scholarly journals The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Megumi Akamatsu ◽  
Takenari Yamashita ◽  
Naoki Hirose ◽  
Sayaka Teramoto ◽  
Shin Kwak
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Ampa Receptor Antagonist ◽  
Sporadic Als ◽  
Lateral Sclerosis

The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis

2003 ◽  
Vol 343 (2) ◽  
pp. 81-84 ◽  
Author(s):  
Philip Van Damme ◽  
Maarten Leyssen ◽  
Geert Callewaert ◽  
Wim Robberecht ◽  
Ludo Van Den Bosch
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Receptor Antagonist ◽  
Transgenic Mouse ◽  
Ampa Receptor ◽  
Transgenic Mouse Model ◽  
Ampa Receptor Antagonist ◽  
Lateral Sclerosis

AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

2018 ◽  
Vol 18 (4) ◽  
pp. 591-596 ◽  
Author(s):  
Domingo Sanchez Ruiz ◽  
Hella Luksch ◽  
Marco Sifringer ◽  
Achim Temme ◽  
Christian Staufner ◽  
...  
Keyword(s):  
Cell Survival ◽  
Receptor Antagonist ◽  
Cancer Cells ◽  
Glutamate Receptors ◽  
Cancer Cell ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Survivin Expression ◽  
Ampa Receptor Antagonist ◽  
Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

scholarly journals Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
James C. Dodge ◽  
Jinlong Yu ◽  
S. Pablo Sardi ◽  
Lamya S. Shihabuddin
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Cholesterol Homeostasis ◽  
Cholesterol Oxidation ◽  
Therapeutic Approaches ◽  
Cellular Survival ◽  
Sporadic Als ◽  
Human Motor ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractAberrant cholesterol homeostasis is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease that is due to motor neuron (MN) death. Cellular toxicity from excess cholesterol is averted when it is enzymatically oxidized to oxysterols and bile acids (BAs) to promote its removal. In contrast, the auto oxidation of excess cholesterol is often detrimental to cellular survival. Although oxidized metabolites of cholesterol are altered in the blood and CSF of ALS patients, it is unknown if increased cholesterol oxidation occurs in the SC during ALS, and if exposure to oxidized cholesterol metabolites affects human MN viability. Here, we show that in the SOD1G93A mouse model of ALS that several oxysterols, BAs and auto oxidized sterols are increased in the lumbar SC, plasma, and feces during disease. Similar changes in cholesterol oxidation were found in the cervical SC of sporadic ALS patients. Notably, auto-oxidized sterols, but not oxysterols and BAs, were toxic to iPSC derived human MNs. Thus, increased cholesterol oxidation is a manifestation of ALS and non-regulated sterol oxidation likely contributes to MN death. Developing therapeutic approaches to restore cholesterol homeostasis in the SC may lead to a treatment for ALS.

scholarly journals Glutathione S-transferase Omega 2 DD genotype is associated with an increased risk of sporadic amyotrophic lateral sclerosis in Chinese men

2021 ◽  
Vol 49 (7) ◽  
pp. 030006052110332
Author(s):  
Zhiliang Fan ◽  
Hong Jiang ◽  
Xueqin Song ◽  
Yansu Guo ◽  
Xinying Tian
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Healthy Subjects ◽  
Chinese Population ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Glutathione S Transferase ◽  
Genotype Frequencies ◽  
Sporadic Als ◽  
Increased Risk ◽  
Chi Squared ◽  
Lateral Sclerosis

Objective To investigate whether GSTA1, GSTO2, and GSTZ1 are relevant to an increased risk of amyotrophic lateral sclerosis (ALS) in a Chinese population. Methods In this study, 143 sporadic ALS (sALS) patients (83 men, 60 women) and 210 age- and sex-matched healthy subjects were enrolled. Blood samples were collected by venipuncture. Genomic DNA was isolated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) according to the manufacturer’s instructions. The potential associations between ALS and GSTA1, GSTO2, and GSTZ1 polymorphisms were estimated using chi-squared analysis and unconditional logistic regression. Results The D allele and genotype frequencies of GSTO2 were increased in sALS patients compared with healthy subjects, indicating that the GSTO2 DD genotype was associated with an increased risk of sALS (odds ratio [OR] = 3.294, 95% confidence interval [CI] = 1.039–10.448). However, a significant association between the DD genotype and the risk of sALS was evident in men only (OR = 7.167, 95% CI = 1.381–37.202). Conclusion This study revealed that the D allele and genotype frequencies of GSTO2 were increased in sALS patients. The GSTO2 DD genotype was associated with an increased risk of sALS in men in a Chinese population.

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.

Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis

Synapse ◽  
2002 ◽  
Vol 45 (4) ◽  
pp. 245-249 ◽  
Author(s):  
Masahiko Tomiyama ◽  
Rafael Rodríguez-Puertas ◽  
Roser Cortés ◽  
Angel Pazos ◽  
José M. Palacios ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Ampa Receptor ◽  
Splice Variants ◽  
Lateral Sclerosis

Structural Determinants of the γ-8 TARP Dependent AMPA Receptor Antagonist

2017 ◽  
Vol 8 (12) ◽  
pp. 2631-2647 ◽  
Author(s):  
Matthew R. Lee ◽  
Kevin M. Gardinier ◽  
Douglas L. Gernert ◽  
Douglas A. Schober ◽  
Rebecca A. Wright ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Structural Determinants ◽  
Ampa Receptor Antagonist

scholarly journals Revealing the Mutational Spectrum in Southern Africans With Amyotrophic Lateral Sclerosis

2022 ◽  
Vol 8 (1) ◽  
pp. e654
Author(s):  
Melissa Nel ◽  
Amokelani C. Mahungu ◽  
Nomakhosazana Monnakgotla ◽  
Gerrit R. Botha ◽  
Nicola J. Mulder ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Population Group ◽  
Genetic Ancestry ◽  
Familial Case ◽  
Data Sets ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Sporadic Als ◽  
Uncertain Significance ◽  
Lateral Sclerosis

Background and ObjectivesTo perform the first screen of 44 amyotrophic lateral sclerosis (ALS) genes in a cohort of African genetic ancestry individuals with ALS using whole-genome sequencing (WGS) data.MethodsOne hundred three consecutive cases with probable/definite ALS (using the revised El Escorial criteria), and self-categorized as African genetic ancestry, underwent WGS using various Illumina platforms. As population controls, 238 samples from various African WGS data sets were included. Our analysis was restricted to 44 ALS genes, which were curated for rare sequence variants and classified according to the American College of Medical Genetics guidelines as likely benign, uncertain significance, likely pathogenic, or pathogenic variants.ResultsThirteen percent of 103 ALS cases harbored pathogenic variants; 5 different SOD1 variants (N87S, G94D, I114T, L145S, and L145F) in 5 individuals (5%, 1 familial case), pathogenic C9orf72 repeat expansions in 7 individuals (7%, 1 familial case) and a likely pathogenic ANXA11 (G38R) variant in 1 individual. Thirty individuals (29%) harbored ≥1 variant of uncertain significance; 10 of these variants had limited pathogenic evidence, although this was insufficient to permit confident classification as pathogenic.DiscussionOur findings show that known ALS genes can be expected to identify a genetic cause of disease in >11% of sporadic ALS cases of African genetic ancestry. Similar to European cohorts, the 2 most frequent genes harboring pathogenic variants in this population group are C9orf72 and SOD1.

scholarly journals Consumption of unregulated food items (false morels) and risk for neurodegenerative disease (amyotrophic lateral sclerosis)

2020 ◽  
pp. 94-99
Author(s):  
P.S. Spencer ◽  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Free Radicals ◽  
Environmental Factors ◽  
Neurodegenerative Disease ◽  
Strong Evidence ◽  
Western Europe ◽  
World War ◽  
Food Items ◽  
Sporadic Als ◽  
Lateral Sclerosis

Unknown environmental factors are thought to contribute to the etiology of sporadic forms of amyotrophic lateral sclerosis (ALS). Strong evidence supporting this view is found in the post-World War decline and disappearance of highincidence ALS in three Western Pacific populations that formerly utilized neurotoxic cycad seed as a traditional source of food and/or medicine. The principal toxins in cycads (cycasin) and in False Morel mushrooms (gyromitrin) generate methyl free radicals that damage DNA and cause mutation and uncontrolled division of cycling cells and degeneration of late-/postmitotic neurons. Since False Morels are scavenged for food in Finland, Russia, Spain, and USA, research studies are underway in Western Europe and USA to determine if the practice is associated with sporadic ALS.

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