Multiple Sclerosis Therapies: Molecular Mechanisms and Future

2009 ◽  
pp. 259-285 ◽  
Author(s):  
Paulo Fontoura ◽  
Hideki Garren
Keyword(s):  
Multiple Sclerosis ◽  
Molecular Mechanisms

scholarly journals Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

2021 ◽  
Vol 141 (4) ◽  
pp. 585-604 ◽  
Author(s):  
Carmen Picon ◽  
Anusha Jayaraman ◽  
Rachel James ◽  
Catriona Beck ◽  
Patricia Gallego ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Signaling Pathway ◽  
Cortical Neurons ◽  
Grey Matter ◽  
Molecular Mechanisms ◽  
Fold Increase ◽  
Cell Types ◽  
Meningeal Inflammation ◽  
Cortical Grey Matter

AbstractSustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

Disentangling the molecular mechanisms of multiple sclerosis: The contribution of twin studies

2020 ◽  
Vol 111 ◽  
pp. 194-198 ◽  
Author(s):  
M.C. Buscarinu ◽  
A. Fornasiero ◽  
M. Ferraldeschi ◽  
S. Romano ◽  
R. Reniè ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Molecular Mechanisms ◽  
Twin Studies

scholarly journals Transcriptomic Profile Reveals Gender-Specific Molecular Mechanisms Driving Multiple Sclerosis Progression

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e90482 ◽  
Author(s):  
Haritz Irizar ◽  
Maider Muñoz-Culla ◽  
Lucia Sepúlveda ◽  
Matías Sáenz-Cuesta ◽  
Álvaro Prada ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Molecular Mechanisms ◽  
Transcriptomic Profile ◽  
Gender Specific

scholarly journals Drugs modulating apoptosis: current status

2021 ◽  
Vol 10 (7) ◽  
pp. 870
Author(s):  
Vimala Ananthy ◽  
Raman P. Priyadharsini ◽  
Umamaheswari Subramanian
Keyword(s):  
Multiple Sclerosis ◽  
Combinatorial Chemistry ◽  
Molecular Mechanisms ◽  
Natural Process ◽  
The Body ◽  
Current Status ◽  
Preclinical Studies ◽  
Bcl2 Family ◽  
Novel Approach ◽  
Novel Approaches

Apoptosis (programmed cell death) is a natural process that helps in removing potentially harmful cells from the body and replacing it with normal ones. Like any other process, it is also subjected to lots of deregulations and can lead to diseases like cancer, neurodegenerative conditions, multiple sclerosis, Parkinson’s disease, autoimmune disorders and inappropriate death of cells after liver failure, stroke and myocardial infarction. The knowledge of the molecular mechanisms involved in apoptosis has been progressed tremendously. Thus, therapeutics targeting apoptosis have been emerged as a novel approach for treating various disease conditions. Current approaches induce or inhibit apoptosis by targeting the key regulators of apoptosis such as Bcl2 family of proteins, TRAIL, caspases, MDM2, IAPs and p53. While many apoptotic drugs proved its efficacy in preclinical studies, some are already approved and entered the clinical setting. Numerous novel approaches such as antisense therapy, gene therapy, recombinant biologics and combinatorial chemistry are being employed to target these regulators. This review focused on the pathways of apoptosis, various therapeutic targets in apoptosis and the drugs modulating these targets.

scholarly journals Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

2021 ◽  
Vol 12 ◽  
Author(s):  
Shashank Kumar Maurya ◽  
Neetu Bhattacharya ◽  
Suman Mishra ◽  
Amit Bhattacharya ◽  
Pratibha Banerjee ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Natural Products ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Neuroprotective Effect ◽  
Inhibitory Effect ◽  
Dual Function ◽  
Redox Imbalance ◽  
The Brain

Microglia, a type of innate immune cell of the brain, regulates neurogenesis, immunological surveillance, redox imbalance, cognitive and behavioral changes under normal and pathological conditions like Alzheimer’s, Parkinson’s, Multiple sclerosis and traumatic brain injury. Microglia produces a wide variety of cytokines to maintain homeostasis. It also participates in synaptic pruning and regulation of neurons overproduction by phagocytosis of neural precursor cells. The phenotypes of microglia are regulated by the local microenvironment of neurons and astrocytes via interaction with both soluble and membrane-bound mediators. In case of neuron degeneration as observed in acute or chronic neurodegenerative diseases, microglia gets released from the inhibitory effect of neurons and astrocytes, showing activated phenotype either of its dual function. Microglia shows neuroprotective effect by secreting growths factors to heal neurons and clears cell debris through phagocytosis in case of a moderate stimulus. But the same microglia starts releasing pro-inflammatory cytokines like TNF-α, IFN-γ, reactive oxygen species (ROS), and nitric oxide (NO), increasing neuroinflammation and redox imbalance in the brain under chronic signals. Therefore, pharmacological targeting of microglia would be a promising strategy in the regulation of neuroinflammation, redox imbalance and oxidative stress in neurodegenerative diseases. Some studies present potentials of natural products like curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane to suppress activation of microglia. These natural products have also been proposed as effective therapeutics to regulate the progression of neurodegenerative diseases. The present review article intends to explain the molecular mechanisms and functions of microglia and molecular dynamics of microglia specific genes and proteins like Iba1 and Tmem119 in neurodegeneration. The possible interventions by curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane on microglia specific protein Iba1 suggest possibility of natural products mediated regulation of microglia phenotypes and its functions to control redox imbalance and neuroinflammation in management of Alzheimer’s, Parkinson’s and Multiple Sclerosis for microglia-mediated therapeutics.

scholarly journals Large-scale genomic study reveals robust activation of the immune system following advanced Inner Engineering meditation retreat.

2021 ◽  
Author(s):  
Vijayendran Chandran ◽  
Mei-Ling Bermudez ◽  
Mert Koka ◽  
Dhanashri Pawale ◽  
Ramana Vishnubhotla ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Positive Impact ◽  
Core Network ◽  
Protein Protein Interaction ◽  
Genomic Study ◽  
Meditation Retreat ◽  
Significant Expression

The positive impact of meditation on human wellbeing is well documented, yet its molecular mechanisms are incompletely understood. We applied a comprehensive systems biology approach starting with whole blood gene expression profiling combined with multi-level bioinformatic analyses to characterize the co-expression, transcriptional, and protein-protein interaction networks to identify meditation-specific core network after an advanced 8-day Inner Engineering retreat program. We found the response to oxidative stress, detoxification, and cell cycle regulation pathways were downregulated after meditation. Strikingly, 220 genes directly associated with immune response, including 68 genes related to interferon (IFN) signaling were upregulated, with no significant expression changes in the inflammatory genes. This robust meditation-specific immune response network is significantly dysregulated in multiple sclerosis and severe COVID-19 patients. The work provides a foundation for understanding the effect of meditation and potential implications to voluntarily and non-pharmacologically improve the immune response before immunotherapy for many conditions, including multiple sclerosis and COVID-19 vaccination.

scholarly journals The Demonstration of an Aqp4/Tgf-Beta 1 Pathway in Murine Astrocytes Holds Implications for Both Neuromyelitis Optica and Progressive Multiple Sclerosis

2020 ◽  
Vol 21 (3) ◽  
pp. 1035 ◽  
Author(s):  
Serge Nataf
Keyword(s):  
Multiple Sclerosis ◽  
Neuromyelitis Optica ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Progressive Multiple Sclerosis ◽  
Effective Control ◽  
Immune Functions ◽  
Pathway Data ◽  
The Central Nervous System

The role exerted by Aquaporin 4 (AQP4) as a regulator of astrocyte immune functions has been poorly explored. A recent report demonstrates that under neuroinflammatory conditions, the expression of Aqp4 on murine astrocytes is mandatory for the effective control of acute inflammation in the central nervous system. Such an immunomodulatory function appears to be mediated by a promotion of the transforming growth factor beta 1 (Tgfb1) pathway. Here, these results are discussed in the context of neuromyelitis optica (NMO) and multiple sclerosis (MS) progressive forms. It is proposed that NMO and progressive MS might rely on opposite molecular mechanisms involving, in NMO, an acutely-defective AQP4/TGFB1 pathway and, in progressive MS, a chronically-stimulated AQP4/TGFB1 pathway. Data supporting the involvement of angiotensin II as a molecular link between AQP4 and TGFB1 are also reviewed.

Molecular mechanisms of oxidative tissue injury differ between multiple sclerosis and experimental disease models

2014 ◽  
Vol 275 (1-2) ◽  
pp. 109
Author(s):  
Isabella Wimmer ◽  
Cornelia Schuh ◽  
Simon Hametner ◽  
Jan Bauer ◽  
Monika Bradl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Disease Models ◽  
Experimental Disease

scholarly journals Intrathecal Inflammation in Progressive Multiple Sclerosis

2020 ◽  
Vol 21 (21) ◽  
pp. 8217
Author(s):  
Salvatore Monaco ◽  
Richard Nicholas ◽  
Richard Reynolds ◽  
Roberta Magliozzi
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Gray Matter ◽  
Molecular Mechanisms ◽  
Progressive Multiple Sclerosis ◽  
Brain Parenchyma ◽  
Inflammatory Factors ◽  
Deep Gray Matter ◽  
Bidirectional Exchange

Progressive forms of multiple sclerosis (MS) are associated with chronic demyelination, axonal loss, neurodegeneration, cortical and deep gray matter damage, and atrophy. These changes are strictly associated with compartmentalized sustained inflammation within the brain parenchyma, the leptomeninges, and the cerebrospinal fluid. In progressive MS, molecular mechanisms underlying active demyelination differ from processes that drive neurodegeneration at cortical and subcortical locations. The widespread pattern of neurodegeneration is consistent with mechanisms associated with the inflammatory molecular load of the cerebrospinal fluid. This is at variance with gray matter demyelination that typically occurs at focal subpial sites, in the proximity of ectopic meningeal lymphoid follicles. Accordingly, it is possible that variations in the extent and location of neurodegeneration may be accounted for by individual differences in CSF flow, and by the composition of soluble inflammatory factors and their clearance. In addition, “double hit” damage may occur at sites allowing a bidirectional exchange between interstitial fluid and CSF, such as the Virchow–Robin spaces and the periventricular ependymal barrier. An important aspect of CSF inflammation and deep gray matter damage in MS involves dysfunction of the blood–cerebrospinal fluid barrier and inflammation in the choroid plexus. Here, we provide a comprehensive review on the role of intrathecal inflammation compartmentalized to CNS and non-neural tissues in progressive MS.

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