stilbenes and Amyotrophic-Lateral-Sclerosis

Molecules of the plant world are proving their effectiveness in countering, slowing down, and regressing many diseases. The resveratrol for its intrinsic properties related to its stilbene structure has been proven to be a universal panacea, especially for a wide range of neurodegenerative diseases. This paper evaluates (in vivo and in vitro) the various molecular targets of this peculiar polyphenol and its ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. What emerges is that, in the deep heterogeneity of the pathologies evaluated, resveratrol through a convergence on the protein targets is able to give therapeutic responses in neuronal cells deeply diversified not only in morphological structure but especially in their function performed in the anatomical district to which they belong.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Humans; Huntington Disease; Mitochondria; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Resveratrol; Stilbenes

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by progressive loss of spinal and cortical motor neurons, leading to muscular atrophy, respiratory failure, and ultimately death. There is no known cure, and the clinical benefit of the two drugs approved to treat ALS remains unclear. Novel disease-modifying therapeutics that are able to modulate the disease course are desperately needed. Our objective was to evaluate the efficacy and tolerability of Elysium Health's candidate drug EH301 in people with ALS (PALS).. This was a single-center, prospective, double-blind, randomized, placebo-controlled pilot study. Thirty-two PALS were recruited thanks to the collaboration of the Spanish Foundation for ALS Research (FUNDELA). Study participants were randomized to receive either EH301 or placebo and underwent evaluation for 4 months. Differences between EH301 and placebo-treated participants were evaluated based on standard clinical endpoints, including the revised ALS functional rating scale (ALSFRS-R), forced vital capacity (FVC), and the Medical Research Council (MRC) grading scale.. Compared to placebo, participants treated with EH301 demonstrated significant improvements in the ALSFRS-R score, pulmonary function, muscular strength, and in skeletal muscle/fat weight ratio. EH301 was shown to significantly slow the progression of ALS relative to placebo, and even showed improvements in several key outcome measures compared with baseline.. This study provides evidence in support of the disease-modifying effects of EH301 for the treatment of ALS.

Topics: Aged; Amyotrophic Lateral Sclerosis; Disease Progression; Double-Blind Method; Drug Combinations; Electromyography; Female; Humans; Male; Middle Aged; Muscle Strength; Niacinamide; Pilot Projects; Ribonucleosides; Stilbenes; Treatment Outcome; Vital Capacity

The neurotoxic effects of cerebrospinal fluid (CSF) from patients suffering amyotrophic lateral sclerosis (ALS), have been reported by various authors. However, variable results have been communicated and the mechanism of such neurotoxicity has been attributed to excess glutamate concentrations in ALS/CSF. We have studied here the properties of 14 CSFs from control patients and 29 CSFs from patients of ALS. We found that while ALS/CSF impairs the viability of rat brain cortical motoneurons maintained in primary cultures, this effect seemed to be exerted through a glutamate-independent mechanism. Resveratrol protected against such neurotoxic effects and antagonized the [Ca(+2)](c) elevation produced by ALS/CSF. However, riluzole did not afford protection and antagonized the resveratrol-elicited neuroprotective effects. We conclude that ALS/CSF elicited neurotoxicity on in vitro cultures of rat brain cortical motor neurons may become a sound microassay to test available novel multitargeted neuroprotective compounds with potential therapeutic application in ALS patients.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Animals; Calcium; Cell Death; Cells, Cultured; Cerebral Cortex; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Embryo, Mammalian; Female; Glutamic Acid; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Motor Neurons; Neuroprotective Agents; Pregnancy; Rats; Resveratrol; Riluzole; Stilbenes

Oxidative stress-induced damage is a major mechanism in the pathophysiology of amyotrophic lateral sclerosis (ALS). A recent human clinical trial showed that the combination of nicotinamide riboside (NR) and pterostilbene (PT), molecules with potential to interfere in that mechanism, was efficacious in ALS patients. We examined the effect of these molecules in SOD1

Topics: Acetylcysteine; Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Apoptosis; Cytokines; Female; Male; Metabolome; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Motor Activity; Motor Neurons; Mutation; NAD; Nerve Degeneration; NF-E2-Related Factor 2; Niacinamide; Oxidation-Reduction; Pyridinium Compounds; Reactive Oxygen Species; Sirtuin 1; Sirtuin 3; Spinal Cord; Stilbenes; Superoxide Dismutase-1; Survival Analysis

Topics: Adult; Amyotrophic Lateral Sclerosis; Humans; Male; Niacinamide; Pyridinium Compounds; Stilbenes

We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS).. This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with (18)F-fluorodeoxyglucose (FDG), and amyloid-PET with (18)F-florbetaben.. Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased (18)F-florbetaben uptake compared to controls.. We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint.

Topics: Amyloid; Amyotrophic Lateral Sclerosis; Aniline Compounds; Brain; Brain Diseases, Metabolic; Female; Fluorodeoxyglucose F18; Humans; Male; Middle Aged; Molecular Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Stilbenes

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1(G93A) ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests. We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1(G93A) mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1(G93A) spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Female; Male; Mice; Mice, Transgenic; Microglia; Mitochondria; Motor Activity; Motor Neurons; Neuroprotective Agents; Resveratrol; Sirtuins; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by the loss of motoneurons (MNs) in the spinal cord, brainstem and motor cortex, causing progressive paralysis and death. Nowadays, there is no effective therapy and most patients die 2-5 years after diagnosis. Sigma-1R is a transmembrane protein highly expressed in the CNS and specially enriched in MNs. Mutations on the Sigma-1R leading to frontotemporal lobar degeneration-ALS were recently described in human patients. We previously reported the therapeutic role of the selective sigma-1R agonist 2-(4-morpholi-nethyl)1-phenylcyclohexanecarboxylate (PRE-084) in SOD1G93A ALS mice, that promoted spinal MN preservation and extended animal survival by controlling NMDA receptor calcium influx. Resveratrol (RSV, trans-3,4',5-trihydroxystilbene) is a natural polyphenol with promising neuroprotective effects. We recently found that RSV administration to SOD1G93A mice preserves spinal MN function and increases mice survival. These beneficial effects were associated to activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) pathways, leading to the modulation of autophagy and an increase of mitochondrial biogenesis. The main goal of this work was to assess the effect of combined RSV and PRE-084 administration in SOD1G93A ALS mice.. We determined the locomotor performance of the animals by rotarod test and evaluated spinal motoneuron function using electrophysiological tests.. RSV plus PRE-084 treatment from 8 weeks of age significantly improved locomotor performance and spinal MN function, accompanied by a significant reduction of MN degeneration and an extension of mice lifespan. In agreement with our previous findings, there was an induction of PKC-specific phosphorylation of the NMDA-NR1 subunit and an increased expression and activation of Sirt1 and AMPK in the ventral spinal cord of treated SOD1G93A animals.. Although combined PRE and RSV treatment significantly ameliorated SOD1G93A mice, it did not show a synergistic effect compared to RSV-only and PRE-084-only treated groups.

Topics: Adenylate Kinase; Amyotrophic Lateral Sclerosis; Animals; Drug Synergism; Mice; Mice, Transgenic; Morpholines; Neural Conduction; Phosphorylation; Protein Kinase C; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Resveratrol; Rotarod Performance Test; Sigma-1 Receptor; Sirtuin 1; Stilbenes; Superoxide Dismutase

Resveratrol has recently been used as a supplemental treatment for several neurological and nonneurological diseases. It is not known whether resveratrol has neuroprotective effect on amyotrophic lateral sclerosis (ALS). To assess the effect of resveratrol on the disease, we tested this agent on an ALS model of SOD1(G93A) transgenic mouse. Rotarod measurement was performed to measure the motor function of the ALS mice. Nissl staining and SMI-32 immunofluorescent staining were used to determine motor neurons survival in the spinal cord of the ALS mice. Hematoxylin-eosin (H&E), succinic dehydrogenase (SDH), and cytochrome oxidase (COX) staining were applied to pathologically analyze the skeletal muscles of the ALS mice. We found that resveratrol treatment significantly delayed the disease onset and prolonged the lifespan of the ALS mice. Furthermore, resveratrol treatment attenuated motor neuron loss, relieved muscle atrophy, and improved mitochondrial function of muscle fibers in the ALS mice. In addition, we demonstrated that resveratrol exerted these neuroprotective effects mainly through increasing the expression of Sirt1, consequently suppressing oxidative stress and downregulating p53 and its related apoptotic pathway. Collectively, our findings suggest that resveratrol might provide a promising therapeutic intervention for ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Apoptosis; Behavior, Animal; Disease Models, Animal; Female; Lipid Peroxidation; Lumbar Vertebrae; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence; Motor Neurons; Muscle, Skeletal; Neurodegenerative Diseases; Oxidative Stress; Resveratrol; Spinal Cord; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Tumor Suppressor Protein p53

Sirtuins have received a lot of attention in biological functions associated with metabolism, survival development, and most recently, neurodegeneration. The versatile role of sirtuins can be readily redirected for drug discovery studies for novel treatment in amyotrophic lateral sclerosis (ALS), as presented in this highlight, by sirtuin-mediated ketogenic responses influencing mitochondrial function.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Nucleus; Cytoplasm; Enzyme Inhibitors; Humans; Mice; Mitochondria; Resveratrol; Sirtuins; Stilbenes

In the present study, we investigated whether resveratrol, a SIRT1 activator, can suppress the motor neuron degeneration in a transgenic mouse model of amyotrophic lateral sclerosis. Chronic intraperitoneal injection of resveratrol delayed the disease onset and extended survival of the transgenic mice overexpressing G93A-SOD1. The number of surviving motor neurons increased in the resveratrol-injected G93A mice. Importantly, the levels of Hsp25 and Hsp70 were elevated while the level of heat shock factor 1 (HSF1) acetylation decreased in the spinal cords of the resveratrol-injected G93A mice. Our data suggest that resveratrol may protect motor neurons from the mutant SOD1-induced neurotoxicity by promoting SIRT1-mediated deacetylation of HSF1 and subsequent upregulation of Hsps.

Topics: Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Disease Models, Animal; DNA-Binding Proteins; Glial Fibrillary Acidic Protein; Heat Shock Transcription Factors; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Macrophage-1 Antigen; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Chaperones; Motor Neurons; Neoplasm Proteins; Resveratrol; Spinal Cord; Stilbenes; Superoxide Dismutase; Survival Analysis; Transcription Factors; Up-Regulation

Resveratrol has recently been widely reported to be an age-delaying and neuroprotective compound, and it appears to produce these benefits by activating silent mating type information regulation 2 homolog 1 (SIRT1). However, the role that SIRT1 activation plays in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. In the present study, SIRT1 expression was found to be much lower in the mutant hSOD1G93A-bearing VSC4.1 cells compared to hSOD1wt cells when both were cultured in low-serum medium, indicating the involvement of SIRT1 activation defects in the pathogenesis of ALS under energetic stress. Further investigation revealed that a 24-h treatment with 0.5-20μM resveratrol had a dose-dependent protective effect on this ALS cell model, and the effects of resveratrol on increasing cell viability, preventing cell apoptosis and elevating cellular ATP levels through promoting mitochondria biogenesis were blocked by SIRT1 inhibition. This further demonstrated a role for SIRT1 activation in the protection of neuronal cells from degeneration. These findings suggest that resveratrol can protect the ALS cell model from mutant SOD1-mediated toxicity through up-regulating the expression of SIRT1, which represents a potential therapeutic target for preventing the motor neuron degeneration in ALS patients.

Topics: Amyotrophic Lateral Sclerosis; Annexin A5; Blotting, Western; Cell Death; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Flow Cytometry; Fluorescent Antibody Technique; Humans; Mitochondria; Motor Neurons; Mutation; Neuroprotective Agents; Niacinamide; Propidium; Real-Time Polymerase Chain Reaction; Resveratrol; Sirtuin 1; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Tetrazolium Salts; Thiazoles; Up-Regulation

The underlying causes of denervation of the neuromuscular junction and eventual motor neuron death in amyotrophic lateral sclerosis (ALS) have not been resolved. The superoxide dismutase 1 (SOD1)(G93A) mutant mouse is a frequently used animal model of ALS. We hypothesized that resveratrol (RSV), a polyphenolic molecule that enhances mammalian NAD(+)-dependent SIRT1 deacetylases and may increase life span, would improve motor function and survival in the SOD1 mouse model via modulation of p53 acetylation. Data were collected for mean survival times, neuromuscular performance on the ROTOR-ROD™ (San Diego Instruments, San Diego, CA, USA), body weight, and p53 acetylation. Mean survival times were not statistically different (P=.23) between control and experimental (RSV-fed) groups (mean +/- SD, control [n=11] 138 +/- 6 days vs. experimental [n=10] 135 +/- 8 days). Performance was not significantly different between groups at time points corresponding to 50%, 80%, and 90% mean life span (P=.46), nor did RSV treatment attenuate body weight loss. Thus although manipulation of SIRT1 deacetylase activity has effects at the protein level in healthy aging organisms, we conclude that RSV treatment does not lead to functional improvement or increased longevity in a mouse model of ALS. We speculate that RSV-mediated modulation of p53 acetylation is either incapable of increasing or insufficient to increase motor performance and longevity in this model of ALS.

Topics: Acetylation; Amyotrophic Lateral Sclerosis; Animals; Body Weight; Diet; Disease Models, Animal; Longevity; Mice; Mice, Mutant Strains; Mutation; Psychomotor Performance; Resveratrol; Sirtuin 1; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Tumor Suppressor Protein p53

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, characterized by progressive dysfunction and death of motor neurons. Although evidence for oxidative stress in ALS pathogenesis is well described, antioxidants have generally shown poor efficacy in animal models and human clinical trials. We have developed an in vitro screening cascade to identify antioxidant molecules capable of rescuing NSC34 motor neuron cells expressing an ALS-associated mutation of superoxide dismutase 1. We have tested known antioxidants and screened a library of 2000 small molecules. The library screen identified 164 antioxidant molecules, which were refined to the 9 most promising molecules in subsequent experiments. Analysis of the in silico properties of hit compounds and a review of published literature on their in vivo effectiveness have enabled us to systematically identify molecules with antioxidant activity combined with chemical properties necessary to penetrate the central nervous system. The top-performing molecules identified include caffeic acid phenethyl ester, esculetin, and resveratrol. These compounds were tested for their ability to rescue primary motor neuron cultures after trophic factor withdrawal, and the mechanisms of action of their antioxidant effects were investigated. Subsequent in vivo studies can be targeted using molecules with the greatest probability of success.

Topics: Amyotrophic Lateral Sclerosis; Animals; Antioxidants; Apoptosis; Blood-Brain Barrier; Caffeic Acids; Cell Culture Techniques; Cell Line; Central Nervous System; Humans; Mice; Mice, Inbred C57BL; Motor Neurons; Mutation; Oxidative Stress; Resveratrol; Small Molecule Libraries; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Transgenes; Umbelliferones

A progressive loss of neurons with age underlies a variety of debilitating neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), yet few effective treatments are currently available. The SIR2 gene promotes longevity in a variety of organisms and may underlie the health benefits of caloric restriction, a diet that delays aging and neurodegeneration in mammals. Here, we report that a human homologue of SIR2, SIRT1, is upregulated in mouse models for AD, ALS and in primary neurons challenged with neurotoxic insults. In cell-based models for AD/tauopathies and ALS, SIRT1 and resveratrol, a SIRT1-activating molecule, both promote neuronal survival. In the inducible p25 transgenic mouse, a model of AD and tauopathies, resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53. Furthermore, injection of SIRT1 lentivirus in the hippocampus of p25 transgenic mice conferred significant protection against neurodegeneration. Thus, SIRT1 constitutes a unique molecular link between aging and human neurodegenerative disorders and provides a promising avenue for therapeutic intervention.

Topics: Acetylation; Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Cells, Cultured; Cyclin-Dependent Kinase 5; Disease Models, Animal; Enzyme Activation; Gene Expression Regulation; Humans; Mice; Mice, Transgenic; Mutation; Nerve Degeneration; Rats; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1; Tumor Suppressor Protein p53

Topics: Amyotrophic Lateral Sclerosis; Animals; Axons; Brain; Cell Death; Exercise; Humans; Male; Motor Neurons; Nerve Degeneration; Nerve Growth Factors; Resveratrol; RNA Interference; Spinal Cord; Stem Cell Transplantation; Stilbenes; Superoxide Dismutase; Superoxide Dismutase-1