally, vaccination-related adverse events were assessed.

Results: After vaccination, we found anti-SARS-CoV-2(S) antibodies in 27.1% and a SARS-CoV-2-specific T cell response in 92.7% of MS cases. T cell-mediated interferon (IFN)-γ release was more pronounced in patients without anti-SARS-CoV-2(S) antibodies. Antibody titres positively correlated with peripheral B cell counts, time since last infusion and total IgM levels. They negatively correlated with the number of previous infusion cycles. Peripheral plasma cells were increased in antibody-positive patients. A positive correlation between T cell response and peripheral lymphocyte counts was observed. Moreover, IFN-γ release was negatively correlated with the time since the last infusion.

Conclusion: In OCR-treated patients with MS, the humoral immune response to SARS-CoV-2 vaccination is attenuated while the T cell response is preserved. However, it is still unclear whether T or B cell-mediated immunity is required for effective clinical protection. Nonetheless, given the long-lasting clinical effects of OCR, monitoring of peripheral B cell counts could facilitate individualised treatment regimens and might be used to identify the optimal time to vaccinate.

Keywords: multiple sclerosis.

Background: Characterized by demyelination, inflammation and axonal damage, multiple sclerosis (MS) is one of the most common disorders of central nervous system led by the immune system. There is an urgent and obvious need for biomarkers for the diagnosis and follow-up of MS.

Objective: To investigate serum levels of sestrin2 (SESN2), a protein that responds to acute stress, in MS patients.

Methods: A total of 85 participants, 40 patients diagnosed previously with relapsing-remitting MS and 45 healthy controls, were included. Serum SESN2 parameters were investigated in blood samples drawn from each participant in the patient and control groups.

Results: SESN2 levels were significantly lower in MS patients than in controls (z: -3.06; p=0.002). In the ROC analysis of SESN2, the predictive level for MS was 2.36 ng/mL [sensitivity, 72.50%; specificity, 55.56%; p=0.002; area under the curve (AUC)=0.693]. For the cut-off value in both groups, SESN2 was an independent predictor for MS [Exp (B)=3.977, 95% confidence interval (95%CI) 1.507-10.494 and p=0.013].

Conclusions: The decreased expression of SESN2 may play a role in MS pathogenesis, and SESN2 could be used as a biomarker for MS and as immunotherapeutic agent to treat MS.