scholarly journals Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 901 ◽  
Author(s):  
Elena Obrador ◽  
Rosario Salvador ◽  
Rafael López-Blanch ◽  
Ali Jihad-Jebbar ◽  
Soraya L. Vallés ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Cell Types ◽  
T Cell Subsets ◽  
Cellular Interactions ◽  
Underlying Mechanisms ◽  
Different Cell Types ◽  
And Oxidative Stress ◽  
Different Levels ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

scholarly journals Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

2021 ◽  
Vol 14 ◽  
Author(s):  
Elise Liu ◽  
Léa Karpf ◽  
Delphine Bohl
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune System ◽  
Frontotemporal Dementia ◽  
Immune Cells ◽  
Immune Cell ◽  
Current Knowledge ◽  
Cell Types ◽  
Induced Pluripotent ◽  
Different Cell Types ◽  
Lateral Sclerosis

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

Amyotrophic Lateral Sclerosis and Oxidative Stress: A Double-Blind Therapeutic Trial After Curcumin Supplementation

2018 ◽  
Vol 17 (10) ◽  
pp. 767-779 ◽  
Author(s):  
Lucia Chico ◽  
Elena Caldarazzo Ienco ◽  
Costanza Bisordi ◽  
Annalisa Lo Gerfo ◽  
Lucia Petrozzi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Control Group ◽  
Therapeutic Trial ◽  
Entire Study ◽  
Reducing Ability ◽  
Group A ◽  
Group B ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Objective: To investigate the efficacy of curcumin oral supplementation (600 mg/day, Brainoil), a natural antioxidant compound, in Amyotrophic Lateral Sclerosis (ALS). Methods: Patients were randomized into two groups: Group A received placebo for 3 months, then Brainoil for the following 3 months, Group B took Brainoil for 6 months. The evaluations were conducted at basal (T0), after 3 months of double blinded Brainoil or placebo treatment (T1), and after the 3 month open-label phase (T2). Clinical evaluations and oxidative stress biomarkers, including oxidative protein products (AOPPs), ferric reducing ability (FRAP), total thiols (T-SH) and lactate, were evaluated, compared to a control group, during an incremental forearm exercise test. Results: Over the entire study Group B showed a stable score of the ALS-FRS-r which decreased in Group A (p<0.01), in parallel with a reduction of AOPPs (p<0.01) which was not detected into Group A. Also FRAP exercise values remained stable in Group B, while in Group A they were reduced without treatment at T1 (0.05<p<0.01), for then increase at T2 with introduction of therapy (p<0.05). In Group B T1>T0 exercise lactate was lower compared to Group A (p<0.01). Compared to controls, the whole ALS population showed a greater oxidative stress (p<0.001), those treated with curcumin (Group B) exhibiting decreased exercise AOPPs at T2 with values approaching those of controls. Conclusion: Although further studies are needed to confirm these data, treatment with curcumin shows encouraging results indicating a slight slowdown in disease progression, improving aerobic metabolism and oxidative damage, this also contributing to deepen knowledge into the pathogenic mechanisms of ALS.

scholarly journals Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Martina Milani ◽  
Eleonora Mammarella ◽  
Simona Rossi ◽  
Chiara Miele ◽  
Serena Lattante ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cell Types ◽  
Specific Protein ◽  
Beneficial Effects ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
Als Patients ◽  
Different Cell Types ◽  
Lateral Sclerosis

Abstract Background An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology. Methods Here, we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology. Results We demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic, and profibrotic pathways in ALS fibroblasts, and interferes with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA, and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA, and PDGFRβ in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis. Conclusion Our findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide which are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.

scholarly journals Biomolecular Modifications Linked to Oxidative Stress in Amyotrophic Lateral Sclerosis: Determining Promising Biomarkers Related to Oxidative Stress

Processes ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1667
Author(s):  
Takashi Hosaka ◽  
Hiroshi Tsuji ◽  
Akira Tamaoka
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Extracellular Proteins ◽  
Clinical Effects ◽  
Oxidation Reactions ◽  
Incurable Disease ◽  
The Central Nervous System ◽  
Underlying Mechanisms ◽  
Lateral Sclerosis

Reduction–oxidation reactions are essential to cellular homeostasis. Oxidative stress transcends physiological antioxidative system damage to biomolecules, including nucleic acids and proteins, and modifies their structures. Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. The cells present in the central nervous system, including motor neurons, are vulnerable to oxidative stress. Neurodegeneration has been demonstrated to be caused by oxidative biomolecular modifications. Oxidative stress has been suggested to be involved in the pathogenesis of ALS. Recent progress in research on the underlying mechanisms of oxidative stress in ALS has led to the development of disease-modifying therapies, including edaravone. However, the clinical effects of edaravone remain limited, and ALS is a heretofore incurable disease. The reason for the lack of reliable biomarkers and the precise underlying mechanisms between oxidative stress and ALS remain unclear. As extracellular proteins and RNAs present in body fluids and represent intracellular pathological neurodegenerative processes, extracellular proteins and/or RNAs are predicted to promise diagnosis, prediction of disease course, and therapeutic biomarkers for ALS. Therefore, we aimed to elucidate the underlying mechanisms between oxidative stress and ALS, and promising biomarkers indicating the mechanism to determine whether therapy targeting oxidative stress can be fundamental for ALS.

scholarly journals Niclosamide Targets Inflammatory and Profibrotic Pathways in Amyotrophic Lateral Sclerosis

2021 ◽  
Author(s):  
Martina Milani ◽  
Eleonora Mammarella ◽  
Simona Rossi ◽  
Serena Lattante ◽  
Mario Sabatelli ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cell Types ◽  
Specific Protein ◽  
Beneficial Effects ◽  
Hexanucleotide Repeat ◽  
Sporadic Als ◽  
Als Patients ◽  
Different Cell Types ◽  
Lateral Sclerosis

Abstract BackgroundAn increasing number of studies evidence that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the up-regulation in ALS models of a gene called fibroblast-specific protein (FSP)-1 or S100A4, generally recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functioning, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology.MethodsHere we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and sporadic ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology.ResultsWe demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic and profibrotic pathways in ALS fibroblasts, and to interfere with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA and PDGFRβ in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis.ConclusionOur findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide that are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.

scholarly journals Microvesicle Formation Induced by Oxidative Stress in Human Erythrocytes

2020 ◽  
Author(s):  
Julia Sudnitsyna ◽  
Elisaveta Skverchinskaya ◽  
Irina Dobrylko ◽  
Elena R. Nikitina ◽  
Stepan Gambaryan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Cell Types ◽  
Band 3 ◽  
Cell Deformability ◽  
Physiological Conditions ◽  
Oxidant Concentration ◽  
Tert Butyl Hydroperoxide ◽  
Different Cell Types ◽  
And Oxidative Stress

Extracellular vesicles (EVs) released by different cell types play significant role in many physiological and pathophysiological processes. In physiological conditions red blood cells (RBCs) derived EVs compose 4 - 8% of all circulating EVs, and oxidative stress (OS) as a consequence of different pathophysiological conditions significantly increases the amount of circulated RBC-derived EVs, however the mechanisms of EV formation are not fully defined yet. To analyze OS-induced EV formation and RBCs transformations we used flow cytometry to evaluate cell esterase activity, caspase-3 activity, and band 3 clustering. Band 3 clustering was additionally analyzed by confocal microscopy. Two original laser diffraction-based approaches were used for analysis of cell deformability and band 3 activity. Hemoglobin species were characterized spectrophotometrically. We showed that cell viability in tert-butyl hydroperoxide-induced OS directly correlated with oxidant concentration to cell count ratio, RBCs-derived EVs contained hemoglobin oxidized to hemichrome (HbChr). OS induced caspase-3 activation and band 3 clustering in cells and EVs. Importantly, we showed that OS-induced EV formation is independent from calcium. Presented data indicated that during OS RBCs eliminate HbChr by vesiculation, in order to sacrifice the cell itself thereby prolonging lifespan and delaying the untimely clearance of in all other respects healthy RBCs.

Neuroprotective potential of adenyl cyclase/cAMP/CREB and mitochondrial CoQ10 activator in amyotrophic lateral sclerosis rats

2020 ◽  
Vol 16 ◽  
Author(s):  
Mohmmad Mamtaj Alam ◽  
Elijabeth Minj ◽  
Rajeshwar Kumar Yadav ◽  
Sidharth Mehan
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Drug Therapy ◽  
Therapeutic Approach ◽  
Methyl Mercury ◽  
Chronic Treatment ◽  
Adenyl Cyclase ◽  
Als Patients ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Aim: To investigate neuroprotective potential of of forskolin (FSK) in combination with solanesol (SNL) along with clinically proven drugs (riluzole, baclofen, citalopram) on behavioral, molecular and neurochemical alterations in methyl mercury-induced amyotrophic lateral sclerosis (ALS) rats. Background: ALS is a motor neuron disease in which oxidative stress is the principle mechanism ofneuronal death which can be mimicked by the dominant mutations in an antioxidant enzyme SOD-1. Due to MeHg neurotoxicity, behavioral and neurochemical alterations occur in rats. During ALS mitochondrial CoQ10 dysfunctioning and downregulation of adenyl cyclase/CREB are major pathological hallmark for neurodegeneration in ALS. Clinically proven drug therapy comes with limited therapeutic involvement, and is used as approachable therapy in ALS patients. Objective: Therefore, current research explores the up-regulation of adenyl cyclase/cAMP/CREB by FSK 30, 60 mg/kg in combination with mitochondrial ETC-coenzyme-Q10 precursor SNL 15, 30 mg/kg can be a preventive therapeutic approach to overcome the ALS like symptoms. Method: MeHg (5 mg/kg) is a neurotoxic compound that leads to ALS like behavioral & neurochemical alterations. Results: Chronic treatment with the combination of FSK 30,60 mg/kg and SNL 15,30 mg/kg alone and along with standard drugs citalopram (5 mg/kg), riluzole (5 mg/kg) and baclofen (3 mg/kg) increased the adenyl cyclase and mitochondrial CoQ10 and ETC-complexes enzyme levels and shows the neuroprotective potential by significantly improving the cognitive deficitslocomotion, , grip strength, and restoration of neurochemicals alterations along with reducing the level of inflammatory mediators and oxidative stress in ALS rats. Conclusion: Thus, we concluded that FSK in combination with SNL along with standard drugs can be a possible therapeutic approach for the treatment of ALS.

scholarly journals Targeting tau mitigates mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Tiziana Petrozziello ◽  
Evan A. Bordt ◽  
Alexandra N. Mills ◽  
Spencer E. Kim ◽  
Ellen Sapp ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Hyperphosphorylated Tau ◽  
Post Mortem ◽  
Related Protein ◽  
Mitochondrial Fragmentation ◽  
Novel Strategy ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

Understanding the mechanisms underlying amyotrophic lateral sclerosis (ALS) is crucial for the development of new therapies. Recent evidence suggest that tau may be involved in ALS pathogenesis. Here, we demonstrated that hyperphosphorylated tau (pTau-S396) is mis-localized to synapses in human post-mortem motor cortex (mCTX) across ALS subtypes. Treatment with ALS synaptoneurosomes (SNs) derived from post-mortem mCTX, enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity in vitro. Furthermore, our findings revealed that pTau-S396 interacts with the pro-fission dynamin-related protein (DRP1), and similar to pTau-S396, DRP1 accumulated in ALS SNs across ALS subtypes. Lastly, reducing tau with a specific bifunctional degrader, QC-01-175, prevented ALS SNs-induced mitochondrial fragmentation and oxidative stress in vitro. Collectively, our findings suggest that increases in pTau-S396 may lead to mitochondrial fragmentation and oxidative stress in ALS and decreasing tau may provide a novel strategy to mitigate mitochondrial dysfunction in ALS.

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