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.

Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part 1: Biogenic components and identification of targets and signaling pathways in amyotrophic lateral sclerosis patients.

BACKGROUND: There is evidence that Bu-Shen-Jian-Pi (BSJP), a traditional Chinese medicine, has curative effects in patients suffering from amyotrophic lateral sclerosis (ALS), a progressive and potentially fatal hypoxic condition. OBJECTIVE: To identify biogenic components in BSJP extracts having potential pharmacological efficacy in ALS. MATERIALS AND METHODS: Biogenic components in BSJP and their potential pharmacological targets and signaling pathways in ALS were identified and assessed using network pharmacology/hub node analysis. RESULTS: Network pharmacology analysis identified icariin, naringenin, kaempferol, quercetin, and formononetin as core components in BSJP with potential activity involving mitochondrial protection in patients with ALS. CONCLUSION: Network pharmacology analysis proved to be a successful screening tool for obtaining information from scientific databases on the pharmacology of biogenic components in BSJP showing potential therapeutic activity in ALS.

Explore the pharmacological basis of ShengJiYiSui decoction in the treatment of amyotrophic lateral sclerosis based on network pharmacology and molecular docking technology.

Neurodegenerative illnesses have long been handled clinically by traditional Chinese medicine. This study is the first time to explore the pharmacological basis of application in amyotrophic lateral sclerosis (ALS) through network pharmacology and molecular docking techniques. In the present investigation, the TCMSP database and HIT2 database were examined for 9 TCM constituents of Sheng Ji Yu Sui Decoction (SJYSD), and the desired sites for the components were searched in the Drugbank database. and the Sjysd-target network was constructed. Associated targets for Amyotrophic lateral sclerosis (ALS) were then retrieved and collected in the OMIM, TTD, Genecards and DisGeNET databases. Protein-protein interaction and enrichment analysis were performed for the common targets of drugs and diseases, and molecular anchoring for the chosen core targets and related molecules was carried out. The results showed that SJYSD had 100 active compounds corresponding to 598 targets. ALS has a total of 5,325 genes. SJYSD and ALS share 163 genes, and these targets involve PI3K-AKT signaling, p53 signaling and IL-17 signaling, etc. The core components of luteolin and quercetin were discovered and may be used to treat ALS by regulating PI3K-AKT signaling pathway by HSP90AB1 protein.

An in silico investigation: Can melatonin serve as an adjuvant in NR1D1-linked chronotherapy for amyotrophic lateral sclerosis?

Chronobiology, which studies biological rhythms and their impacts on health, presents a potential avenue for treating amyotrophic lateral sclerosis. Clock gene-related therapies, focusing on genes responsible for regulating biological rhythms, may hold promise in the treatment. Among these clock genes, nuclear receptor subfamily 1 Group D member 1 (NR1D1) plays a vital role in neurodegenerative diseases. In this particular study, it was aimed to investigate the potential of FDA-approved drugs commonly used in amyotrophic lateral sclerosis treatment and melatonin, a hormone known for its role in regulating sleep-wake cycles, as ligands for clock gene-related therapy. The ligands were subjected to molecular docking and molecular dynamics simulation methods against the NR1D1 clock gene. These results suggested that combining melatonin with FDA-approved medications commonly used in the treatment might yield positive outcomes. This study provides preliminary data and lays the groundwork for future investigations involving in vitro (laboratory-based) and in vivo (animal or human-based) research on chronotherapy. In summary, this research highlights the potential of clock gene-related therapy utilizing melatonin in conjunction with FDA-approved drugs for amyotrophic lateral sclerosis treatment, offering insights into novel treatment strategies. The findings underscore the need for further studies to explore the effectiveness of this hypothetical approach in experimental and clinical settings.

Therapeutic Effects of Combination of Nebivolol and Donepezil: Targeting Multifactorial Mechanisms in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1G93A mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.

Ginsenoside-Rg1 combined with a conditioned medium from induced neuron-like hUCMSCs alleviated the apoptosis in a cell model of ALS through regulating the NF-κB/Bcl-2 pathway.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons in the brain and spinal cord. One important aspect of ALS pathogenesis is superoxide dismutase 1 (SOD1) mutant-mediated mitochondrial toxicity, leading to apoptosis in neurons. This study aimed to evaluate the neural protective synergistic effects of ginsenosides Rg1 (G-Rg1) and conditioned medium (CM) on a mutational SOD1 cell model, and to explore the underlying mechanisms. We found that the contents of nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor significantly increased in CM after human umbilical cord mesenchymal stem cells (hUCMSCs) were exposed to neuron differentiation reagents for seven days. CM or G-Rg1 decreased the apoptotic rate of SOD1G93A-NSC34 cells to a certain extent, but their combination brought about the least apoptosis, compared with CM or G-Rg1 alone. Further research showed that the anti-apoptotic protein Bcl-2 was upregulated in all the treatment groups. Proteins associated with mitochondrial apoptotic pathways, such as Bax, caspase 9 (Cas-9), and cytochrome c (Cyt c), were downregulated. Furthermore, CM or G-Rg1 also inhibited the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by reducing the phosphorylation of p65 and IκBα. CM/G-Rg1 or their combination also reduced the apoptotic rate induced by betulinic acid (BetA), an agonist of the NF-κB signaling pathway. In summary, the combination of CM and G-Rg1 effectively reduced the apoptosis of SOD1G93A-NSC34 cells through suppressing the NF-κB/Bcl-2 signaling pathway (Fig. 1 is a graphical representation of the abstract).

Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial.

INTRODUCTION/AIMS: Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS. METHODS: This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). DISCUSSION: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.

Network Pharmacology and Molecular Docking to Unveil the Mechanism of Shudihuang against Amyotrophic Lateral Sclerosis.

BACKGROUND: Shudihuang has been clinically proven to be an effective Chinese medicine compatible with the treatment of amyotrophic lateral sclerosis. However, the underlying mechanism of Shudihuang against amyotrophic lateral sclerosis remains unclear. OBJECTIVES: The present study aims to elucidate the possible mechanism of Shudihuang in treating ALS using network pharmacology and molecular docking. METHODS: The primary active components of Shudihuang and their relevant targets were identified by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the Swiss Target Prediction database, respectively. The ALS-related targets were obtained from the Disgenet and OMIM databases. The shared targets were derived by the intersection of disease-associated and component-associated targets and then introduced into the Cytoscape software to construct a network of drug-component-target. In addition, protein interaction relationships among the shared targets were analyzed by the STRING and Cytoscape software. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) functional enrichment analysis were conducted by the Metascape platform. The binding activities between the hub targets and the active components were assessed with molecular docking. RESULTS: Stigmasterol and sitosterol were identified as the core components of Shudihuang, and the hub targets of ALS are PTGS2, PPARG, ESR1, IGF-1R, and MAPK3, with the highest degrees in the PPI network. The finding that stigmasterol and sitosterol had a good affinity with PTGS2, PPARG, ESR1, IGF-1R, and MAPK3 also supported this. Finally, it was revealed that Shudihuang treatment of ALS predominantly involves estrogen- related pathways such as nuclear receptor activity and steroid binding. CONCLUSION: In summary, this study suggested that the main active components of Shudihuang (stigmasterol and sitosterol) may exert a critical effect in ALS treatment by binding to hub targets (PTGS2, PPARG, ESR1, IGF-1R, and MAPK3) and then modulating estrogen receptor-related pathways to attenuate glutamate excitotoxicity, inhibit oxidative stress and antagonize inflammation.

Association of Polyunsaturated Fatty Acids and Clinical Progression in Patients With ALS: Post Hoc Analysis of the EMPOWER Trial.

BACKGROUND AND OBJECTIVES: Polyunsaturated fatty acids (PUFAs) have neuroprotective and anti-inflammatory effects and could be beneficial in amyotrophic lateral sclerosis (ALS). Higher dietary intake and plasma levels of PUFAs, in particular alpha-linolenic acid (ALA), have been associated with a lower risk of ALS in large epidemiologic cohort studies, but data on disease progression in patients with ALS are sparse. We examined whether plasma levels of ALA and other PUFAs contributed to predicting survival time and functional decline in patients with ALS. METHODS: We conducted a study among participants in the EMPOWER clinical trial who had plasma samples collected at the time of randomization that were available for fatty acid analyses. Plasma fatty acids were measured using gas chromatography. We used Cox proportional hazards models and linear regression to evaluate the association of individual fatty acids with risk of death and joint rank test score of functional decline and survival. RESULTS: Fatty acid analyses were conducted in 449 participants. The mean (SD) age of these participants at baseline was 57.5 (10.7) years, and 293 (65.3%) were men; 126 (28.1%) died during follow-up. Higher ALA levels were associated with lower risk of death (age-adjusted and sex-adjusted hazard ratio comparing highest vs lowest quartile 0.50, 95% CI 0.29-0.86, p-trend = 0.041) and higher joint rank test score (difference in score according to 1 SD increase 10.7, 95% CI 0.2-21.1, p = 0.045), consistent with a slower functional decline. The estimates remained similar in analyses adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole use, family history of ALS, predicted upright slow vital capacity, and treatment group. Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up. DISCUSSION: Higher levels of ALA were associated with longer survival and slower functional decline in patients with ALS. These results suggest that ALA may have a favorable effect on disease progression in patients with ALS.

Efficacy of mecasin for treatment of amyotrophic lateral sclerosis: A phase IIa multicenter randomized double-blinded placebo-controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by progressive paralysis of voluntary muscles. Mecasin, the extract of modified jakyakgamchobuja-tang-a herbal preparation comprising of Radix Paeoniae Alba, Radix Glycyrrhizae, Radix Aconiti Lateralis Preparata, Radix Salviae Miltiorrhizae, Rhizoma Gastrodiae, Radix Polygalae, Curcuma Root, Fructus Chaenomelis, and Rhizoma Atractylodis Japonicae-shows neuroprotective and anti-neuroinflammatory effects and alleviates the symptoms in patients with ALS. AIM OF THE STUDY: This trial aimed to evaluate the efficacy and safety of mecasin in these patients. MATERIAL AND METHODS: Patients were randomized to receive mecasin 1.6 g daily, mecasin 2.4 g daily, or placebo for 12 weeks. The primary endpoint was the Korean version of ALS Functional Rating Scale-Revised (K-ALSFRS-R) score. The secondary endpoints were muscular atrophy measurements, pulmonary function test results, creatine kinase levels, body weight, safety, and scores of the Medical Research Council (MRC) scale for muscle strength; Visual Analog Scale for pain (VAS pain); Hamilton Rating Scale for Depression; and Fatigue Severity Scale. RESULTS: Among the 30 patients randomized, 24 completed the follow-up. Significant between-group differences were detected in the primary endpoint using the omnibus F-test. The changes in the K-ALSFRS-R score between 12 weeks and baseline were -0·25, -1·32, and -2·78 in the mecasin 1.6 g, mecasin 2.4 g, and placebo groups, respectively. The difference in the K-ALSFRS-R score between the mecasin 1.6 g and placebo groups was 2·53 points (95% confidence interval [CI]: 0·61-4·45), and that between the 2.4 g and placebo groups was 1·46 points (95% CI: 0·48-3·40). However, no significant differences were detected in the secondary endpoints (MRC: dyspnea, p = 0·139; VAS pain, p = 0·916; forced vital capacity, p = 0·373). The incidence of adverse events was similar and low in all groups. CONCLUSIONS: Mecasin may retard symptomatic progression without major adverse effects. A phase IIb study to evaluate its long-term effects in ALS is ongoing.

In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is regarded as a fatal neurodegenerative disease that is featured by progressive damage of the upper and lower motor neurons. To date, over 45 genes have been found to be connected with ALS pathology. The aim of this work was to computationally identify unique sets of protein hydrolysate peptides that could serve as therapeutic agents against ALS. Computational methods which include target prediction, protein-protein interaction, and peptide-protein molecular docking were used. The results showed that the network of critical ALS-associated genes consists of ATG16L2, SCFD1, VAC15, VEGFA, KEAP1, KIF5A, FIG4, TUBA4A, SIGMAR1, SETX, ANXA11, HNRNPL, NEK1, C9orf72, VCP, RPSA, ATP5B, and SOD1 together with predicted kinases such as AKT1, CDK4, DNAPK, MAPK14, and ERK2 in addition to transcription factors such as MYC, RELA, ZMIZ1, EGR1, TRIM28, and FOXA2. The identified molecular targets of the peptides that support multi-metabolic components in ALS pathogenesis include cyclooxygenase-2, angiotensin I-converting enzyme, dipeptidyl peptidase IV, X-linked inhibitor of apoptosis protein 3, and endothelin receptor ET-A. Overall, the results showed that AGL, APL, AVK, IIW, PVI, and VAY peptides are promising candidates for further study. Future work would be needed to validate the therapeutic properties of these hydrolysate peptides by in vitro and in vivo approaches.

The Neuroprotective Activities of the Novel Multi-Target Iron-Chelators in Models of Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Aging.

The concept of chelation therapy as a valuable therapeutic approach in neurological disorders led us to develop multi-target, non-toxic, lipophilic, brain-permeable compounds with iron chelation and anti-apoptotic properties for neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), age-related dementia and amyotrophic lateral sclerosis (ALS). Herein, we reviewed our two most effective such compounds, M30 and HLA20, based on a multimodal drug design paradigm. The compounds have been tested for their mechanisms of action using animal and cellular models such as APP/PS1 AD transgenic (Tg) mice, G93A-SOD1 mutant ALS Tg mice, C57BL/6 mice, Neuroblastoma × Spinal Cord-34 (NSC-34) hybrid cells, a battery of behavior tests, and various immunohistochemical and biochemical techniques. These novel iron chelators exhibit neuroprotective activities by attenuating relevant neurodegenerative pathology, promoting positive behavior changes, and up-regulating neuroprotective signaling pathways. Taken together, these results suggest that our multifunctional iron-chelating compounds can upregulate several neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain and might function as ideal drugs for neurodegenerative disorders, such as PD, AD, ALS, and aging-related cognitive decline, in which oxidative stress and iron-mediated toxicity and dysregulation of iron homeostasis have been implicated.

The promise of stem cells in amyotrophic lateral sclerosis: a review of clinical trials.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition with high cost of care, poor treatment outcomes, and a significant decrease in quality of life, eventually culminating in high mortality rates. Stem cells present an attractive alternative to conventional therapies as they can regenerate tissue and introduce growth factors to slow down the progression of disease. We conducted a comprehensive review of literature available in the MEDLINE (PUBMED), Scopus, and Cochrane Library databases, of current usage of stem cells and stem cell-based biomaterials for ALS treatment. Clinical trials, less than 10 years old, on human subjects were included in the study. Overall, stem cells, whether mesenchymal, non-lineage, or neural stem cells all seem safe for use in therapy for ALS. However, due to the chronic nature of the disease the efficacy of the treatment is not proven and warrants further investigation.

ALSUntangled # 69: astaxanthin.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review astaxanthin which has plausible mechanisms for slowing ALS progression including antioxidant, anti-inflammatory, and anti-apoptotic effects. While there are no ALS-specific pre-clinical studies, one verified "ALS reversal" occurred in a person using a combination of alternative therapies which included astaxanthin. There have been no trials of astaxanthin in people living with ALS. Natural astaxanthin appears to be safe and inexpensive. Based on the above information, we support further pre-clinical and/or clinical trials of astaxanthin in disease models and PALS, respectively, to further elucidate efficacy.

ALSUntangled #68: ozone therapy.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.

Combination of ciprofloxacin/celecoxib as a novel therapeutic strategy for ALS.

OBJECTIVE: This study aimed to evaluate the safety and tolerability of a fixed-dose co-formulation of ciprofloxacin and celecoxib (PrimeC) in patients with amyotrophic lateral sclerosis (ALS), and to examine its effects on disease progression and ALS-related biomarkers. METHODS: In this proof of concept, open-label, phase IIa study of PrimeC in 15 patients with ALS, participants were administered PrimeC thrice daily for 12 months. The primary endpoints were safety and tolerability. Exploratory endpoints included disease progression outcomes such as forced vital capacity, revised ALS functional rating scale, and effect on algorithm-predicted survival. In addition, indications of a biological effect were assessed by selected biomarker analyses, including TDP-43 and LC3 levels in neuron-derived exosomes (NDEs), and serum neurofilaments. RESULTS: Four participants experienced adverse events (AEs) related to the study drug. None of these AEs were unexpected, and most were mild or moderate (69%). Additionally, no serious AEs were related to the study drug. One participant tested positive for COVID-19 and recovered without complications, and no other abnormal laboratory investigations were found. Participants' survival compared to their predictions showed no safety concerns. Biomarker analyses demonstrated significant changes associated with PrimeC in neural-derived exosomal TDP-43 levels and levels of LC3, a key autophagy marker. INTERPRETATION: This study supports the safety and tolerability of PrimeC in ALS. Biomarker analyses suggest early evidence of a biological effect. A placebo-controlled trial is required to disentangle the biomarker results from natural progression and to evaluate the efficacy of PrimeC for the treatment of ALS. Summary for social media if publishedTwitter handles: @NeurosenseT, @ShiranZimri•What is the current knowledge on the topic? ALS is a severe neurodegenerative disease, causing death within 2-5 years from diagnosis. To date there is no effective treatment to halt or significantly delay disease progression.•What question did this study address? This study assessed the safety, tolerability and exploratory efficacy of PrimeC, a fixed dose co-formulation of ciprofloxacin and celecoxib in the ALS population.•What does this study add to our knowledge? This study supports the safety and tolerability of PrimeC in ALS, and exploratory biomarker analyses suggest early insight for disease related-alteration.•How might this potentially impact the practice of neurology? These results set the stage for a larger, placebo-controlled study to examine the efficacy of PrimeC, with the potential to become a new drug candidate for ALS.

Anti-Inflammatory Effects of Chaenomeles sinensis Extract in an ALS Animal Model.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a systemic disease with multiple pathological effects, including neuroinflammation, oxidative stress, autophagy, mitochondrial dysfunction, and endoplasmic reticulum stress. Despite many studies seeking to identify and develop effective therapies, effective ALS treatment has yet to be approved. Hence, patients with ALS ultimately experience muscle atrophy and loss of motor neurons. Herbal medicines have been used to treat numerous diseases by modulating multiple biological processes and exerting pharmacological effects, including anti-inflammatory and antioxidant properties. In particular, Chaenomeles sinensis Koehne (CS) exhibits anti-hyperuricemic and nephroprotective effects and is used to treat anaphylaxis, viral infections, and neurodegenerative diseases, such as Alzheimer's disease. This study monitored the effects of CS supplementation on muscle function and motor neurons in hSOD1G93A mice, an established ALS animal model. METHODS: Body weight measurements and behavioral tests were performed; additionally, western blotting and immunohistochemistry analyses were conducted using the mice gastrocnemius, tibialis anterior, and spinal cord. RESULTS: CS augmented anti-inflammatory and antioxidant effects in the muscle and spinal cord of hSOD1G93A mice. Furthermore, CS improved motor function and regulated autophagy in the muscles of the hSOD1G93A mice. CONCLUSIONS: CS might represent a promising supplement for improving motor function and delaying ALS progression. However, its development for clinical use warrants further investigation.

Effectiveness of herbal medicine on patients with amyotrophic lateral sclerosis: Analysis of the PRO-ACT data using propensity score matching.

BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) have restricted pharmacotherapy options and thus resort to herbal medicines (HMs), despite limited and conflicting evidence. Therefore, use of HMs needs to be assessed in patients with ALS. PURPOSE: This study aimed to evaluate the benefits of HMs in ALS and to describe the characteristics of HM users. STUDY DESIGN: The correlation between HMs and prognosis was determined based on data obtained from the largest ALS database with high-quality clinical trials. Propensity score (PS) matching was used to address confounding and selection bias. METHODS: In total, 321 and 231 HM users with at least a 4-week HM prescription were identified and PS-matched with non-HM users at a 1:1 ratio based on predefined confounders. Time-to-event models with censoring at 12 or 18 months were established for survival analyses. For evaluating activity limitation and respiratory function, 320 and 376 HM users were included, respectively, and analyzed using multivariate analysis of variance (MANOVA). RESULTS: The profiles of 321 HM users indicated a better condition compared with that of non-HM users before PS-matching, including higher weight (median [IQR], 77.90 [21.8] kg vs. 74.00 [21.2] kg, p < 0.01), higher body mass index (26.00 [5.4] vs. 25.20 [5.8], p < 0.01), more percentage of limb onset (261 [81.3%] vs. 2366 [67.2%], p < 0.01), and slower progression (0.47 [0.5] vs. 0.51 [0.5], p = 0.03). HM did not significantly affect survival at 12 months (adjusted hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.49-1.03; log-rank p = 0.069), but it significantly prolonged survival at 18 months (adjusted HR 0.74, 95% CI 0.56-0.98; log-rank p = 0.038). After imputation of missing data, MANOVA revealed significant effectiveness of HMs in improving activity limitation (Pillai trace, 0.0195; p = 0.03). CONCLUSION: PS-based methods eliminated baseline differences between HM and non-HM users. Overall, the use of HM to treat patients with ALS is favored based on their association with prolonged overall survival within 18 months and improved activity limitation.

Inosine in Neurodegenerative Diseases: From the Bench to the Bedside.

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), currently represent major unmet medical needs. Therefore, novel therapeutic strategies are needed in order to improve patients' quality of life and prognosis. Since oxidative stress can be strongly involved in neurodegenerative diseases, the potential use of inosine, known for its antioxidant properties, in this context deserves particular attention. The protective action of inosine treatment could be mediated by its metabolite urate. Here, we review the current preclinical and clinical studies investigating the use of inosine in AD, PD, ALS, and MS. The most important properties of inosine seem to be its antioxidant action and its ability to raise urate levels and to increase energetic resources by improving ATP availability. Inosine appears to be generally safe and well tolerated; however, the possible formation of kidney stones should be monitored, and data on its effectiveness should be further explored since, so far, they have been controversial. Overall, inosine could be a promising potential strategy in the management of neurodegenerative diseases, and additional studies are needed in order to further investigate its safety and efficacy and its use as a complementary therapy along with other approved drugs.

Altered Bioenergetics and Metabolic Homeostasis in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects motor neurons and causes muscle atrophy, paralysis, and death. While a great deal of progress has been made in deciphering the underlying pathogenic mechanisms, no effective treatments for the disease are currently available. This is mainly due to the high degree of complexity and heterogeneity that characterizes the disease. Over the last few decades of research, alterations to bioenergetic and metabolic homeostasis have emerged as a common denominator across many different forms of ALS. These alterations are found at the cellular level (e.g., mitochondrial dysfunction and impaired expression of monocarboxylate transporters) and at the systemic level (e.g., low BMI and hypermetabolism) and tend to be associated with survival or disease outcomes in patients. Furthermore, an increasing amount of preclinical evidence and some promising clinical evidence suggests that targeting energy metabolism could be an effective therapeutic strategy. This review examines the evidence both for and against these ALS-associated metabolic alterations and highlights potential avenues for therapeutic intervention.