scholarly journals Metformin as a Potential Agent in the Treatment of Multiple Sclerosis

2020 ◽  
Vol 21 (17) ◽  
pp. 5957
Author(s):  
Angela Dziedzic ◽  
Joanna Saluk-Bijak ◽  
Elzbieta Miller ◽  
Michal Bijak
Keyword(s):  
Multiple Sclerosis ◽  
Inflammatory Diseases ◽  
Coagulation Cascade ◽  
Oral Antidiabetic Agent ◽  
Immunological Mechanisms ◽  
Increased Risk ◽  
The Central Nervous System ◽  
Synthetic Derivative ◽  
Ischemic Events ◽  
Ms Therapy

Metformin, a synthetic derivative of guanidine, is commonly used as an oral antidiabetic agent and is considered a multi-vector application agent in the treatment of other inflammatory diseases. Recent studies have confirmed the beneficial effect of metformin on immune cells, with special emphasis on immunological mechanisms. Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by various clinical courses. Although the pathophysiology of MS remains unknown, it is most likely a combination of disturbances of the immune system and biochemical pathways with a disruption of blood–brain barrier (BBB), and it is strictly related to injury of intracerebral blood vessels. Metformin has properties which are greatly desirable for MS therapy, including antioxidant, anti-inflammatory or antiplatelet functions. The latest reports relating to the cardiovascular disease confirm an increased risk of ischemic events in MS patients, which are directly associated with a coagulation cascade and an elevated pro-thrombotic platelet function. Hence, this review examines the potential favourable effects of metformin in the course of MS, its role in preventing inflammation and endothelial dysfunction, as well as its potential antiplatelet role.

scholarly journals Ozanimod to Treat Relapsing Forms of Multiple Sclerosis: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

2020 ◽  
Vol 12 (3) ◽  
pp. 89-108
Author(s):  
Grace Lassiter ◽  
Carlie Melancon ◽  
Tyler Rooney ◽  
Anne-Marie Murat ◽  
Jessica S. Kaye ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Drug Efficacy ◽  
Receptor Modulator ◽  
Increased Risk ◽  
Relapsing Remitting ◽  
The Us ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System ◽  
Us Fda ◽  
Reversible Encephalopathy

Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing–remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators.

scholarly journals Investigation of multiple sclerosis-related pathways through the integration of genomic and proteomic data

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11922
Author(s):  
Elif Everest ◽  
Ege Ülgen ◽  
Ugur Uygunoglu ◽  
Melih Tutuncu ◽  
Sabahattin Saip ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
False Negative ◽  
Proteome Analysis ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Coagulation Cascade ◽  
Differentially Expressed Proteins ◽  
Proteomic Data ◽  
Genome Wide ◽  
Immunological Mechanisms

Background Multiple sclerosis (MS) has a complex pathophysiology, variable clinical presentation, and unpredictable prognosis; understanding the underlying mechanisms requires combinatorial approaches that warrant the integration of diverse molecular omics data. Methods Here, we combined genomic and proteomic data of the same individuals among a Turkish MS patient group to search for biologically important networks. We previously identified differentially-expressed proteins by cerebrospinal fluid proteome analysis of 179 MS patients and 42 non-MS controls. Among this study group, 11 unrelated MS patients and 60 independent, healthy controls were subjected to whole-genome SNP genotyping, and genome-wide associations were assessed. Pathway enrichment analyses of MS-associated SNPs and differentially-expressed proteins were conducted using the functional enrichment tool, PANOGA. Results Nine shared pathways were detected between the genomic and proteomic datasets after merging and clustering the enriched pathways. Complement and coagulation cascade was the most significantly associated pathway (hsa04610, P = 6.96 × 10−30). Other pathways involved in neurological or immunological mechanisms included adherens junctions (hsa04520, P = 6.64 × 10−25), pathogenic Escherichia coli infection (hsa05130, P = 9.03 × 10−14), prion diseases (hsa05020, P = 5.13 × 10−13). Conclusion We conclude that integrating multiple datasets of the same patients helps reducing false negative and positive results of genome-wide SNP associations and highlights the most prominent cellular players among the complex pathophysiological mechanisms.

Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic Implications

2021 ◽  
Vol 19 ◽  
Author(s):  
Xu Wang ◽  
Zhen Liang ◽  
Shengnan Wang ◽  
Di Ma ◽  
Mingqin Zhu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gut Microbiota ◽  
Demyelinating Disease ◽  
Inflammatory Diseases ◽  
Intestinal Barrier ◽  
Autoimmune Response ◽  
Therapeutic Implications ◽  
The Central Nervous System ◽  
Underlying Mechanisms

: The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on the gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota has also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.

The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes

2014 ◽  
Vol 0 (0) ◽  
Author(s):  
Maziar Gooshe ◽  
Amir Hossein Abdolghaffari ◽  
Maria Elsa Gambuzza ◽  
Nima Rezaei
Keyword(s):  
Multiple Sclerosis ◽  
Host Defense ◽  
Toll Like Receptors ◽  
Autoimmune Encephalomyelitis ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Ms Therapy ◽  
Experimental Autoimmune

AbstractThe interaction between the immune and nervous systems suggests invaluable mechanisms for several pathological conditions, especially neurodegenerative disorders. Multiple sclerosis (MS) is a potentially disabling chronic autoimmune disease, characterized by chronic inflammation and neurodegenerative pathology of the central nervous system. Toll-like receptors (TLRs) are an important family of receptors involved in host defense and in recognition of invading pathogens. The role of TLRs in the pathogenesis of autoimmune disorders such as MS is only starting to be uncovered. Recent studies suggest an ameliorative role of TLR3 and a detrimental role of other TLRs in the onset and progression of MS and experimental autoimmune encephalomyelitis, a murine model of MS. Thus, modulating TLRs can represent an innovative immunotherapeutic approach in MS therapy. This article outlines the role of these TLRs in MS, also discussing TLR-targeted agonist or antagonists that could be used in the different stages of the disease.

scholarly journals The Molecular Aspects of Disturbed Platelet Activation Through ADP/P2Y12 Pathway in Multiple Sclerosis

2021 ◽  
Vol 22 (12) ◽  
pp. 6572
Author(s):  
Angela Dziedzic ◽  
Elzbieta Miller ◽  
Joanna Saluk-Bijak ◽  
Marta Niwald ◽  
Michal Bijak
Keyword(s):  
Multiple Sclerosis ◽  
Platelet Activation ◽  
Platelet Reactivity ◽  
Adenosine Diphosphate ◽  
Receptor Expression ◽  
P2y12 Receptor ◽  
Platelet Surface ◽  
Molecular Abnormalities ◽  
Increased Risk ◽  
Ischemic Events

Epidemiological studies confirm a high risk of ischemic events in secondary-progressive multiple sclerosis (SP MS) patients, directly associated with an increased level of pro-thrombotic activity of platelets. Our work aimed to verify potential molecular abnormalities of the platelet P2Y12 receptor expression and functionality as a cause of an increased risk of thromboembolism observed in the course of MS. We have demonstrated an enhanced platelet reactivity in response to adenosine diphosphate (ADP) in SP MS relative to controls. We have also shown an increased mRNA expression for the P2RY12 gene in both platelets and megakaryocytes, as well as enhanced density of these receptors on the platelet surface. We postulate that one of the reasons for the elevated risk of ischemic events observed in MS may be a genetically or phenotypically reinforced expression of the platelet P2Y12 receptor. In order to analyze the effect of the PAR1 (protease activated receptor type 1) signaling pathway on the expression level of P2Y12, we also analyzed the correlation parameters between P2Y12 expression and the markers of platelet activation in MS induced by selective PAR1 agonist (thrombin receptor activating peptide-6, TRAP-6). Identifying the molecular base responsible for the enlarged pro-thrombotic activity of platelets in SP MS could contribute to the implementation of prevention and targeted treatment, reducing the development of cardiovascular disorders in the course of the disease.

scholarly journals Role of CCR2 in Inflammatory Conditions of the Central Nervous System

2014 ◽  
Vol 34 (9) ◽  
pp. 1425-1429 ◽  
Author(s):  
Hannah X Chu ◽  
Thiruma V Arumugam ◽  
Mathias Gelderblom ◽  
Tim Magnus ◽  
Grant R Drummond ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Ischemic Stroke ◽  
Inflammatory Diseases ◽  
Protective Effects ◽  
Cns Inflammation ◽  
Inflammatory Conditions ◽  
The Central Nervous System ◽  
Effective Development

CC chemokine receptor 2 (CCR2) plays important roles in extravasation and transmigration of monocytes under inflammatory conditions. CCR2 and its ligands have been extensively studied in a range of inflammatory diseases in the central nervous system (CNS), including multiple sclerosis, Alzheimer's disease and ischemic stroke. This brief review summarizes our current understanding of the physiologic and pathologic roles of CCR2, focusing on its involvement in CNS inflammatory diseases. There appears to be a rationale for exploring therapies involving CCR2 inhibition in multiple sclerosis and ischemic stroke, but there is also evidence for immunomodulatory and protective effects of CCR2 activity during CNS inflammation. The critical balance between protective and detrimental roles of CCR2-dependent recruitment of leukocytes must therefore be carefully examined to guide safe and effective development of any therapies involving CCR2 modulation.

scholarly journals Th17-Related Cytokines as Potential Discriminatory Markers between Neuromyelitis Optica (Devic’s Disease) and Multiple Sclerosis—A Review

2021 ◽  
Vol 22 (16) ◽  
pp. 8946
Author(s):  
Karina Maciak ◽  
Sylwia Pietrasik ◽  
Angela Dziedzic ◽  
Justyna Redlicka ◽  
Joanna Saluk-Bijak ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Neuromyelitis Optica ◽  
Inflammatory Diseases ◽  
Similar Treatment ◽  
Devic’S Disease ◽  
Devic's Disease ◽  
The Central Nervous System ◽  
Clinical Pictures

Multiple sclerosis (MS) and Devic’s disease (NMO; neuromyelitis optica) are autoimmune, inflammatory diseases of the central nervous system (CNS), the etiology of which remains unclear. It is a serious limitation in the treatment of these diseases. The resemblance of the clinical pictures of these two conditions generates a partial possibility of introducing similar treatment, but on the other hand, a high risk of misdiagnosis. Therefore, a better understanding and comparative characterization of the immunopathogenic mechanisms of each of these diseases are essential to improve their discriminatory diagnosis and more effective treatment. In this review, special attention is given to Th17 cells and Th17-related cytokines in the context of their potential usefulness as discriminatory markers for MS and NMO. The discussed results emphasize the role of Th17 immune response in both MS and NMO pathogenesis, which, however, cannot be considered without taking into account the broader perspective of immune response mechanisms.

scholarly journals Caspase-11 Mediates Oligodendrocyte Cell Death and Pathogenesis of Autoimmune-Mediated Demyelination

2001 ◽  
Vol 193 (1) ◽  
pp. 111-122 ◽  
Author(s):  
Shin Hisahara ◽  
Junying Yuan ◽  
Takashi Momoi ◽  
Hideyuki Okano ◽  
Masayuki Miura
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Central Nervous System ◽  
Cell Death ◽  
Caspase 3 ◽  
Inflammatory Diseases ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Deficient Mice ◽  
Experimental Autoimmune

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11–deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11–deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.

scholarly journals Computational modeling of the immune response in multiple sclerosis using epimod framework

2020 ◽  
Vol 21 (S17) ◽  
Author(s):  
Simone Pernice ◽  
Laura Follia ◽  
Alessandro Maglione ◽  
Marzio Pennisi ◽  
Francesco Pappalardo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Well Being ◽  
Individual Variability ◽  
New Model ◽  
Peripheral Lymph ◽  
Immunological Mechanisms ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Cell Balance

Abstract Background Multiple Sclerosis (MS) represents nowadays in Europe the leading cause of non-traumatic disabilities in young adults, with more than 700,000 EU cases. Although huge strides have been made over the years, MS etiology remains partially unknown. Furthermore, the presence of various endogenous and exogenous factors can greatly influence the immune response of different individuals, making it difficult to study and understand the disease. This becomes more evident in a personalized-fashion when medical doctors have to choose the best therapy for patient well-being. In this optics, the use of stochastic models, capable of taking into consideration all the fluctuations due to unknown factors and individual variability, is highly advisable. Results We propose a new model to study the immune response in relapsing remitting MS (RRMS), the most common form of MS that is characterized by alternate episodes of symptom exacerbation (relapses) with periods of disease stability (remission). In this new model, both the peripheral lymph node/blood vessel and the central nervous system are explicitly represented. The model was created and analysed using Epimod, our recently developed general framework for modeling complex biological systems. Then the effectiveness of our model was shown by modeling the complex immunological mechanisms characterizing RRMS during its course and under the DAC administration. Conclusions Simulation results have proven the ability of the model to reproduce in silico the immune T cell balance characterizing RRMS course and the DAC effects. Furthermore, they confirmed the importance of a timely intervention on the disease course.

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