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

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2644 ◽  
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.

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

2021 ◽  
Vol 15 ◽  
Author(s):  
Sun Hwa Lee ◽  
Mudan Cai ◽  
Eun Jin Yang
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Herbal Extract ◽  
Motor Neuron Loss ◽  
Related Proteins ◽  
And Oxidative Stress ◽  
Lateral Sclerosis

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.

scholarly journals Mutant Profilin1 Aggregation in Amyotrophic Lateral Sclerosis: An in Vivo Biochemical Analysis

2021 ◽  
Vol 12 (2) ◽  
pp. 213-222
Author(s):  
Mina Nekouei ◽  
◽  
Atousa Aliahmadi ◽  
Mahmoud Kiaei ◽  
Ali Reza Ghassempour ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neuron ◽  
Actin Polymerization ◽  
Insoluble Fraction ◽  
Neuron Death ◽  
Molecular Weights ◽  
Lateral Sclerosis

Introduction: Profilin1 (PFN1) is a ubiquitously expressed protein known for its function as a regulator of actin polymerization and dynamics. A recent discovery linked mutant PFN1 to Amyotrophic Lateral Sclerosis (ALS), which is a fatal and progressive motor neuron disease. We have also demonstrated that Gly118Val mutation in PFN1 is a cause of ALS, and the formation of aggregates containing mutant PFN1 may be a mechanism for motor neuron death. Hence, we were interested in investigating the aggregation of PFN1 further and searching for co-aggregated proteins in our mouse model overexpressing mutant PFN1. Methods: We investigated protein aggregation in several tissues of transgenic and no-transgenic mice using western blotting. To further understand the neurotoxicity of mutant PFN1, we conducted a pull-down assay using an insoluble fraction of spinal cord lysates from hPFN1G118V transgenic mice. For this assay, we expressed His6-tagged PFN1WT and PFN1G118V in E. coli and purified these proteins using the Ni-NTA column. Results: In this study, we demonstrated that mutant PFN1 forms aggregate in the brain and spinal cord of hPFN1G118V mice, while WT-PFN1 remains soluble. Among these tissues, spinal cord lysates were found to have PFN1 bands at higher molecular weights recognized with anti-PFN1. Moreover, the pull-down assay using His6-PFN1G118V showed that Myelin Binding Protein (MBP) was present in the insoluble fraction. Conclusion: Our analysis of PFN1 aggregation in vivo revealed further details of mutant PFN1 aggregation and its possible complex formation with other proteins, providing new insights into the ALS mechanism.

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

Cells ◽  
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.

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

2020 ◽  
Vol 29 (16) ◽  
pp. 2647-2661 ◽  
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.

scholarly journals Role of PET and SPECT in the Study of Amyotrophic Lateral Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Angelina Cistaro ◽  
Vincenzo Cuccurullo ◽  
Natale Quartuccio ◽  
Marco Pagani ◽  
Maria Consuelo Valentini ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Primary Motor Cortex ◽  
Clinical Laboratory ◽  
Resonance Imaging ◽  
Muscle Paralysis ◽  
Additional Information ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis has been defined as a “heterogeneous group of neurodegenerative syndromes characterized by progressive muscle paralysis caused by the degeneration of motor neurons allocated in primary motor cortex, brainstem, and spinal cord.” A comprehensive diagnostic workup for ALS usually includes several electrodiagnostic, clinical laboratory and genetic tests. Neuroimaging exams, such as computed tomography, magnetic resonance imaging and spinal cord myelogram, may also be required. Nuclear medicine, with PET and SPECT, may also play a role in the evaluation of patients with ALS, and provide additional information to the clinicians. This paper aims to offer to the reader a comprehensive review of the different radiotracers for the assessment of the metabolism of glucose (FDG), the measurement of cerebral blood flow (CBF), or the evaluation of neurotransmitters, astrocytes, and microglia by means of newer and not yet clinically diffuse radiopharmaceuticals.

scholarly journals A Comprehensive Profile of ChIP-Seq-Based Olig2 Target Genes in Motor Neuron Progenitor Cells Suggests the Possible Involvement of Olig2 in the Pathogenesis of Amyotrophic Lateral Sclerosis

2015 ◽  
Vol 7 ◽  
pp. JCNSD.S23210 ◽  
Author(s):  
Jun-Ichi Satoh ◽  
Naohiro Asahina ◽  
Shouta Kitano ◽  
Yoshihiro Kino
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Progenitor Cells ◽  
Motor Neurons ◽  
Target Genes ◽  
Molecular Networks ◽  
Bhlh Transcription Factor ◽  
Wide Range ◽  
Lateral Sclerosis

Background Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease that primarily affects motor neurons in the cerebral cortex and the spinal cord. Recent evidence indicates that dysfunction of oligodendrocytes is implicated in the pathogenesis of ALS. The basic helix–loop–helix (bHLH) transcription factor Olig2 plays a pivotal role in the development of both motor neurons and oligodendrocytes in the progenitor of motor neuron (pMN) domain of the spinal cord, supporting evidence for the shared motor neuron/oligodendrocyte lineage. However, a comprehensive profile of Olig2 target genes in pMNs and oligodendrocyte progenitor cells (OPCs) with relevance to the pathogenesis of ALS remains to be characterized. Methods By analyzing the ChIP-Seq datasets numbered SRP007566 and SRP015333 with the Strand NGS program, we identified genome-wide Olig2 target genes in pMNs and OPCs, followed by molecular network analysis using three distinct bioinformatics tools. Results We identified 5966 Olig2 target genes in pMNs, including Nkx2.2, Pax6, Irx3, Ngn2, Zep2 (Cip1), Trp3, Mnx1 (Hb9), and Cdkn1a, and 1553 genes in OPCs. The genes closely related to the keyword “alternative splicing” were enriched in the set of 740 targets overlapping between pMNs and OPCs. Furthermore, approximately one-third of downregulated genes in purified motor neurons of presymptomatic mutant SOD1 transgenic mice and in lumbar spinal cord tissues of ALS patients corresponded to Olig2 target genes in pMNs. Molecular networks of Olig2 target genes indicate that Olig2 regulates a wide range of genes essential for diverse neuronal and glial functions. Conclusions These observations lead to a hypothesis that aberrant regulation of Olig2 function, by affecting biology of both motor neurons and oligodendrocytes, might be involved in the pathogenesis of ALS.

scholarly journals Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yafa Fetfet Malada Edelstein ◽  
Yulia Solomonov ◽  
Nurit Hadad ◽  
Leenor Alfahel ◽  
Adrian Israelson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Dependent Manner ◽  
Mutant Sod1 ◽  
Over Expression ◽  
Cytosolic Phospholipase ◽  
Misfolded Sod1 ◽  
Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA2α upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1G93A) was detected long before the development of the disease, and inhibition of cPLA2α upregulation delayed the disease’s onset. The aim of the present study was to determine the mechanism for cPLA2α upregulation. Methods Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA2α and inflammatory markers were performed in the spinal cord sections of SOD1G93A transgenic mice and in primary motor neurons. Over expression of mutant SOD1 was performed by induction or transfection in primary motor neurons and in differentiated NSC34 motor neuron like cells. Results Misfolded SOD1 was detected in the spinal cord of 3 weeks old mutant SOD1G93A mice before cPLA2α upregulation. Elevated expression of both misfolded SOD1 and cPLA2α was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFα levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1G93A mice. Elevated TNFα was specifically detected in the motor neurons and its expression was highly correlated with cPLA2α expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA2α and TNFα upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA2α upregulation which was prevented by antibodies against TNFα. The addition of TNFα to NSC34 cells caused cPLA2α upregulation in a dose dependent manner. Conclusions Motor neurons expressing elevated cPLA2α and TNFα are in an inflammatory state as early as at 6 weeks old mutant SOD1G93A mice long before the development of the disease. Accumulated misfolded SOD1 in the motor neurons induced cPLA2α upregulation via induction of TNFα.

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