Department of Chemistry, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Belgrade, Serbia
Edaravone May Prevent Ferroptosis in ALS
https://pubmed.ncbi.nlm.nih.gov/3207782 ... is-in-als/
Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. ALS is a disease were multiple cell types are involved in the devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.
Multiple Sclerosis and Amyotrophic Lateral Sclerosis: Is There a Link?
https://pubmed.ncbi.nlm.nih.gov/2214661 ... re-a-link/
Department of Microbiology and Molecular Biology, Provo, United States
The Effects of Diet and Sex in Amyotrophic Lateral Sclerosis
https://pubmed.ncbi.nlm.nih.gov/3214720 ... sclerosis/
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, suggesting there are multiple contributing factors that influence the disease risk, onset, and progression. Diet and sex are two factors that have been reported to alter ALS risk, onset and progression in humans and in animal models, providing potential modifiers of disease. Several epidemiological studies have identified diets that positively affect ALS patients, including various high-calorie fat or sugar-based diets, while animal models have been developed to test how these diets are working on a molecular level. These diets may offset the metabolic alterations that occur in ALS, such as hypermetabolism, lowered body mass index(BMI), and hyperlipidemia. Sex-dependent differences have also come forth from large-scale epidemiological studies as well as mouse-model studies. In addition, sex hormones have been shown to affect disease risk or progression. Herein, studies on the effects of diet and sex on ALS risk, onset, and progression will be reviewed. Understanding these diet- and sex-dependent outcomes may lead to optimized patient-specific therapies for ALS.
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, US
Formaldehyde and Brain Disorders: A Meta-Analysis and Bioinformatics Approach
While there is significant investigation and investment in brain and neurodegenerative disease research, current understanding of the etiologies of illnesses like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and brain cancer remains limited. Environmental exposure to the pollutant formaldehyde, an emerging neurotoxin widely used in industry, is suspected to play a critical role in mediating these disorders, although findings are limited and inconsistent. Focusing on highly exposed groups, we performed a meta-analysis of human epidemiological studies of formaldehyde and neurodegenerative disease (N = 19) or brain tumors (N = 12). To assess the biological plausibility of observed associations, we then conducted a bioinformatics analysis using WikiPathways and the Comparative Toxicogenomics Database and identified candidate genes and pathways that may be related to these interactions. We reported the meta-relative risk (meta-RR) of ALS following high exposures to formaldehyde was increased by 78% (meta-RR = 1.78, 95% confidence interval, CI 1.20-2.65). Similarly, the meta-RR for brain cancer was increased by 71% (meta-RR = 1.71; 95% CI 1.07-2.73) among highly exposed individuals. Multiple sensitivity analyses did not reveal sources of heterogeneity or bias. Our bioinformatics analysis revealed that the oxidative stress genes superoxide dismutase (SOD1, SOD2) and the pro-inflammatory marker tumor necrosis factor (TNF) were identified as the top relevant genes, and the folate metabolism, vitamin B12 metabolism, and the ALS pathways were highly affected by formaldehyde and related to the most brain diseases of interest. Further inquiry revealed the two metabolic pathways are also intimately tied with the formaldehyde cycle. Overall, our bioinformatics analysis supports the link of formaldehyde exposure to ALS or brain tumor reported from our meta-analysis. This new multifactorial approach enabled us to both interrogate the robustness of the epidemiological data and identify genes and pathways that may be involved in these interactions, ultimately lending strong evidence and potential biological plausibility for the association between formaldehyde exposure and brain disease.
Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain
Targeting the CB 2 receptor and other endocannabinoid elements to delay disease progression in amyotrophic lateral sclerosis
Cannabinoids form a singular group of plant-derived compounds, endogenous lipids and synthetic derivatives with multiple therapeutic effects exerted by targeting different elements of the so-called endocannabinoid system. One of their therapeutic applications is the preservation of neuronal integrity exerted by attenuating the multiple neurotoxic events that kill neurons in neurodegenerative disorders. In this review, we will address the potential of cannabinoids as neuroprotective agents in amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder characterized by muscle denervation, atrophy and paralysis, and progressive deterioration in upper and/or lower motor neurons. The emphasis will be paid on the cannabinoid receptor type-2 (CB2 ), whose activation limits glial reactivity, but the potential of additional endocannabinoid-related targets will be also addressed. The evidence accumulated so far at the preclinical level supports the need to move soon towards the patients and initiate clinical trials to confirm the potential of cannabinoid-based medicines as disease modifiers in ALS.
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
Ghrelin as a treatment for amyotrophic lateral sclerosis
Ghrelin is a gut hormone best known for its role in regulating appetite and stimulating the secretion of the anabolic hormone growth hormone (GH). However, there is considerable evidence to show wider-ranging biological actions of ghrelin that favour improvements in cellular and systemic metabolism, as well as neuroprotection. Activation of these ghrelin-mediated pathways may alleviate pathogenic processes that are assumed to contribute to accelerated progression of disease in patients with neurodegenerative disease. Here, we provide a brief overview on the history of discoveries that led to the identification of ghrelin. Focussing on the neurodegenerative disease amyotrophic lateral sclerosis (ALS), we also present an overview of emerging evidence that suggests that ghrelin and ghrelin mimetics may serve as potential therapies for the treatment of ALS. Given that ALS is a highly heterogeneous disease, where multiple disease mechanisms contribute to variability in disease onset and rate of disease progression, we speculate that the wide-ranging biological actions of ghrelin might offer therapeutic benefit through modulating multiple disease-relevant processes observed in ALS. Expanding on the well-known actions of ghrelin in regulating food intake and GH secretion, we consider the potential of ghrelin-mediated pathways in improving body weight regulation, metabolism and the anabolic and neuroprotective actions of GH and insulin-like growth factor-1 (IGF-1). This is of clinical significance because loss of body weight, impairments in systemic and cellular metabolism, and reductions in IGF-1 are associated with faster disease progression and worse disease outcome in patients with ALS.
Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China
Diphenyl diselenide protects motor neurons through inhibition of microglia-mediated inflammatory injury in amyotrophic lateral sclerosis
Microglia-mediated neuroinflammatory response and neuron damage are considered as a self-propelling progressive cycle, being strongly implicated in the progression of neurodegeneration in amyotrophic lateral sclerosis (ALS). Diphenyl diselenide (DPDS), a simple organoselenium compound, has been known to possess multiple pharmacological properties. The purpose of this study was to explore the neuroprotective effects of DPDS against microglia-mediated neuroinflammatory injury in ALS models. We found that DPDS pretreatment inhibited LPS-induced activation of IκB/NF-κB pathway and subsequent release of proinflammatory factors from activated primary hSOD1G93A microglia. Moreover, DPDS suppressed NLRP3 inflammasome activation by decreasing protein nitration via reduction in NO and ROS levels, whose low levels are related to NF-κB inhibition responsible for iNOS and NOX2 down-regulations, respectively. Notably, DPDS-mediated ROS attenuation was not linked to Nrf2 activation in this cellular model. Furthermore, in the absence of activated microglia, DPDS has no significant effect on the individual hSOD1G93A-NSC34 cells; however, in in vitro neuron-microglia conditional culture and co-culture experiments, DPDS protected motor neurons from neurotoxic damage caused by LPS or BzATP-stimulated microglia activation. Above observations suggest that DPDS-afforded neuroprotection is linked to inhibition of microglia-mediated neuroinflammation in ALS, which was further verified in vivo as shown by improvements of motor deficits, prolonged survival, and reduction of motor neuron loss and reactive microgliosis in hSOD1G93A transgenic mouse. Altogether, our results show that DPDS elicited neuroprotection in ALS models through inactivation of microglia by inhibiting IκB/NF-κB pathway and NLRP3 inflammasome activation, suggesting that DPDS may be a promising candidate for potential therapy for ALS.
Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, China
Type II diabetes mellitus and amyotrophic lateral sclerosis: genetic overlap, causality, and mediation
Objective: To disentangle the nature of the inverse relationship between type II diabetes (T2D) mellitus and amyotrophic lateral sclerosis (ALS).
Methods: Depending on summary statistics of T2D (n=898,130) and ALS (n=80,610), we estimated the genetic correlation between them and prioritized pleiotropic genes through a multiple-tissue eQTL weighted integrative analysis and the ccFDR method. We implemented Mendelian randomization (MR) analyses to evaluate the causal relationship between the two diseases. A mediation analysis was performed to assess the mediating role of T2D in the pathway from T2D-related glycemic/anthropometric traits to ALS.
Results: We found supportive evidence of common genetic foundation between T2D and ALS (rg=-0.223, p=0.004), and identified eight pleiotropic genes (ccFDR<0.10). The MR analysis confirmed that T2D exhibited a neuroprotective effect on ALS, leading to an approximately 5% (95% confidence intervals 0~9.6%, p=0.038) reduction in disease risk. In contrast, no substantial evidence was observed that supported the causal influence of ALS on T2D. The mediation analysis revealed T2D can also serve as an active mediator for several glycemic/anthropometric traits, including high-density lipoprotein cholesterol, overweight, body mass index, obesity class 1, obesity class 2, with the mediation effect estimated to be 0.024, -0.022, -0.041, -0.016, and -0.012, respectively.
Conclusion: We provided new evidence supporting the observed inverse link between T2D and ALS, and revealed that shared genetic component and causal association commonly drove such relationship. We also demonstrated the mediating role of T2D standing in the pathway from T2D-related glycemic/anthropometric traits to ALS.
ALS Center, Department of Neuroscience "Rita Levi Montalcini", University of Turin, Italy
Unraveling the complex interplay between genes, environment, and climate in ALS
Various genetic and environmental risk factors have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, the cause of most ALS cases remains obscure. In this review, we describe the current evidence implicating genetic and environmental factors in motor neuron degeneration. While the risk exerted by many environmental factors may appear small, their effect could be magnified by the presence of a genetic predisposition. We postulate that gene-environment interactions account for at least a portion of the unknown etiology in ALS. Climate underlies multiple environmental factors, some of which have been implied in ALS etiology, and the impact of global temperature increase on the gene-environment interactions should be carefully monitored. We describe the main concepts underlying such interactions. Although a lack of large cohorts with detailed genetic and environmental information hampers the search for gene-environment interactions, newer algorithms and machine learning approaches offer an opportunity to break this stalemate. Understanding how genetic and environmental factors interact to cause ALS may ultimately pave the way towards precision medicine becoming an integral part of ALS care.
Poznan University of Physical Education, Poznan, Poland
Swim training affects Akt signaling and ameliorates loss of skeletal muscle mass in a mouse model of amyotrophic lateral sclerosis
We tested the hypothesis that swim training reverses the impairment of Akt/FOXO3a signaling, ameliorating muscle atrophy in ALS mice. Transgenic male mice B6SJL-Tg (SOD1G93A) 1Gur/J were used as the ALS model (n = 35), with wild-type B6SJL (WT) mice as controls (n = 7). ALS mice were analyzed before ALS onset, at ALS onset, and at terminal ALS. Levels of insulin/Akt signaling pathway proteins were determined, and the body and tibialis anterior muscle mass and plasma creatine kinase. Significantly increased levels of FOXO3a in ALS groups (from about 13 to 21-fold) compared to WT mice were observed. MuRF1 levels in the ONSET untrained group (12.0 ± 1.7 AU) were significantly higher than in WT mice (1.12 ± 0.2 AU) and in the BEFORE ALS group (3.7 ± 0.9 AU). This was associated with body mass and skeletal muscle mass reduction. Swim training significantly ameliorated the reduction of skeletal muscle mass in both TERMINAL groups (p < 0.001) and partially reversed changes in the levels of Akt signaling pathway proteins. These findings shed light on the swimming-induced attenuation of skeletal muscle atrophy in ALS with possible practical implications for anti-cachexia approaches.
Department of Public Health Sciences, Medical University of South Carolina, Charleston, USA
Long-term air pollution and risk of amyotrophic lateral sclerosis mortality in the Women's Health Initiative cohort
Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure. Although the etiology of sporadic ALS is largely unknown, environmental exposures may affect ALS risk.
Objective: We investigated relationships between exposure to long-term ambient particulate matter (PM) and gaseous air pollution (AP) and ALS mortality.
Methods: Within the Women's Health Initiative (WHI) cohort of 161,808 postmenopausal women aged 50-79 years at baseline (1993-1998), we performed a nested case-control study of 256 ALS deaths and 2486 matched controls with emphasis on PM constituents (PM2.5, PM10, and coarse PM [PM10-2.5]) and gaseous pollutants (NOx, NO2, SO2, and ozone). Time-varying AP exposures estimates were averaged 5, 7.5, and 10 years prior to ALS death using both a GIS-based spatiotemporal generalized additive mixed model and ordinary kriging (empirical and multiple imputation, MI). Conditional logistic regression was used to estimate the relative risk of ALS death.
Results: In general, PM2.5 and PM10-related risks were not significantly elevated using either method. However, for PM10-2.5, odds ratios (ORs) were >1.0 for both methods at all time periods using MI and empirical data for PM10-2.5 (coarse) except for 5 and 7.5 years using the kriging method with covariate adjustment.
Conclusion: This investigation adds to the body of information on long-term ambient AP exposure and ALS mortality. Specifically, the 2019 US Environmental Protection Agency (EPA) Integrated Science Assessment summarized the neurotoxic effects of PM2.5, PM10, and PM10-2.5. The conclusion was that evidence of an effect of coarse PM is suggestive but the data is presently not sufficient to infer a causal relationship. Further research on AP and ALS is warranted. As time from symptom onset to death in ALS is ∼2-4 years, earlier AP measures may also be of interest to ALS development. This is the first study of ALS and AP in postmenopausal women controlling for individual-level confounders.
HanseMerkur Center for Traditional Chinese Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Slower progression of amyotrophic lateral sclerosis with external application of a Chinese herbal plaster-The randomized, placebo-controlled triple-blinded ALS-CHEPLA trial
Background: Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by gradually increasing damage to the upper and lower motor neurons. However, definitive and efficacious treatment for ALS is not available, and oral intake in ALS patients with bulbar involvement is complicated due to swallowing difficulties.
Hypothesis/purpose: This study investigated whether the external plaster application of the herbal composition Ji-Wu-Li efficiently slows ALS progression because prior studies obtained promising evidence with oral herbal applications.
Study design: The randomized, triple-blinded study compared the efficacy, safety, and tolerability of the application of Ji-Wu-Li plaster (JWLP) with placebo plaster (PLAP).
Methods: In total, 120 patients with definite ALS, clinically probable ALS, or clinically probable laboratory-supported ALS were randomized in a 1:1 ratio to receive JWLP or PLAP. Patients were treated and observed for 20 weeks. The primary outcome was the ALSFRS-R score, while the secondary outcomes were the ALS-SSIT score and weight loss.
Results: The mean±SD decrease in the ALSFRS-R over 20 weeks differed by 0.84 points in a group comparison (JWLP, -4.44 ± 1.15; PLAP, -5.28 ± 1.98; p = 0.005). The mean increase in the ALS-SSIT over 20 weeks differed by 2.7 points in a group comparison (JWLP, 5.361.15; PLAP, 8.06 ± 1.72; p < 0.001). The mean weight loss over 20 weeks differed by 1.65 kg in a group comparison (JWLP, -3.98 ± 2.61; PLAP, -5.63 ± 3.17; p = 0.002). Local allergic dermatitis suspected as causal to the intervention occurred in 10 of 60 participants in the JWLP group and 9 of 60 participants in the PLAP group. Systemic adverse events were mild, temporary, and considered unrelated to the intervention.
Conclusion: The JWLP showed clinical efficacy in the progression of ALS, as measured by the ALSFRS-R, ALS-SSIT, and weight loss in a randomized, placebo-controlled trial. Because skin reactions occurred in both groups, the covering material needs improvement. All of the Ji Wu Li herbal ingredients regulate multiple mechanisms of neurodegeneration in ALS. Hence, JWLP may offer a promising and safe add-on therapy for ALS, particularly in patients with bulbar involvement, but a confirmative long-term multicentre study is required.