Course Of Amyotrophic Lateral Sclerosis Research Articles

The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity.

In the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the "astrocytic signature" in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as "producers" and "targets" of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation.

Different patterns of spreading direction and motor neurons involvement in a cohort of limb-onset amyotrophic lateral sclerosis patients from Southern Italy: Potential implication on disease course or progression?

Currently, there is a lack of knowledge concerning where the pathological process starts and how the neurodegeneration spreads during the course of amyotrophic lateral sclerosis (ALS). This study aims to evaluate the spreading direction of the disease and the corresponding clinical characteristics in a cohort of patients with limb-onset ALS. Consecutive incident ALS patients referring to an ALS tertiary center from Southern Italy, between 2015 and 2021, were recruited in the study. According to the initial directions of spread, patients were dichotomized into horizontal spreading pattern (HSP) or vertical spreading pattern (VSP) groups. Among 137 newly diagnosed ALS, 87 presented a spinal onset. Ten patients with pure LMN were not included in the study. All cases reported a clear spread direction. ThefrequencyofHSP and VSP spreading was similar overall (47 vs. 30). The prevalence of HSP was higher (74%vs. 50%) in patients with upper limb-onset (UL-ALS), compared to patients with lower limb-onset (LL-ALS; p < .05). Conversely, the occurrence of VSP spread was threefold higher in patients with LL-ALS, compared to UL-ALS (p < .05). Patients with VSP showed a wider upper motor neuron impairment, whereas the involvement of LMN resulted greater in patients with HSP. Patients with HSP exhibited a greater drop of ALSFRS-r sub-score in the region of onset, while VSP showed a slighter but more diffuse reduction of ASLFRS-r subscore in more body districts beyond the site of onset. Patients with VSP were also characterized by a higher median progression rate and an earlier median bulbar involvement, compared to HSP. Our findings suggested investigating the spreading direction of ALS among patients with spinal onset, to better delineate the clinical profiles of patients with ALS, and predict an earlier impairment of bulbar muscle and a more rapid progression of the disease.

The influence of uric acid on the course of amyotrophic lateral sclerosis

Uric acid has antioxidant and neuroprotective properties. A number of studies show that high levels of uric acid may have a positive influence on the course of amyotrophic lateral sclerosis (ALS), especially in males. The frequency of ALS is lower in patients with gout than in the general population. We present a case of a patient with gout and slowly progressive ALS. More research is needed on the potential role of uric acid in ALS and other neurodegenerative disorders.

Multidisciplinary care and therapeutic advances in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that mainly affects the motor system, resulting in progressive weakness and muscle wasting. Despite the tremendous advances in physiopathological and clinical characterization, we do not have a curative treatment yet. The progressive and fatal course of ALS makes its management particularly complex and challenging given the diversity of symptoms presenting during the disease progression. The main goal in the treatment of ALS patients is to minimize morbidity and maximize the quality of life. Currently, a series of therapeutic interventions improve the quality of life and prolong survival, including multidisciplinary care, respiratory management, and disease-modifying therapy. Within the supportive interventions, weight maintenance through nutritional and metabolic support is critical. In addition, the management of neuropsychiatric manifestations and preservation of communicative capacity before speech loss are also crucial. Lastly, early palliative care intervention is essential to optimize symptomatic management. Anticipatory guidelines to face the inevitable patient deterioration should be devised. This article updates the main therapeutic strategies used in these patients, including evolving clinical trials with promising novel therapies.

Amyotrophic Lateral Sclerosis-The Complex Phenotype-From an Epidemiological Perspective: A Focus on Extrapyramidal and Non-Motor Features.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND) and has emerged, among the disorders, with the largest increase in incidence in Western countries. Although the typical clinical phenotype of ALS involves simultaneous upper and lower motor neurons, there is growing evidence that the neurodegeneration during the course of the disease can also involve other motor and non-motor regions. In this review, we analyzed and discussed available data from epidemiological population-based studies on extrapyramidal and non-motor features during the course of ALS.

A novel quantitative indicator for disease progression rate in amyotrophic lateral sclerosis

ObjectiveThe current study sought to develop a new indicator for disease progression rate in amyotrophic lateral sclerosis (ALS). MethodsWe used a nonparametric method to score diverse patterns of decline in the percentage of predicted forced vital capacity (%FVC) in patients with ALS. This involved 6317 longitudinal %FVC data sets from 920 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database volunteered by PRO-ACT Consortium members. To assess the utility of the derived scores as a disease indicator, we examined changes over time, the association with prognosis, and correlation with the Risk Profile of the Treatment Research Initiative to Cure ALS (TRICALS). Our local cohort (n = 92) was used for external validation. ResultsWe derived scores ranging from 35 to 106 points to construct the FVC Decline Pattern scale (FVC-DiP). Individuals' FVC-DiP scores were determined from a single measurement of %FVC and disease duration at assessment. Although the %FVC declined over the disease course (p < 0.0001), the FVC-DiP remained relatively stable. Low FVC-DiP scores were associated with rapid disease progression. Using our cohort, we demonstrated an association between FVC-DiP and the survival prognosis, the stability of the FVC-DiP per individual, and a correlation between FVC-DiP scores and the TRICALS Risk Profile (r2 = 0.904, p < 0.0001). ConclusionsFVC-DiP scores reflected patterns of declining %FVC over the natural course of ALS and indicated the disease progression rate. The FVC-DiP may enable easy assessment of disease progression patterns and could be used for assessing treatment efficacy.

Predictive parameters of early respiratory decline in amyotrophic lateral sclerosis.

Respiratory insufficiency is a common symptom during the course of amyotrophic lateral sclerosis (ALS). The diagnostic workup may be challenging and includes a wide array of diagnostic measures. In this study, the aim was to analyze the relationship between hypercapnia-associated symptoms, blood gas parameters and pulmonary function tests. In total, 109 patients (56 women, 53 men, 62.4 ± 11.9 years) with definite, possible or probable ALS according to El Escorial criteria were included. All patients received either arterial blood gas analysis, nocturnal capnometry or both. Pulmonary function was assessed by spirometry and peak cough flow. Clinical symptoms potentially indicating hypercapnia were assessed using 17 dichotomous (yes/no) items. Of 109 ALS patients, 40 had hypercapnia. The highest accuracy and specificity for predicting hypercapnia was observed for dyspnea at rest (Youden's index 17%, 95% confidence interval [CI] 2%-34%; sensitivity 23%, 95% CI 9%-38%; specificity 95%, 95% CI 88%-100%). Daytime fatigue yielded the highest sensitivity of 58% (95% CI 40%-76%). Logistic regression for all assessed symptoms combined yielded an area under the receiver operating charteristic curve of 0.8 (95% CI 0.7-0.9). Compared to the clinical symptoms, forced vital capacity and peak cough flow showed higher sensitivity (70% and 87%, respectively) but lacked specificity (33% and 20%). Evaluation of the presence of hypercapnic symptoms can be utilized to predict incipient respiratory insufficiency and should complement pulmonary function tests. Further studies are needed to validate specific questionnaires in this regard. No single hypercapnia-associated symptom or pulmonary function test on its own seems sufficient to safely predict hypercapnia.

Respiratory onset in amyotrophic lateral sclerosis: clinical features and spreading pattern

Objective To describe the clinical features and progression of patients with respiratory onset amyotrophic lateral sclerosis (ALS). Methods: We analyzed the clinical features, including respiratory tests, functional score, noninvasive ventilation (NIV) time and survival of ALS patients with respiratory-onset in our database consisting of 1688 patients. In a subset of 625 ALS patients we analyzed the spreading pattern to other bodily regions. Results: We included 1579 patients with ALS. Sixty-three patients (4%) presented respiratory-onset (79.4% men, mean onset-age 67.7 ± 8.9yrs). All had predominant LMN involvement, and significant weight loss (>10%) was identified in 38.9%. The respiratory tests were abnormal in these respiratory-onset patients (p < 0.001). ALSFRS-R respiratory subscore was lower in this population (p < 0.001). NIV was adapted in 84.1%, sooner than in the larger group of ALS patients (p < 0.001), and survival from disease onset was shorter (p < 0.001). Respiratory-onset was a predictor of time to NIV (X 2=42.0, p < 0.001) and of survival (X 2=7.1, p = 0.008). The spreading pattern was studied in 18 patients with isolated respiratory-onset. The progression interval to the 2nd region was 4.7 ± 5.7mo and to a 3rd region 6.1 ± 8.7mo. Different patterns of spread had no impact on survival. Conclusions: This phenotype is typically seen in emaciated older men with predominant lower motor neuron involvement, and is associated with diaphragm paresis and central respiratory involvement. NIV adaptation is rapid but total survival is shorter than in the other patients. Spreading pattern did not affect time to NIV adaptation or total survival, as NIV support is a modifying treatment in the course of ALS.

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.

Fat-rich versus carbohydrate-rich nutrition in ALS: a randomised controlled study

ObjectiveThere is growing evidence that the course of amyotrophic lateral sclerosis (ALS) may be influenced beneficially by applying high-caloric food supplements (HCSs). However, it is unknown which composition of nutrients...

KLF15 overexpression in myocytes fails to ameliorate ALS-related pathology or extend the lifespan of SOD1G93A mice

Amyotrophic Lateral Sclerosis (ALS) is a currently incurable disease that causes progressive motor neuron loss, paralysis and death. Skeletal muscle pathology occurs early during the course of ALS. It is characterized by impaired mitochondrial biogenesis, metabolic dysfunction and deterioration of the neuromuscular junction (NMJ), the synapse through which motor neurons communicate with muscles. Therefore, a better understanding of the molecules that underlie this pathology may lead to therapies that slow motor neuron loss and delay ALS progression. Kruppel Like Factor 15 (KLF15) has been identified as a transcription factor that activates alternative metabolic pathways and NMJ maintenance factors, including Fibroblast Growth Factor Binding Protein 1 (FGFBP1), in skeletal myocytes. In this capacity, KLF15 has been shown to play a protective role in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), however its role in ALS has not been evaluated. Here, we examined whether muscle-specific KLF15 overexpression promotes the health of skeletal muscles and NMJs in the SOD1G93A ALS mouse model. We show that muscle-specific KLF15 overexpression did not elicit a significant beneficial effect on skeletal muscle atrophy, NMJ health, motor function, or survival in SOD1G93A ALS mice. Our findings suggest that, unlike in mouse models of DMD and SMA, KLF15 overexpression has a minimal impact on ALS disease progression in SOD1G93A mice.

Alterations in Leptin Signaling in Amyotrophic Lateral Sclerosis (ALS).

Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin’s effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin’s actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43A315T mice compared to age-matched WT littermates. In addition, at selected time-points, an immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines resistin and leptin, and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.

Caregivers’ divergent perspectives on patients’ well-being and attitudes towards hastened death in Germany, Poland and Sweden

Background: During the course of amyotrophic lateral sclerosis (ALS), patients and their families are faced with existential decisions concerning life-prolonging and -shortening measures. Correct anticipation of patient’s well-being and preferences is a prerequisite for patient-centered surrogate decision making. Methods: In Germany (N = 84), Poland (N = 77) and Sweden (N = 73) patient-caregiver dyads were interviewed. Standardized questionnaires on well-being (ADI-12 for depressiveness; ACSA for global quality of life) and wish for hastened death (SAHD) were used in ALS patients. Additionally, caregivers were asked to fill out the same questionnaires by anticipating patients’ perspective (surrogate perspective). Results: Caregivers significantly underestimated patients’ well-being in Germany and Poland. For Swedish caregivers, there were just as many who underestimated and overestimated well-being. The same was true for wish for hastened death in all three countries. For Swedish and Polish patients, caregivers’ estimation of well-being was not even associated with patients’ responses and the same was true for estimation of wish for hastened death in all three countries. Older caregivers and those with the most frequent encounter with the patient were the closest in their rating of well-being and wish for hastened death to the patients’ actual state, while caregivers with chronic disease him/herself were more likely to underestimate patient’s well-being. Discussion: Despite distinct cultural differences, there was a clear discrepancy between patients’ and caregivers’ perspective on patients’ well-being and preferences towards life in all three countries. This possible bias in caregivers’ judgment needs to be taken into account in surrogate decision making.

Diabetes Mellitus and Amyotrophic Lateral Sclerosis: A Systematic Review.

Background: Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder which affects the motor neurons. Growing evidence suggests that ALS may impact the metabolic system, including the glucose metabolism. Several studies investigated the role of Diabetes Mellitus (DM) as risk and/or prognostic factor. However, a clear correlation between DM and ALS has not been defined. In this review, we focus on the role of DM in ALS, examining the different hypotheses on how perturbations of glucose metabolism may interact with the pathophysiology and the course of ALS. Methods: We undertook an independent PubMed literature search, using the following search terms: ((ALS) OR (Amyotrophic Lateral Sclerosis) OR (Motor Neuron Disease)) AND ((Diabetes) OR (Glucose Intolerance) OR (Hyperglycemia)). Review and original articles were considered. Results: DM appears not to affect ALS severity, progression, and survival. Contrasting data suggested a protective role of DM on the occurrence of ALS in elderly and an opposite effect in younger subjects. Conclusions: The actual clinical and pathophysiological correlation between DM and ALS is unclear. Large longitudinal prospective studies are needed. Achieving large sample sizes comparable to those of common complex diseases like DM is a challenge for a rare disease like ALS. Collaborative efforts could overcome this specific issue.

Cognitive and behavioural impairment in amyotrophic lateral sclerosis: A landmark of the disease? A mini review of longitudinal studies

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease marked by progressive loss of motor abilities. Approximately half of patents with ALS experience cognitive (ALSci) or behavioural impairment (ALSbi) during the course of the disease, with a small percentage developing overt frontotemporal dementia (FTD). ALSci and/or ALSbi can occur simultaneously with motor neuron degeneration or develop in advanced stages of the disease, but it can even precede motor involvement in some cases, namely in ALS patients meeting criteria for FTD. Despite clear evidence that cognitive/behavioural impairment may appear early in the course of ALS, no prominent deterioration seems to occur with disease progression. Longitudinal studies have failed to reach conclusive results on the progression of cognitive and behavioural involvement in ALS. This may be due to some structural limitations of the studies, such as attrition rate, practice effect, short-time interval between neuropsychological assessments, but it can also be due to the heterogeneity of ALS phenotypes. The objective of this review is to provide a comprehensive and critical analysis of results of longitudinal studies highlighting cognitive and behavioural domains mainly affected by neurodegeneration pointing out the determinants that might be associate with the development and worsening of frontotemporal symptoms in ALS. At this regard, older age, rapidly progressing ALS, bulbar-onset, advanced disease stages are among factors mainly associated with cognitive and behavioural involvement. Moreover, the progression of cognitive and behavioural deficits seems to be not directly related to the slope of motor disability, thus suggesting the independence of neuropsychological and motor functional decline in ALS. Cognitive and motor involvement may indeed present with distinct trajectories suggesting a differential vulnerability of motor and non-motor cortical networks. In this scenario, determining the progression of extra-motor involvement in ALS may help refine understanding of the clinical implications of cognitive and behavioural abnormalities, and provide clues to the aetiology of the disease.

Effects of vitamin E on neurodegenerative diseases: an update.

Vitamin E deficiency is associated with many neurological problems. Although the mechanisms of vitamin E action in neurodegenerative diseases are not clear, there are many possible mechanisms. Examples of such mechanisms are the protective effects of vitamin E against oxidative stress damage and its suppressive role in the expression of many genes involved in the development of neurodegeneration. Many studies have evaluated the relationship between vitamin E intake or vitamin E levels in body fluids and neurodegenerative diseases. Some studies concluded that vitamin E can play a protective role in neurodegeneration with respect to diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke and amyotrophic lateral sclerosis (ALS). Vitamin E supplementation was also associated with risk factors for some neurodegenerative diseases. In this review, we discuss the possible effects of vitamin E on the development and course of AD, PD, stroke and ALS, and the potential mechanisms involved. Vitamin E deficiency is associated with many neurological problems. Although the mechanisms of vitamin E action in neurodegenerative diseases are not clear, there are many possible mechanisms. Examples of such mechanisms are the protective effects of vitamin E against oxidative stress damage and its suppressive role in the expression of many genes involved in the development of neurodegeneration. Many studies have evaluated the relationship between vitamin E intake or vitamin E levels in body fluids and neurodegenerative diseases. Some studies concluded that vitamin E can play a protective role in neurodegeneration with respect to diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke and amyotrophic lateral sclerosis (ALS). Vitamin E supplementation was also associated with risk factors for some neurodegenerative diseases. In this review, we discuss the possible effects of vitamin E on the development and course of AD, PD, stroke and ALS, and the potential mechanisms involved.

Clinical Course of Amyotrophic Lateral Sclerosis according to Initial Symptoms: An Analysis of 500 Cases.

PurposeOne obstacle in early diagnosis of amyotrophic lateral sclerosis (ALS) is its vague initial presentation, which is generally classified into limb- and bulbar-dominant types and may be mistaken for other musculoskeletal conditions. We analyzed clinical data from patients in relation to their initial presentation and prognosis from symptom onset to diagnosis.Materials and MethodsWe retrospectively analyzed the medical records of patients with ALS who were admitted for pulmonary rehabilitation between January 2007 and December 2019. We collected data on time of onset, initial presenting symptoms, unnecessary operations due to misdiagnosis, and the time between symptom onset and final diagnosis of ALS.ResultsAmong 500 patients, unnecessary operations were performed in 43 patients. The median durations between symptom onset and ALS diagnosis for patients with and without operations were 11 and 9 months, respectively (p=0.008). 67.0%, 28.8%, and 4.2% of the patients presented with limb-, bulbar-, and respiratory-dominant symptoms, respectively, as initial presentations. The median ages at symptom onset were significantly different for limb-, bulbar-, and respiratory-dominant onset (57.5, 60.6, and 66.7 years, respectively; p<0.001). Compared to the other two types, patients with the respiratory-dominant onset were all male and showed higher rate of emergent endotracheal intubation before ALS diagnosis.ConclusionInappropriate operations significantly delayed the diagnosis of ALS. Respiratory difficulty can account for a significant proportion among initial presentations in ALS. Compared to limb- and bulbar-dominant types, respiratory-dominant onset appears to show male predominance, older age at symptom onset, and poor respiratory prognosis.

Combination of acamprosate and baclofen (PXT864) as a potential new therapy for amyotrophic lateral sclerosis.

There is currently no therapy impacting the course of amyotrophic lateral sclerosis (ALS). The only approved treatments are riluzole and edaravone, but their efficacy is modest and short‐lasting, highlighting the need for innovative therapies. We previously demonstrated the ability of PXT864, a combination of low doses of acamprosate and baclofen, to synergistically restore cellular and behavioral activity in Alzheimer's and Parkinson's disease models. The overlapping genetic, molecular, and cellular characteristics of these neurodegenerative diseases supported investigating the effectiveness of PXT864 in ALS. As neuromuscular junction (NMJ) alterations is a key feature of ALS, the effects of PXT864 in primary neuron‐muscle cocultures injured by glutamate were studied. PXT864 significantly and synergistically preserved NMJ and motoneuron integrity following glutamate excitotoxicity. PXT864 added to riluzole significantly improved such protection. PXT864 activity was then assessed in primary cultures of motoneurons derived from SOD1G93A rat embryos. These motoneurons presented severe maturation defects that were significantly improved by PXT864. In this model, glutamate application induced an accumulation of TDP‐43 protein in the cytoplasm, a hallmark that was completely prevented by PXT864. The anti‐TDP‐43 aggregation effect was also confirmed in a cell line expressing TDP‐43 fused to GFP. These results demonstrate the value of PXT864 as a promising therapeutic strategy for the treatment of ALS.

Rofecoxib Attenuates the Pathogenesis of Amyotrophic Lateral Sclerosis by Alleviating Cyclooxygenase-2-Mediated Mechanisms

Cyclooxygenase-2 (COX-2) is reported to be activated during the course of amyotrophic lateral sclerosis (ALS) development and progression. However, the roles of COX-2 in aggravating ALS and the underlying mechanism have been largely overlooked. To reveal the mechanisms, the canonical SOD1G93A mouse model was used as an experimental model for ALS in the current study. In addition, a specific inhibitor of COX-2 activity, rofecoxib, was orally administered to SOD1G93A mice. With this in vivo approach, we revealed that COX-2 proinflammatory signaling cascades were inhibited by rofecoxib in SOD1G93A mice. Specifically, the protein levels of COX-2, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were elevated as a result of activation of astrocytes and microglia during the course of ALS development and progression. These proinflammatory reactions may contribute to the death of neurons by triggering the movement of astrocytes and microglia to neurons in the context of ALS. Treatment with rofecoxib alleviated this close association between glial cells and neurons and significantly decreased the density of inflammatory cells, which helped to restore the number of motor neurons in SOD1G93A mice. Mechanistically, rofecoxib treatment decreased the expression of COX-2 and its downstream signaling targets, including IL-1β and TNF-α, by deactivating glial cells, which in turn ameliorated the progression of SOD1G93A mice by postponing disease onset and modestly prolonging survival. Collectively, these results provide novel insights into the mechanisms of ALS and aid in the development of new drugs to improve the clinical treatment of ALS.

Neuroprotective and Neurodegenerative Aspects of Coffee and Its Active Ingredients in View of Scientific Literature.

Coffee and its components have several neuroprotective properties that lower the risk of cognitive decline and other neurodegenerative diseases. This study reviews the mechanisms by which coffee and its respective compounds affect the brain and its pathologies. Many epidemiological studies in this literature review have shown coffee to reduce the risk of developing dementia, stroke, and Alzheimer's disease. It may also have a positive impact on the disease course of amyotrophic lateral sclerosis, Parkinson's disease, and depression. The optimal benefits achieved from coffee in these pathologies rely on higher daily doses. Most of its effects are attributed to caffeine by the antagonism of adenosine receptors in the central nervous system; however, other coffee constituents like chlorogenic acids have also shown much promise in therapeutic value. Existing research considers coffee to have great potential, but additional studies are still needed to clarify the mechanisms and actual causal relationships in certain neuropathologies.