Modelos experimentales murinos en la esclerosis lateral amiotrófica. Puesta al día / Murine experimental models of amyotrophic lateral sclerosis: An update

Introducción: La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa, progresiva y de etiología desconocida caracterizada por la degeneración de motoneuronas superiores e inferiores. Aproximadamente el 90% de los casos de ELA son esporádicos, mientras que el 10% restante se consideran familiares. Independientemente de si son familiares o esporádicas, los pacientes desarrollan una debilidad progresiva, atrofia muscular con espasticidad y contracturas. Por lo general, la esperanza de vida en los pacientes de ELA es de 2 a 5 años. Desarrollo: Los modelos in vivo han ayudado a explicar la etiología y la patogénesis, así como los mecanismos de la ELA. Sin embargo, estos mecanismos no están del todo esclarecidos aún, por lo que los modelos experimentales son fundamentales para continuar con el estudio de los mismos, así como para la búsqueda de posibles dianas terapéuticas. A pesar de que el 90% de los casos son esporádicos, la mayoría de los modelos utilizados hasta la actualidad para estudiar la patogénesis están basados en las mutaciones genéticas asociadas a la enfermedad familiar, lo que provoca que la patogénesis de la ELA esporádica no sea aún conocida. Por tanto, sería fundamental el estudio de la enfermedad en modelos basados en la enfermedad esporádica. Conclusión: En el presente artículo se han revisado los principales modelos experimentales, tanto genéticos como esporádicos, utilizados en el estudio de esta enfermedad, enfocándonos en los que se han desarrollado utilizando el roedor como plataforma experimental.(AU)

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose aetiology is unknown. It is characterised by upper and lower motor neuron degeneration. Approximately 90% of cases of ALS are sporadic, whereas the other 10% are familial. Regardless of whether the case is familial or sporadic, patients will develop progressive weakness, muscle atrophy with spasticity, and muscle contractures. Life expectancy of these patients is generally 2–5 years after diagnosis. Development: In vivo models have helped to clarify the aetiology and pathogenesis of ALS, as well as the mechanisms of the disease. However, as these mechanisms are not yet fully understood, experimental models are essential to the continued study of the pathogenesis of ALS, as well as in the search for possible therapeutic targets. Although 90% of cases are sporadic, most of the models used to study ALS pathogenesis are based on genetic mutations associated with the familial form of the disease; the pathogenesis of sporadic ALS remains unknown. Therefore, it would be critical to establish models based on the sporadic form. Conclusion: This article reviews the main genetic and sporadic experimental models used in the study of this disease, focusing on those that have been developed using rodents.(AU)

Harnessing Big Data in Amyotrophic Lateral Sclerosis: Machine Learning Applications for Clinical Practice and Pharmaceutical Trials.

The arrival of genotype-specific therapies in amyotrophic lateral sclerosis (ALS) signals the dawn of precision medicine in motor neuron diseases (MNDs). After decades of academic studies in ALS, we are now witnessing tangible clinical advances. An ever increasing number of well-designed descriptive studies have been published in recent years, characterizing typical disease-burden patterns in vivo and post mortem. Phenotype- and genotype-associated traits and "typical" propagation patterns have been described based on longitudinal clinical and biomarker data. The practical caveat of these studies is that they report "group-level", stereotyped trajectories representative of ALS as a whole. In the clinical setting, however, "group-level" biomarker signatures have limited practical relevance and what matters is the meaningful interpretation of data from a single individual. The increasing availability of large normative data sets, national registries, extant academic data, consortium repositories, and emerging data platforms now permit the meaningful interpretation of individual biomarker profiles and allow the categorization of single patients into relevant diagnostic, phenotypic, and prognostic categories. A variety of machine learning (ML) strategies have been recently explored in MND to demonstrate the feasibility of interpreting data from a single patient. Despite the considerable clinical prospects of classification models, a number of pragmatic challenges need to be overcome to unleash the full potential of ML in ALS. Cohort size limitations, administrative hurdles, data harmonization challenges, regulatory differences, methodological obstacles, and financial implications and are just some of the barriers to readily implement ML in routine clinical practice. Despite these challenges, machine-learning strategies are likely to be firmly integrated in clinical decision-making and pharmacological trials in the near future.

Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases.

Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and stress granule formation in response to cellular insult. Modulation of the ISR has been proposed as a therapeutic strategy for treatment of neurodegenerative diseases such as vanishing white matter (VWM) disease and amyotrophic lateral sclerosis (ALS) based on its ability to improve cellular homeostasis and prevent neuronal degeneration. Herein, we report the small-molecule discovery campaign that identified potent, selective, and CNS-penetrant eIF2B activators using both structure- and ligand-based drug design. These discovery efforts culminated in the identification of DNL343, which demonstrated a desirable preclinical drug profile, including a long half-life and high oral bioavailability across preclinical species. DNL343 was progressed into clinical studies and is currently undergoing evaluation in late-stage clinical trials for ALS.

FM19G11-loaded nanoparticles modulate energetic status and production of reactive oxygen species in myoblasts from ALS mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Considerable evidence indicates that early skeletal muscle atrophy plays a crucial role in the disease pathogenesis, leading to an altered muscle-motor neuron crosstalk that, in turn, may contribute to motor neuron degeneration. Currently, there is no effective treatment for ALS, highlighting the need to dig deeper into the pathological mechanisms for developing innovative therapeutic strategies. FM19G11 is a novel drug able to modulate the global cellular metabolism, but its effects on ALS skeletal muscle atrophy and mitochondrial metabolism have never been evaluated, yet. This study investigated whether FM19G11-loaded nanoparticles (NPs) may affect the bioenergetic status in myoblasts isolated from G93A-SOD1 mice at different disease stages. We found that FM19G1-loaded NP treatment was able to increase transcriptional levels of Akt1, Akt3, Mef2a, Mef2c and Ucp2, which are key genes associated with cell proliferation (Akt1, Akt3), muscle differentiation (Mef2c), and mitochondrial activity (Ucp2), in G93A-SOD1 myoblasts. These cells also showed a significant reduction of mitochondrial area and networks, in addition to decreased ROS production after treatment with FM19G11-loaded NPs, suggesting a ROS clearance upon the amelioration of mitochondrial dynamics. Our overall findings demonstrate a significant impact of FM19G11-loaded NPs on muscle cell function and bioenergetic status in G93A-SOD1 myoblasts, thus promising to open new avenues towards possible adoption of FM19G11-based nanotherapies to slow muscle degeneration in the frame of ALS and muscle disorders.

Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases.

The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.

BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Structural insights into the modulation Of SOD1 aggregation By a fungal metabolite Phialomustin-B: Therapeutic potential in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal human motor neuron disease leading to muscle atrophy and paralysis. Mutations in superoxide dismutase 1 (SOD1) are associated with familial ALS (fALS). The SOD1 mutants in ALS have a toxic-gain of function by destabilizing the functional SOD1 homodimer, consequently inducing fibril-like aggregation with a cytotoxic non-native trimer intermediate. Therefore, reducing SOD1 oligomerization via chemical modulators is an optimal therapy in ALS. Here, we report the discovery of Phialomustin-B, an unsaturated secondary metabolite from the endophytic fungus Phialophora mustea, as a modulator of SOD1 aggregation. The crystal structure of the SOD1-Phialomustin complex refined to 1.90 Å resolution demonstrated for the first time that the ligand binds to the dimer interface and the lateral region near the electrostatic loop. The aggregation analyses of SOD1WT and the disease mutant SOD1A4V revealed that Phialomustin-B reduces cytotoxic trimerization. We propose that Phialomustin-B is a potent lead molecule with therapeutic potential in fALS.

Ensemble-imbalance-based classification for amyotrophic lateral sclerosis prognostic prediction: identifying short-survival patients at diagnosis.

Prognosticating Amyotrophic Lateral Sclerosis (ALS) presents a formidable challenge due to patients exhibiting different onset sites, progression rates, and survival times. In this study, we have developed and evaluated Machine Learning (ML) algorithms that integrate Ensemble and Imbalance Learning techniques to classify patients into Short and Non-Short survival groups based on data collected during diagnosis. We aimed to identify individuals at high risk of mortality within 24 months of symptom onset through analysis of patient data commonly encountered in daily clinical practice. Our Ensemble-Imbalance approach underwent evaluation employing six ML algorithms as base classifiers. Remarkably, our results outperformed those of individual algorithms, achieving a Balanced Accuracy of 88% and a Sensitivity of 96%. Additionally, we used the Shapley Additive Explanations framework to elucidate the decision-making process of the top-performing model, pinpointing the most important features and their correlations with the target prediction. Furthermore, we presented helpful tools to visualize and compare patient similarities, offering valuable insights. Confirming the obtained results, our approach could aid physicians in devising personalized treatment plans at the time of diagnosis or serve as an inclusion/exclusion criterion in clinical trials.

Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 3: Alleviation of hypoxia, muscle-wasting, and modulation of redox functions in amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this clinical study is to obtain evidence for the clinical efficacy of Bu-Shen-Jian-Pi formula (BSJP), a traditional Chinese medicine, used for the treatment of amyotrophic lateral sclerosis, a relatively rare, progressive and usually fatal disease possibly associated with alterations in tissue redox status, hypoxia, and muscular injury. BACKGROUND: The active agents in BSJP formula† causing apoptosis, modulation of redox changes, and alterations in the immune status have been studied previously by us using cell cultures. The findings from these investigations have been incorporated into pharmacology databases employed in our analysis of BSJP using network pharmacology analysis/artifical intelligence. This information has been used here in the design of the investigation and to optimize evaluation of the clinical efficacy and usefulness of this herbal medicine, as far as possible using evidence-based medicine criteria. MATERIALS AND METHODS: The design of the study was a randomized multi-center, controlled clinical trial in 127 patients with confirmed diagnoses of amyotrophic lateral sclerosis. Patients and investigator were double-blinded. Clinical efficacy was determined using the Amyotrophic Lateral Sclerosis Symptom Score in Integrative Treatment Scale (ALS-SSIT) and the Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R), together with tests of limb muscle strength using the manual muscle test (MMT), forced vital capacity (FVC), and clinical chemistry laboratory tests over a 20-week observation period. RESULTS: The scores of ALS-SSIT in the BSJP group increased significantly (22%) after treatment. The ALSFRS-R score in the BSJP group decreased significantly after treatment (19%). The rate of decrease in muscle function (MMT score) in most BSJP patients was lower than that in the control group, where the differences in the scores for the trapezius and triceps brachii were statistically significant compared to the control group. The fall in FVC in the BJSP group was significantly slower than in the control group. There were no marked differences observed in the frequency of side effects. Serum vitamin D3 levels in the BSJP group showed greater increases compared to the control group. CONCLUSION: BSJP treatment reduced the rate of progression of amyotrophic lateral sclerosis according to the ALS-SSITS and ALSFRS scores and significantly reduced the rate of deterioration in muscle function in the limbs of amyotrophic lateral sclerosis patients. The modes of action of BSJP in treating amyotrophic lateral sclerosis are probably diverse and multi targeted, some of which may involve regulation of serum vitamin D3 and alleviation of the impairments in liver and kidney function.

A new potential therapeutic approach for ALS: A case report with NGS analysis.

RATIONALE: Amyotrophic lateral sclerosis (ALS) poses a significant clinical challenge due to its rapid progression and limited treatment options, often leading to deadly outcomes. Looking for effective therapeutic interventions is critical to improve patient outcomes in ALS. PATIENT CONCERNS: The patient, a 75-year-old East Asian male, manifested an insidious onset of right-hand weakness advancing with dysarthria. Comprehensive Next-generation sequencing analysis identified variants in specific genes consistent with ALS diagnosis. DIAGNOSES: ALS diagnosis is based on El Escorial diagnostic criteria. INTERVENTIONS: This study introduces a novel therapeutic approach using artificial intelligence phenotypic response surface (AI-PRS) technology to customize personalized drug-dose combinations for ALS. The patient underwent a series of phases of AI-PRS-assisted trials, initially incorporating a 4-drug combination of Ibudilast, Riluzole, Tamoxifen, and Ropinirole. Biomarkers and regular clinical assessments, including nerve conduction velocity, F-wave, H-reflex, electromyography, and motor unit action potential, were monitored to comprehensively evaluate treatment efficacy. OUTCOMES: Neurophysiological assessments supported the ALS diagnosis and revealed the co-presence of diabetic polyneuropathy. Hypotension during the trial necessitated an adaptation to a 2-drug combinational trial (ibudilast and riluzole). Disease progression assessment shifted exclusively to clinical tests of muscle strength, aligning with the patient's well-being. LESSONS: The study raises the significance of personalized therapeutic strategies in ALS by AI-PRS. It also emphasizes the adaptability of interventions based on patient-specific responses. The encountered hypotension incident highlights the importance of attentive monitoring and personalized adjustments in treatment plans. The described therapy using AI-PRS, offering personalized drug-dose combinations technology is a potential approach in treating ALS. The promising outcomes warrant further evaluation in clinical trials for searching a personalized, more effective combinational treatment for ALS patients.

Excitotoxicity and ALS: New therapy targets an old mechanism.

Excitotoxicity-induced cell death in motor neurons is a major therapeutic target for amyotrophic lateral sclerosis (ALS). Yan et al.1 present a novel compound to specifically disrupt extra-synaptic NMDAR complexes, extending the lifespan of the SOD1G93A ALS mouse and ameliorating cell death.

Sulfated disaccharide protects membrane and DNA damages from arginine-rich dipeptide repeats in ALS.

Hexanucleotide repeat expansion in C9ORF72 (C9) is the most prevalent mutation among amyotrophic lateral sclerosis (ALS) patients. The patients carry over ~30 to hundreds or thousands of repeats translated to dipeptide repeats (DPRs) where poly-glycine-arginine (GR) and poly-proline-arginine (PR) are most toxic. The structure-function relationship is still unknown. Here, we examined the minimal neurotoxic repeat number of poly-GR and found that extension of the repeat number led to a loose helical structure disrupting plasma and nuclear membrane. Poly-GR/PR bound to nucleotides and interfered with transcription. We screened and identified a sulfated disaccharide that bound to poly-GR/PR and rescued poly-GR/PR-induced toxicity in neuroblastoma and C9-ALS-iPSC-derived motor neurons. The compound rescued the shortened life span and defective locomotion in poly-GR/PR expressing Drosophila model and improved motor behavior in poly-GR-injected mouse model. Overall, our results reveal structural and toxicity mechanisms for poly-GR/PR and facilitate therapeutic development for C9-ALS.

The ALSFRS-R Summit: a global call to action on the use of the ALSFRS-R in ALS clinical trials.

The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures.

Can Some Anticancer Drugs Be Repurposed to Treat Amyotrophic Lateral Sclerosis? A Brief Narrative Review.

Amyotrophic lateral sclerosis (ALS) is a rare progressive motor neuron disease that, due to its high complexity, still lacks effective treatments. Development of a new drug is a highly costly and time-consuming process, and the repositioning of approved drugs can represent an efficient strategy to provide therapeutic opportunities. This is particularly true for rare diseases, which are characterised by small patient populations and therefore attract little commercial interest. Based on the overlap between the biological background of cancer and neurodegeneration, the repurposing of antineoplastic drugs for ALS has been suggested. The objective of this narrative review was to summarise the current experimental evidence on the use of approved anticancer drugs in ALS. Specifically, anticancer drugs belonging to different classes were found to act on mechanisms involved in the ALS pathogenesis, and some of them proved to exert beneficial effects in ALS models. However, additional studies are necessary to confirm the real therapeutic potential of anticancer drugs for repositioning in ALS treatment.

PERK modulation, with GSK2606414, Sephin1 or salubrinal, failed to produce therapeutic benefits in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) has been linked to overactivity of the protein kinase RNA-like ER kinase (PERK) branch of the unfolded protein response (UPR) pathway, both in ALS patients and mouse models. However, attempts to pharmacologically modulate PERK for therapeutic benefit have yielded inconsistent and often conflicting results. This study sought to address these discrepancies by comprehensively evaluating three commonly used, CNS-penetrant, PERK modulators (GSK2606414, salubrinal, and Sephin1) in the same experimental models, with the goal of assessing the viability of targeting the PERK pathway as a therapeutic strategy for ALS. To achieve this goal, a tunicamycin-challenge assay was developed using wild-type mice to monitor changes in liver UPR gene expression in response to PERK pathway modulation. Subsequently, multiple dosing regimens of each PERK modulator were tested in standardized, well-powered, gender-matched, and litter-matched survival efficacy studies using the SOD1G93A mouse model of ALS. The alpha-2-adrenergic receptor agonist clonidine was also tested to elucidate the results obtained from the Sephin1, and of the previously reported guanabenz studies, by comparing the effects of presence or absence of α-2 agonism. The results revealed that targeting PERK may not be an ideal approach for ALS treatment. Inhibiting PERK with GSK2606414 or activating it with salubrinal did not confer therapeutic benefits. While Sephin1 showed some promising therapeutic effects, it appears that these outcomes were mediated through PERK-independent mechanisms. Clonidine also produced some favorable therapeutic effects, which were unexpected and not linked to the UPR. In conclusion, this study highlights the challenges of pharmacologically targeting PERK for therapeutic purposes in the SOD1G93A mouse model and suggests that exploring other targets within, and outside, the UPR may be more promising avenues for ALS treatment.

Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD.

Inorganic polyphosphate (polyP) is a simple, negatively charged biopolymer with chain lengths ranging from just a few to over a thousand ortho-phosphate (Pi) residues. polyP is detected in every cell type across all organisms in nature thus far analyzed. Despite its structural simplicity, polyP has been shown to play important roles in a remarkably broad spectrum of biological processes, including blood coagulation, bone mineralization and inflammation. Furthermore, polyP has been implicated in brain function and the neurodegenerative diseases amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease and Parkinson's disease. In this review, we first address the challenges associated with identifying mammalian polyP metabolizing enzymes, such as Nudt3, and quantifying polyP levels in brain tissue, cultured neural cells and cerebrospinal fluid. Subsequently, we focus on recent studies that unveil how the excessive release of polyP by human and mouse ALS/FTD astrocytes contributes to these devastating diseases by inducing hyperexcitability, leading to motoneuron death. Potential implications of elevated polyP levels in ALS/FTD patients for innovative diagnostic and therapeutic approaches are explored. It is emphasized, however, that caution is required in targeting polyP in the brain due to its diverse physiological functions, serving as an energy source, a chelator for divalent cations and a scaffold for amyloidogenic proteins. Reducing polyP levels, especially in neurons, might thus have adverse effects in brain functioning. Finally, we discuss how activated mast cells and platelets also can significantly contribute to ALS progression, as they can massively release polyP.

TwinF interface inhibitor FP802 stops loss of motor neurons and mitigates disease progression in a mouse model of ALS.

Toxic signaling by extrasynaptic NMDA receptors (eNMDARs) is considered an important promoter of amyotrophic lateral sclerosis (ALS) disease progression. To exploit this therapeutically, we take advantage of TwinF interface (TI) inhibition, a pharmacological principle that, contrary to classical NMDAR pharmacology, allows selective elimination of eNMDAR-mediated toxicity via disruption of the NMDAR/TRPM4 death signaling complex while sparing the vital physiological functions of synaptic NMDARs. Post-disease onset treatment of the SOD1G93A ALS mouse model with FP802, a modified TI inhibitor with a safe pharmacology profile, stops the progressive loss of motor neurons in the spinal cord, resulting in a reduction in the serum biomarker neurofilament light chain, improved motor performance, and an extension of life expectancy. FP802 also effectively blocks NMDA-induced death of neurons in ALS patient-derived forebrain organoids. These results establish eNMDAR toxicity as a key player in ALS pathogenesis. TI inhibitors may provide an effective treatment option for ALS patients.

Edaravone: A Novel Possible Drug for Cancer Treatment?

Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.