scholarly journals ILB® Attenuates Clinical Symptoms and Serum Biomarkers of Oxidative/Nitrosative Stress and Mitochondrial Dysfunction in Patients with Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (8) ◽  
pp. 794
Author(s):  
Giacomo Lazzarino ◽  
Renata Mangione ◽  
Antonio Belli ◽  
Valentina Di Pietro ◽  
Zsuzsanna Nagy ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mitochondrial Dysfunction ◽  
High Performance ◽  
Nitrosative Stress ◽  
Clinical Symptoms ◽  
Serum Levels ◽  
Significant Amelioration ◽  
Inflammatory Processes ◽  
Clinical Conditions ◽  
Lateral Sclerosis

Oxidative/nitrosative stress and mitochondrial dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS), an invariably fatal progressive neurodegenerative disease. Here, as an exploratory arm of a phase II clinical trial (EudraCT Number 2017-005065-47), we used high performance liquid chromatography(HPLC) to investigate changes in the metabolic profiles of serum from ALS patients treated weekly for 4 weeks with a repeated sub-cutaneous dose of 1 mg/kg of a proprietary low molecular weight dextran sulphate, called ILB®. A significant normalization of the serum levels of several key metabolites was observed over the treatment period, including N-acetylaspartate (NAA), oxypurines, biomarkers of oxidative/nitrosative stress and antioxidants. An improved serum metabolic profile was accompanied by significant amelioration of the patients’ clinical conditions, indicating a response to ILB® treatment that appears to be mediated by improvement of tissue bioenergetics, decrease of oxidative/nitrosative stress and attenuation of (neuro)inflammatory processes.

scholarly journals Implication of 5-HT in the Dysregulation of Chloride Homeostasis in Prenatal Spinal Motoneurons from the G93A Mouse Model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 21 (3) ◽  
pp. 1107 ◽  
Author(s):  
Elodie Martin ◽  
William Cazenave ◽  
Anne-Emilie Allain ◽  
Daniel Cattaert ◽  
Pascal Branchereau
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
High Performance ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Lumbar Spinal Cord ◽  
Spinal Motoneurons ◽  
Chloride Homeostasis ◽  
Lumbar Spinal ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. The early presymptomatic onset of abnormal processes is indicative of cumulative defects that ultimately lead to a late manifestation of clinical symptoms. It remains of paramount importance to identify the primary defects that underlie this condition and to determine how these deficits lead to a cycle of deterioration. We recently demonstrated that prenatal E17.5 lumbar spinal motoneurons (MNs) from SOD1G93A mice exhibit a KCC2-related alteration in chloride homeostasis, i.e., the EGABAAR is more depolarized than in WT littermates. Here, using immunohistochemistry, we found that the SOD1G93A lumbar spinal cord is less enriched with 5-HT descending fibres than the WT lumbar spinal cord. High-performance liquid chromatography confirmed the lower level of the monoamine 5-HT in the SOD1G93A spinal cord compared to the WT spinal cord. Using ex vivo perforated patch-clamp recordings of lumbar MNs coupled with pharmacology, we demonstrated that 5-HT strongly hyperpolarizes the EGABAAR by interacting with KCC2. Therefore, the deregulation of the interplay between 5-HT and KCC2 may explain the alteration in chloride homeostasis detected in prenatal SOD1G93A MNs. In conclusion, 5-HT and KCC2 are two likely key factors in the presymptomatic phase of ALS, particular in familial ALS involving the SOD1G93A mutation.

scholarly journals Role of Oxidative Stress in the Pathogenesis of Amyotrophic Lateral Sclerosis: Antioxidant Metalloenzymes and Therapeutic Strategies

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 437
Author(s):  
Pavlína Hemerková ◽  
Martin Vališ
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Antioxidant Enzymes ◽  
Oxygen Radicals ◽  
Clinical Symptoms ◽  
Free Oxygen Radicals ◽  
Free Oxygen ◽  
Sporadic Als ◽  
Familial Form ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) affects motor neurons in the cerebral cortex, brainstem and spinal cord and leads to death due to respiratory failure within three to five years. Although the clinical symptoms of this disease were first described in 1869 and it is the most common motor neuron disease and the most common neurodegenerative disease in middle-aged individuals, the exact etiopathogenesis of ALS remains unclear and it remains incurable. However, free oxygen radicals (i.e., molecules containing one or more free electrons) are known to contribute to the pathogenesis of this disease as they very readily bind intracellular structures, leading to functional impairment. Antioxidant enzymes, which are often metalloenzymes, inactivate free oxygen radicals by converting them into a less harmful substance. One of the most important antioxidant enzymes is Cu2+Zn2+ superoxide dismutase (SOD1), which is mutated in 20% of cases of the familial form of ALS (fALS) and up to 7% of sporadic ALS (sALS) cases. In addition, the proper functioning of catalase and glutathione peroxidase (GPx) is essential for antioxidant protection. In this review article, we focus on the mechanisms through which these enzymes are involved in the antioxidant response to oxidative stress and thus the pathogenesis of ALS and their potential as therapeutic targets.

scholarly journals IL6 receptor358Ala variant and trans-signaling are disease modifiers in amyotrophic lateral sclerosis

2019 ◽  
Vol 6 (6) ◽  
pp. e631 ◽  
Author(s):  
Marlena Wosiski-Kuhn ◽  
Mac Robinson ◽  
Jane Strupe ◽  
Phonepasong Arounleut ◽  
Matthew Martin ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Interleukin 6 ◽  
Serum Levels ◽  
Interleukin 6 Receptor ◽  
The Common ◽  
Paired Serum ◽  
Control Study ◽  
Lateral Sclerosis

ObjectiveTo test the hypothesis that patients with amyotrophic lateral sclerosis (ALS) inheriting the common interleukin 6 receptor (IL6R) coding variant (Asp358Ala, rs2228145, C allele) have associated increases in interleukin 6 (IL6) and IL6R levels in serum and CSF and faster disease progression than noncarriers.MethodsAn observational, case-control study of paired serum and CSF of 47 patients with ALS, 46 healthy, and 23 neurologic disease controls from the Northeastern ALS Consortium Biofluid Repository (cohort 1) was performed to determine serum levels of IL6, sIL6R, and soluble glycoprotein 130 and compared across groups and IL6R genotype. Clinical data regarding disease progression from a separate cohort of 35 patients with ALS from the Wake Forest ALS Center (cohort 2) were used to determine change in ALSFRS-R scores by genotype.ResultsPatients with ALS had increased CSF IL6 levels compared with healthy (p < 0.001) and neurologic (p = 0.021) controls. Patients with ALS also had increased serum IL6 compared with healthy (p = 0.040) but not neurologic controls. Additive allelic increases in serum IL6R were observed in all groups (average increase of 52% with the presence of the IL6R C allele; p < 0.001). However, only subjects with ALS had significantly increased CSF sIL6R levels compared with controls (p < 0.001). When compared across genotypes, only patients with ALS inheriting the IL6R C allele exhibit increased CSF IL6. ALSFRS-R scores decreased more in patients with ALS with the IL6R C allele than in those without (p = 0.019).ConclusionsTheses results suggest that for individuals inheriting the IL6R C allele, the cytokine exerts a disease- and location-specific role in ALS. Follow-up, prospective studies are necessary, as this subgroup of patients may be identified as ideally responsive to IL6 receptor–blocking therapies.

scholarly journals A(a)LS: Ammonia-induced amyotrophic lateral sclerosis

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 119 ◽  
Author(s):  
Bhavin Parekh
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Er Stress ◽  
Motor Neuron ◽  
Calcium Binding ◽  
Binding Proteins ◽  
Nitrosative Stress ◽  
Calcium Binding Proteins ◽  
Ammonia Removal ◽  
Extensive Literature ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a dreadful, devastating and incurable motor neuron disease. Aetiologically, it is a multigenic, multifactorial and multiorgan disease. Despite intense research, ALS pathology remains unexplained. Following extensive literature review, this paper posits a new integrative explanation. This framework proposes that ammonia neurotoxicity is a main player in ALS pathogenesis. According to this explanation, a combination of impaired ammonia removal— mainly because of impaired hepatic urea cycle dysfunction—and increased ammoniagenesis— mainly because of impaired glycolytic metabolism in fast twitch skeletal muscle—causes chronic hyperammonia in ALS. In the absence of neuroprotective calcium binding proteins (calbindin, calreticulin and parvalbumin), elevated ammonia—a neurotoxin—damages motor neurons. Ammonia-induced motor neuron damage occurs through multiple mechanisms such as macroautophagy-endolysosomal impairment, endoplasmic reticulum (ER) stress, CDK5 activation, oxidative/nitrosative stress, neuronal hyperexcitability and neuroinflammation. Furthermore, the regional pattern of calcium binding proteins’ loss, owing to either ER stress and/or impaired oxidative metabolism, determines clinical variability of ALS. Most importantly, this new framework can be generalised to explain other neurodegenerative disorders such as Huntington’s disease and Parkinsonism.

scholarly journals Targeting mitochondrial dysfunction in amyotrophic lateral sclerosis: a systematic review and meta-analysis

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Arpan R Mehta ◽  
Rachel Walters ◽  
Fergal M Waldron ◽  
Suvankar Pal ◽  
Bhuvaneish T Selvaraj ◽  
...  
Keyword(s):  
Systematic Review ◽  
Amyotrophic Lateral Sclerosis ◽  
Mitochondrial Dysfunction ◽  
Effect Size ◽  
Survival Data ◽  
Meta Analysis ◽  
Disease Onset ◽  
Publication Date ◽  
Improvement In Survival ◽  
Lateral Sclerosis

Abstract Interventions targeting mitochondrial dysfunction have the potential to extend survival in preclinical models of amyotrophic lateral sclerosis. The aim of this systematic review was to assess the efficacy of targeting mitochondria as a potential therapeutic target in amyotrophic lateral sclerosis. Preclinical studies written in the English language were identified with no restrictions on publication date from PubMed, Medline and EMBASE databases. All studies adopting interventions targeting mitochondria to treat amyotrophic lateral sclerosis in genetic or drug-induced organism models were considered for inclusion. A total of 76 studies were included in the analysis. Survival data were extracted, and the meta-analysis was completed in RevMan 5 software. We show that targeting mitochondrial dysfunction in amyotrophic lateral sclerosis results in a statistically significant improvement in survival (Z = 5.31; P &lt; 0.00001). The timing of administration of the intervention appears to affect the improvement in survival, with the greatest benefit occurring for interventions given prior to disease onset. Interventions at other time points were not significant, although this is likely to be secondary to a lack of publications examining these timepoints. The quality score had no impact on efficacy, and publication bias revealed an overestimation of the effect size, owing to one outlier study; excluding this led to the recalculated effect size changing from 5.31 to 3.31 (P &lt; 0.00001). The extant preclinical literature indicates that targeting mitochondrial dysfunction may prolong survival in amyotrophic lateral sclerosis, particularly if the intervention is administered early. A limitation of current research is a significant bias towards models based on superoxide dismutase 1, with uncertainty about generalisability to amyotrophic lateral sclerosis with an underlying TAR DNA binding protein 43 proteinopathy. However, further mechanistic research is clearly warranted in this field.

scholarly journals Mitochondrial Dysfunction, Neurogenesis, and Epigenetics: Putative Implications for Amyotrophic Lateral Sclerosis Neurodegeneration and Treatment

2020 ◽  
Vol 14 ◽  
Author(s):  
Michele Longoni Calió ◽  
Elisandra Henriques ◽  
Amanda Siena ◽  
Clélia Rejane Antonio Bertoncini ◽  
Joana Gil-Mohapel ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mitochondrial Dysfunction ◽  
Lateral Sclerosis

Mitochondrial dysfunction in blood cells from amyotrophic lateral sclerosis patients

2015 ◽  
Vol 262 (6) ◽  
pp. 1493-1503 ◽  
Author(s):  
Johannes K. Ehinger ◽  
Saori Morota ◽  
Magnus J. Hansson ◽  
Gesine Paul ◽  
Eskil Elmér
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mitochondrial Dysfunction ◽  
Blood Cells ◽  
Lateral Sclerosis
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