Anti-inflammatory Effects of a Novel Herbal Extract in the Muscle and Spinal Cord of an Amyotrophic Lateral Sclerosis Animal Model

Amyotrophic lateral sclerosis (ALS) is a complex disease characterized by motor neuron loss and muscle atrophy. There is no prominent treatment for ALS as the pathogenic process in the skeletal muscle and spinal cord is complex and multifactorial. Therefore, we investigated the effects of a herbal formula on the multi-target effects in the skeletal muscle and spinal cord in hSOD1G93A transgenic mice. We prepared a herbal extract (HE) from Glycyrrhiza uralensis, Atractylodes macrocephala Koidzumi, Panax ginseng, and Astragalus membranaceus. Control and HE-treated mice underwent rotarod and footprint tests. We also performed immunohistochemical and Western blotting analyses to assess expression of inflammation-related and oxidative stress-related proteins in the muscle and spinal cord tissues. We found that the HE increased motor activity and reduced motor neuron loss in hSOD1G93A mice. In addition, the HE significantly reduced the levels of inflammatory proteins and oxidative stress-related proteins in the skeletal muscles and spinal cord of hSOD1G93A mice. Furthermore, we demonstrated that the HE regulated autophagy function and augmented neuromuscular junction in the muscle of hSOD1G93A mice. Based on these results, we propose that the HE formula may be a potential therapeutic strategy for multi-target treatment in complex and multifactorial pathological diseases.

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Hochu-Ekki-To Improves Motor Function in an Amyotrophic Lateral Sclerosis Animal Model

Nutrients ◽

10.3390/nu11112644 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2644 ◽

Cited By ~ 2

Author(s):

Mudan Cai ◽

Eun Jin Yang

Keyword(s):

Skeletal Muscle ◽

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Immune System ◽

Herbal Medicine ◽

Transgenic Mice ◽

Motor Neuron ◽

Motor Function ◽

Muscle Paralysis ◽

Lateral Sclerosis

Hochu-ekki-to (Bojungikgi-Tang (BJIGT) in Korea; Bu-Zhong-Yi-Qi Tang in Chinese), a traditional herbal prescription, has been widely used in Asia. Hochu-ekki-to (HET) is used to enhance the immune system in respiratory disorders, improve the nutritional status associated with chronic diseases, enhance the mucosal immune system, and improve learning and memory. Amyotrophic lateral sclerosis (ALS) is pathologically characterized by motor neuron cell death and muscle paralysis, and is an adult-onset motor neuron disease. Several pathological mechanisms of ALS have been reported by clinical and in vitro/in vivo studies using ALS models. However, the underlying mechanisms remain elusive, and the critical pathological target needs to be identified before effective drugs can be developed for patients with ALS. Since ALS is a disease involving both motor neuron death and skeletal muscle paralysis, suitable therapy with optimal treatment effects would involve a motor neuron target combined with a skeletal muscle target. Herbal medicine is effective for complex diseases because it consists of multiple components for multiple targets. Therefore, we investigated the effect of the herbal medicine HET on motor function and survival in hSOD1G93A transgenic mice. HET was orally administered once a day for 6 weeks from the age of 2 months (the pre-symptomatic stage) of hSOD1G93A transgenic mice. We used the rota-rod test and foot printing test to examine motor activity, and Western blotting and H&E staining for evaluation of the effects of HET in the gastrocnemius muscle and lumbar (L4–5) spinal cord of mice. We found that HET treatment dramatically inhibited inflammation and oxidative stress both in the spinal cord and gastrocnemius of hSOD1G93A transgenic mice. Furthermore, HET treatment improved motor function and extended the survival of hSOD1G93A transgenic mice. Our findings suggest that HET treatment may modulate the immune reaction in muscles and neurons to delay disease progression in a model of ALS.

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Anti-Inflammatory Effect of Gamisoyo-San in an Animal Model of Amyotrophic Lateral Sclerosis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/8580152 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Sunjung Park ◽

Eun Jin Yang

Keyword(s):

Oxidative Stress ◽

Animal Model ◽

Amyotrophic Lateral Sclerosis ◽

Transgenic Mice ◽

Iron Homeostasis ◽

Heme Oxygenase 1 ◽

Cd11b Expression ◽

Related Proteins ◽

And Oxidative Stress ◽

Lateral Sclerosis

Inflammation is considered a critical factor in the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to evaluate the effect of the herbal formula Gamisoyo-San (GSS) on the muscles of hSOD1G93A transgenic mice, a mouse model of ALS, by examining the tissue expression of inflammation- and oxidative stress-related proteins. The mice were randomly divided into three groups: nontransgenic mice (non-Tg, n = 4), hSOD1G93A transgenic mice (Tg, n = 4), and GSS-treated hSOD1G93A transgenic mice (Tg+GSS, n = 4). Eight-week-old female hSOD1G93A transgenic mice were fed GSS (1 mg/g body weight) for 6 weeks. Gastrocnemius (GA) tissues were analyzed for inflammatory proteins [CD11b and toll-like receptor 4 (TLR4)] and oxidative stress-related proteins [heme oxygenase 1 (HO1) and ferritin] by western blot analysis. Administration of GSS significantly reduced the level of inflammation- and oxidative stress-related proteins in hSOD1G93A transgenic mice. GSS ameliorated inflammation by downregulating TLR4 and CD11b expression and regulated iron homeostasis in the GA muscle of hSOD1G93A mice. GSS could help reduce inflammation by regulating immune reactions in patients with ALS. To the best of our knowledge, this is the first study to demonstrate the effect of GSS on muscle inflammation in an ALS animal model.

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Chapter 10 Excitotoxicity and Oxidative Stress in Pathogenesis of Amyotrophic Lateral Sclerosis/Motor Neuron Disease

Motor Neuron Disorders - Blue Books of Practical Neurology ◽

10.1016/s1877-3419(09)70111-4 ◽

2003 ◽

pp. 259-cp1

Author(s):

Philip Van Damme ◽

Ludo Van Den Bosch ◽

Wim Robberecht

Keyword(s):

Oxidative Stress ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neuron Disease ◽

And Oxidative Stress ◽

Lateral Sclerosis

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Faculty Opinions recommendation of Oxidative stress in skeletal muscle stimulates early expression of Rad in a mouse model of amyotrophic lateral sclerosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.7576956.7874055 ◽

2011 ◽

Author(s):

Brett Adams ◽

Roger Bannister

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Early Expression ◽

Lateral Sclerosis

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Skeletal Muscle Metabolism: Origin or Prognostic Factor for Amyotrophic Lateral Sclerosis (ALS) Development?

Cells ◽

10.3390/cells10061449 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1449

Author(s):

Cyril Quessada ◽

Alexandra Bouscary ◽

Frédérique René ◽

Cristiana Valle ◽

Alberto Ferri ◽

...

Keyword(s):

Skeletal Muscle ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Motor Neurons ◽

Muscle Metabolism ◽

The Body ◽

Energy Deficit ◽

Acid Oxidation ◽

Progression Of Disease ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose–fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.

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RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Molecular and Cellular Biology ◽

10.1128/mcb.00087-15 ◽

2015 ◽

Vol 35 (14) ◽

pp. 2385-2399 ◽

Cited By ~ 12

Author(s):

Nadine Bakkar ◽

Arianna Kousari ◽

Tina Kovalik ◽

Yang Li ◽

Robert Bowser

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Antioxidant Response ◽

Cytoplasmic Inclusions ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulatedin vitroin motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.

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Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis

Molecular Brain ◽

10.1186/s13041-021-00867-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Junmei Wang ◽

Lydia Tierney ◽

Ranjeet Mann ◽

Thomas Lonsway ◽

Chandler L. Walker

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Lumbar Spinal Cord ◽

Therapeutic Effects ◽

Spinal Cord Tissue ◽

Neuron Loss ◽

Neuroprotective Therapy ◽

Motor Neuron Loss ◽

Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival. However, accumulating evidence suggests PTEN is detrimental for MN survival in ALS. Therefore, we hypothesized that treating the mutant superoxide dismutase 1 G93A (mSOD1G93A) mouse model of ALS during motor neuron degeneration and an in vitro model of mSOD1G93A motor neuron injury with bpV(pic) would prevent motor neuron loss. To test our hypothesis, we treated mSOD1G93A mice intraperitoneally daily with 400 μg/kg bpV(pic) from 70 to 90 days of age. Immunolabeled MNs and microglial reactivity were analyzed in lumbar spinal cord tissue, and bpV(pic) treatment significantly ameliorated ventral horn motor neuron loss in mSOD1G93A mice (p = 0.003) while not significantly altering microglial reactivity (p = 0.701). Treatment with bpV(pic) also significantly increased neuromuscular innervation (p = 0.018) but did not affect muscle atrophy. We also cultured motor neuron-like NSC-34 cells transfected with a plasmid to overexpress mutant SOD1G93A and starved them in serum-free medium for 24 h with and without bpV(pic) and downstream inhibitor of Akt signaling, LY294002. In vitro, bpV(pic) improved neuronal viability, and Akt inhibition reversed this protective effect (p < 0.05). In conclusion, our study indicates systemic bpV(pic) treatment could be a valuable neuroprotective therapy for ALS.

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Oxidative Stress, Neuroinflammation and Mitochondria in the Pathophysiology of Amyotrophic Lateral Sclerosis

Antioxidants ◽

10.3390/antiox9090901 ◽

2020 ◽

Vol 9 (9) ◽

pp. 901 ◽

Cited By ~ 3

Author(s):

Elena Obrador ◽

Rosario Salvador ◽

Rafael López-Blanch ◽

Ali Jihad-Jebbar ◽

Soraya L. Vallés ◽

...

Keyword(s):

Oxidative Stress ◽

Amyotrophic Lateral Sclerosis ◽

Cell Types ◽

T Cell Subsets ◽

Cellular Interactions ◽

Underlying Mechanisms ◽

Different Cell Types ◽

And Oxidative Stress ◽

Different Levels ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron (MN) disease. Its primary cause remains elusive, although a combination of different causal factors cannot be ruled out. There is no cure, and prognosis is poor. Most patients with ALS die due to disease-related complications, such as respiratory failure, within three years of diagnosis. While the underlying mechanisms are unclear, different cell types (microglia, astrocytes, macrophages and T cell subsets) appear to play key roles in the pathophysiology of the disease. Neuroinflammation and oxidative stress pave the way leading to neurodegeneration and MN death. ALS-associated mitochondrial dysfunction occurs at different levels, and these organelles are involved in the mechanism of MN death. Molecular and cellular interactions are presented here as a sequential cascade of events. Based on our present knowledge, the discussion leads to the idea that feasible therapeutic strategies should focus in interfering with the pathophysiology of the disease at different steps.

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Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis models

Human Molecular Genetics ◽

10.1093/hmg/ddaa140 ◽

2020 ◽

Vol 29 (16) ◽

pp. 2647-2661 ◽

Cited By ~ 1

Author(s):

Rita F Marques ◽

Jan B Engler ◽

Katrin Küchler ◽

Ross A Jones ◽

Thomas Lingner ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Symptom Onset ◽

Rna Binding ◽

Affinity Purification ◽

Disease Onset ◽

Motor Symptom ◽

Pathological Feature ◽

Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is an incurable neurological disease with progressive loss of motor neuron (MN) function in the brain and spinal cord. Mutations in TARDBP, encoding the RNA-binding protein TDP-43, are one cause of ALS, and TDP-43 mislocalization in MNs is a key pathological feature of >95% of ALS cases. While numerous studies support altered RNA regulation by TDP-43 as a major cause of disease, specific changes within MNs that trigger disease onset remain unclear. Here, we combined translating ribosome affinity purification (TRAP) with RNA sequencing to identify molecular changes in spinal MNs of TDP-43–driven ALS at motor symptom onset. By comparing the MN translatome of hTDP-43A315T mice to littermate controls and to mice expressing wild type hTDP-43, we identified hundreds of mRNAs that were selectively up- or downregulated in MNs. We validated the deregulated candidates Tex26, Syngr4, and Plekhb1 mRNAs in an independent TRAP experiment. Moreover, by quantitative immunostaining of spinal cord MNs, we found corresponding protein level changes for SYNGR4 and PLEKHB1. We also observed these changes in spinal MNs of an independent ALS mouse model caused by a different patient mutant allele of TDP-43, suggesting that they are general features of TDP-43-driven ALS. Thus, we identified SYNGR4 and PLEKHB1 to be deregulated in MNs at motor symptom onset in TDP-43-driven ALS models. This spatial and temporal pattern suggests that these proteins could be functionally important for driving the transition to the symptomatic phase of the disease.

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