Advertisement

Molecular Neurobiology

, Volume 56, Issue 4, pp 2394–2407 | Cite as

Bojungikgi-tang Improves Muscle and Spinal Cord Function in an Amyotrophic Lateral Sclerosis Model

  • MuDan Cai
  • Sun Hwa Lee
  • Eun Jin YangEmail author
Article
  • 143 Downloads

Abstract

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive motor function impairment, dysphagia, and respiratory failure. Owing to the complexity of its pathogenic mechanisms, an effective therapy for ALS is lacking. Herbal medicines with multiple targets have good efficacy and low adverse reactions for the treatment of neurodegenerative diseases. In this study, the effects of Bojungikgi-tang (BJIGT), an herbal medicine with eight component herbs, on muscle and spinal cord function were evaluated in an ALS animal model. Animals were randomly divided into three groups: a non-transgenic group (nTg, n = 24), a hSOD1G93A transgenic group (Tg, n = 24), and a hSOD1G93A transgenic group in which 8-week-old mice were orally administered BJIGT (1 mg/g) once daily for 6 weeks (Tg+BJIGT, n = 24). The effects of BJIGT were evaluated using a rotarod test, foot-printing, and survival analyses based on Kaplan–Meier survival curves. To determine the biological mechanism underlying the effects of BJIGT in hSOD1G93A mice, western blotting, transmission electron microscopy, and Bungarotoxin staining were used. BJIGT improved motor function and extended the survival duration of hSOD1G93A mice. In addition, BJIGT had protective effects, including anti-oxidative and anti-inflammatory effects, in both the spinal cord and muscle of hSOD1G93A mice. Our results demonstrated that BJIGT causes muscle atrophy and the denervation of neuromuscular junctions in the gastrocnemius of hSOD1G93A mice. The components of BJIGT may alleviate the symptoms of ALS via different mechanisms, and accordingly, BJIGT treatment may be an effective therapeutic approach.

Keywords

Amyotrophic lateral sclerosis Bojungikgi-tang Motor function Muscle atrophy 

Notes

Authors’ Contributions

MDC performed western blotting and immunohistochemistry experiments and contributed to writing a part of the manuscript; SHL performed the behavior test (rotarod and foot printing) and administered BJIGT; EJY designed the research, performed TEM, analyzed data, and completed the final proof.

Funding Information

This study was supported by the Korea Institute of Oriental Medicine (KIOM) under grant C16051 and C18040, and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning, South Korea, under grant NRF-2015R1C1A2A01053248.

Compliance with Ethical Standards

All mouse experiments were performed in accordance with the US National Institutes of Health guidelines and approved by the Institutional Animal Care and Use Committees of the Korea Institute of Oriental Medicine (protocol number: 13-109).

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Vandoorne T, De Bock K, Van Den Bosch L (2018) Energy metabolism in ALS: an underappreciated opportunity? Acta Neuropathol 135(4):489–509PubMedPubMedCentralGoogle Scholar
  2. 2.
    Philips T, Rothstein JD (2015) Rodent models of amyotrophic lateral sclerosis. Curr Protoc Pharmacol 69:5 67 61–5 67 21Google Scholar
  3. 3.
    Geevasinga N, Menon P, Ozdinler PH, Kiernan MC, Vucic S (2016) Pathophysiological and diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol 12(11):651–661PubMedGoogle Scholar
  4. 4.
    Kumar V, Islam A, Hassan MI, Ahmad F (2016) Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning. Eur J Med Chem 121:903–917PubMedGoogle Scholar
  5. 5.
    Pansarasa O, Rossi D, Berardinelli A, Cereda C (2014) Amyotrophic lateral sclerosis and skeletal muscle: an update. Mol Neurobiol 49(2):984–990PubMedGoogle Scholar
  6. 6.
    Jensen L, Jorgensen LH, Bech RD, Frandsen U, Schroder HD (2016) Skeletal muscle remodelling as a function of disease progression in amyotrophic lateral sclerosis. Biomed Res Int 2016:5930621PubMedPubMedCentralGoogle Scholar
  7. 7.
    Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Boncompagni S, Belia S, Wannenes F et al (2008) Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 8(5):425–436PubMedGoogle Scholar
  8. 8.
    Tewari D, Stankiewicz AM, Mocan A, Sah AN, Tzvetkov NT, Huminiecki L, Horbanczuk JO, Atanasov AG (2018) Ethnopharmacological approaches for dementia therapy and significance of natural products and herbal drugs. Front Aging Neurosci 10:3PubMedPubMedCentralGoogle Scholar
  9. 9.
    Shi J, Tian J, Li T, Qin B, Fan D, Ni J, Wei M, Zhang X et al (2017) Efficacy and safety of SQJZ herbal mixtures on nonmotor symptoms in Parkinson disease patients: protocol for a randomized, double-blind, placebo-controlled trial. Medicine (Baltimore) 96(50):e8824Google Scholar
  10. 10.
    Lin SK, Yan SH, Lai JN, Tsai TH (2016) Patterns of Chinese medicine use in prescriptions for treating Alzheimer’s disease in Taiwan. Chin Med 11:12PubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhang X, Hong YL, Xu DS, Feng Y, Zhao LJ, Ruan KF, Yang XJ (2014) A review of experimental research on herbal compounds in amyotrophic lateral sclerosis. Phytother Res 28(1):9–21PubMedGoogle Scholar
  12. 12.
    Ouyang M, Liu Y, Tan W, Xiao Y, Yu K, Sun X, Huang Y, Cheng J et al (2014) Bu-zhong-yi-qi pill alleviate the chemotherapy-related fatigue in 4 T1 murine breast cancer model. BMC Complement Altern Med 14:497PubMedPubMedCentralGoogle Scholar
  13. 13.
    Utsuyama M, Seidlar H, Kitagawa M, Hirokawa K (2001) Immunological restoration and anti-tumor effect by Japanese herbal medicine in aged mice. Mech Ageing Dev 122(3):341–352PubMedGoogle Scholar
  14. 14.
    Yamaoka Y, Kawakita T, Nomoto K (2000) Protective effect of a traditional Japanese medicine, Bu-zhong-yi-qi-tang (Japanese name: Hochu-ekki-to), on the restraint stress-induced susceptibility against Listeria monocytogenes. Immunopharmacology 48(1):35–42PubMedGoogle Scholar
  15. 15.
    Kaneko M, Kawakita T, Kumazawa Y, Takimoto H, Nomoto K, Yoshikawa T (1999) Accelerated recovery from cyclophosphamide-induced leukopenia in mice administered a Japanese ethical herbal drug, Hochu-ekki-to. Immunopharmacology 44(3):223–231PubMedGoogle Scholar
  16. 16.
    Lee MY, Shin IS, Jeon WY, Seo CS, Ha H, Huh JI, Shin HK (2012) Protective effect of Bojungikki-tang, a traditional herbal formula, against alcohol-induced gastric injury in rats. J Ethnopharmacol 142(2):346–353PubMedGoogle Scholar
  17. 17.
    Shih HC, Chang KH, Chen FL, Chen CM, Chen SC, Lin YT, Shibuya A (2000) Anti-aging effects of the traditional Chinese medicine bu-zhong-yi-qi-tang in mice. Am J Chin Med 28(1):77–86PubMedGoogle Scholar
  18. 18.
    Toshiaki K, Nobuhiko S, Eiichi T, Shinya S, Yutaka S, Hiroshi O, Hideki O, Katsutoshi T (2004) Assessment of effects of traditional herbal medicines on elderly patients with weakness using a self-controlled trial. Geriatr Gerontol Int 4(3):169–174Google Scholar
  19. 19.
    Kimura M, Sasada T, Kanai M, Kawai Y, Yoshida Y, Hayashi E, Iwata S, Takabayashi A (2008) Preventive effect of a traditional herbal medicine, Hochu-ekki-to, on immunosuppression induced by surgical stress. Surg Today 38(4):316–322PubMedGoogle Scholar
  20. 20.
    Yoo SR, Ha H, Lee MY, Shin HK, Han SC, Seo CS (2017) A 4-week repeated-dose oral toxicity study of Bojungikgi-tang in Crl:CD Sprague Dawley rats. Evid Based Complement Alternat Med 2017:4748904PubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim J, Seo C, Kim S, Shin H (2013) Compositional differences of Bojungikgi-tang decoctions using pressurized or non-pressurized extraction methods with variable extraction times. Kor J Herbol 28(4):1–6Google Scholar
  22. 22.
    Jun Y, Moon S, Ko C, Cho K, Kim Y, Bae H, Lee K (1997) Clinical study on the ALS (amyotrophic lateral sclerosis) patients in the Department of Circulatory Internal Medicine of Kyung Hee Oriental Medical Hospital. J Int Korean Med 18(3):236–245Google Scholar
  23. 23.
    Yang EJ, Jiang JH, Lee SM, Yang SC, Hwang HS, Lee MS, Choi SM (2010) Bee venom attenuates neuroinflammatory events and extends survival in amyotrophic lateral sclerosis models. J Neuroinflammation 7:69PubMedPubMedCentralGoogle Scholar
  24. 24.
    Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22(3):659–661PubMedGoogle Scholar
  25. 25.
    Filali M, Lalonde R, Rivest S (2011) Sensorimotor and cognitive functions in a SOD1(G37R) transgenic mouse model of amyotrophic lateral sclerosis. Behav Brain Res 225(1):215–221PubMedGoogle Scholar
  26. 26.
    Mancuso R, Olivan S, Osta R, Navarro X (2011) Evolution of gait abnormalities in SOD1(G93A) transgenic mice. Brain Res 1406:65–73PubMedGoogle Scholar
  27. 27.
    Kirkinezos IG, Bacman SR, Hernandez D, Oca-Cossio J, Arias LJ, Perez-Pinzon MA, Bradley WG, Moraes CT (2005) Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice. J Neurosci 25(1):164–172PubMedGoogle Scholar
  28. 28.
    Turner MR, Bowser R, Bruijn L, Dupuis L, Ludolph A, McGrath M, Manfredi G, Maragakis N et al (2013) Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 14(Suppl 1):19–32PubMedPubMedCentralGoogle Scholar
  29. 29.
    Fan J, Dawson TM, Dawson VL (2017) Cell death mechanisms of neurodegeneration. Adv Neurobiol 15:403–425PubMedGoogle Scholar
  30. 30.
    Lim J, Yue Z (2015) Neuronal aggregates: formation, clearance, and spreading. Dev Cell 32(4):491–501PubMedPubMedCentralGoogle Scholar
  31. 31.
    Crippa V, Boncoraglio A, Galbiati M, Aggarwal T, Rusmini P, Giorgetti E, Cristofani R, Carra S et al (2013) Differential autophagy power in the spinal cord and muscle of transgenic ALS mice. Front Cell Neurosci 7:234PubMedPubMedCentralGoogle Scholar
  32. 32.
    Tripathi P, Rodriguez-Muela N, Klim JR, de Boer AS, Agrawal S, Sandoe J, Lopes CS, Ogliari KS et al (2017) Reactive astrocytes promote ALS-like degeneration and intracellular protein aggregation in human motor neurons by disrupting autophagy through TGF-beta1. Stem Cell Reports 9(2):667–680PubMedPubMedCentralGoogle Scholar
  33. 33.
    Cai M, Choi SM, Yang EJ (2015) The effects of bee venom acupuncture on the central nervous system and muscle in an animal hSOD1G93A mutant. Toxins (Basel) 7(3):846–858Google Scholar
  34. 34.
    Narai H, Manabe Y, Nagai M, Nagano I, Ohta Y, Murakami T, Takehisa Y, Kamiya T et al (2009) Early detachment of neuromuscular junction proteins in ALS mice with SODG93A mutation. Neurol Int 1(1):e16PubMedPubMedCentralGoogle Scholar
  35. 35.
    Budnik V, Salinas PC (2011) Wnt signaling during synaptic development and plasticity. Curr Opin Neurobiol 21(1):151–159PubMedPubMedCentralGoogle Scholar
  36. 36.
    Cisternas P, Henriquez JP, Brandan E, Inestrosa NC (2014) Wnt signaling in skeletal muscle dynamics: myogenesis, neuromuscular synapse and fibrosis. Mol Neurobiol 49(1):574–589PubMedGoogle Scholar
  37. 37.
    Sta M, Sylva-Steenland RM, Casula M, de Jong JM, Troost D, Aronica E, Baas F (2011) Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis 42(3):211–220PubMedGoogle Scholar
  38. 38.
    Liu JX, Brannstrom T, Andersen PM, Pedrosa-Domellof F (2013) Distinct changes in synaptic protein composition at neuromuscular junctions of extraocular muscles versus limb muscles of ALS donors. PLoS One 8(2):e57473PubMedPubMedCentralGoogle Scholar
  39. 39.
    D'Ambrosi N, Cozzolino M, Carri MT (2017) Neuroinflammation in amyotrophic lateral sclerosis: role of redox (dys)regulation. Antioxid Redox Signal 29(1):15–36Google Scholar
  40. 40.
    Zhao W, Beers DR, Appel SH (2013) Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J NeuroImmune Pharmacol 8(4):888–899PubMedPubMedCentralGoogle Scholar
  41. 41.
    Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM et al (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6(12):1045–1053PubMedGoogle Scholar
  42. 42.
    Kriz J, Nguyen MD, Julien JP (2002) Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 10(3):268–278PubMedGoogle Scholar
  43. 43.
    Corti S, Donadoni C, Ronchi D, Bordoni A, Fortunato F, Santoro D, Del Bo R, Lucchini V et al (2009) Amyotrophic lateral sclerosis linked to a novel SOD1 mutation with muscle mitochondrial dysfunction. J Neurol Sci 276(1–2):170–174PubMedGoogle Scholar
  44. 44.
    Dupuis L, di Scala F, Rene F, de Tapia M, Oudart H, Pradat PF, Meininger V, Loeffler JP (2003) Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. FASEB J 17(14):2091–2093PubMedGoogle Scholar
  45. 45.
    Muller FL, Song W, Jang YC, Liu Y, Sabia M, Richardson A, Van Remmen H (2007) Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Am J Phys Regul Integr Comp Phys 293(3):R1159–R1168Google Scholar
  46. 46.
    Dupuis L, Gonzalez de Aguilar JL, Echaniz-Laguna A, Eschbach J, Rene F, Oudart H, Halter B, Huze C et al (2009) Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. PLoS One 4(4):e5390PubMedPubMedCentralGoogle Scholar
  47. 47.
    Takanashi K, Dan K, Kanzaki S, Hasegawa H, Watanabe K, Ogawa K (2017) Hochuekkito, a Japanese herbal medicine, restores metabolic homeostasis between mitochondrial and glycolytic pathways impaired by influenza A virus infection. Pharmacology 99(5–6):240–249PubMedGoogle Scholar
  48. 48.
    Borthwick GM, Johnson MA, Ince PG, Shaw PJ, Turnbull DM (1999) Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death. Ann Neurol 46(5):787–790PubMedGoogle Scholar
  49. 49.
    Vielhaber S, Winkler K, Kirches E, Kunz D, Buchner M, Feistner H, Elger CE, Ludolph AC et al (1999) Visualization of defective mitochondrial function in skeletal muscle fibers of patients with sporadic amyotrophic lateral sclerosis. J Neurol Sci 169(1–2):133–139PubMedGoogle Scholar
  50. 50.
    Zhao W, Varghese M, Yemul S, Pan Y, Cheng A, Marano P, Hassan S, Vempati P et al (2011) Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1alpha) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis. Mol Neurodegener 6(1):51PubMedPubMedCentralGoogle Scholar
  51. 51.
    Lu C, Thompson CB (2012) Metabolic regulation of epigenetics. Cell Metab 16(1):9–17PubMedPubMedCentralGoogle Scholar
  52. 52.
    Dobrowolny G, Aucello M, Musaro A (2011) Muscle atrophy induced by SOD1G93A expression does not involve the activation of caspase in the absence of denervation. Skelet Muscle 1(1):3PubMedPubMedCentralGoogle Scholar
  53. 53.
    Rudnick ND, Griffey CJ, Guarnieri P, Gerbino V, Wang X, Piersaint JA, Tapia JC, Rich MM et al (2017) Distinct roles for motor neuron autophagy early and late in the SOD1(G93A) mouse model of ALS. Proc Natl Acad Sci U S A 114(39):E8294–E8303PubMedPubMedCentralGoogle Scholar
  54. 54.
    Xie Y, Zhou B, Lin MY, Wang S, Foust KD, Sheng ZH (2015) Endolysosomal deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS mice. Neuron 87(2):355–370PubMedPubMedCentralGoogle Scholar
  55. 55.
    Katsuno M, Adachi H, Minamiyama M, Waza M, Doi H, Kondo N, Mizoguchi H, Nitta A et al (2010) Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy. J Neurosci 30(16):5702–5712PubMedGoogle Scholar
  56. 56.
    Katsuno M, Adachi H, Banno H, Suzuki K, Tanaka F, Sobue G (2011) Transforming growth factor-beta signaling in motor neuron diseases. Curr Mol Med 11(1):48–56PubMedGoogle Scholar
  57. 57.
    Endo F, Komine O, Fujimori-Tonou N, Katsuno M, Jin S, Watanabe S, Sobue G, Dezawa M et al (2015) Astrocyte-derived TGF-beta1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells. Cell Rep 11(4):592–604PubMedGoogle Scholar
  58. 58.
    Phatnani HP, Guarnieri P, Friedman BA, Carrasco MA, Muratet M, O'Keeffe S, Nwakeze C, Pauli-Behn F et al (2013) Intricate interplay between astrocytes and motor neurons in ALS. Proc Natl Acad Sci U S A 110(8):E756–E765PubMedPubMedCentralGoogle Scholar
  59. 59.
    Gonzalez D, Contreras O, Rebolledo DL, Espinoza JP, van Zundert B, Brandan E (2017) ALS skeletal muscle shows enhanced TGF-beta signaling, fibrosis and induction of fibro/adipogenic progenitor markers. PLoS One 12(5):e0177649PubMedPubMedCentralGoogle Scholar
  60. 60.
    Petchey LK, Risebro CA, Vieira JM, Roberts T, Bryson JB, Greensmith L, Lythgoe MF, Riley PR (2014) Loss of Prox1 in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy. Proc Natl Acad Sci U S A 111(26):9515–9520PubMedPubMedCentralGoogle Scholar
  61. 61.
    Pedersen BK (2011) Muscles and their myokines. J Exp Biol 214(Pt 2):337–346PubMedGoogle Scholar
  62. 62.
    Bonaldo P, Sandri M (2013) Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech 6(1):25–39PubMedPubMedCentralGoogle Scholar
  63. 63.
    Wong M, Martin LJ (2010) Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet 19(11):2284–2302PubMedPubMedCentralGoogle Scholar
  64. 64.
    Van Dyke JM, Smit-Oistad IM, Macrander C, Krakora D, Meyer MG, Suzuki M (2016) Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS). Exp Neurol 277:275–282PubMedPubMedCentralGoogle Scholar
  65. 65.
    Koh SH, Kim Y, Kim HY, Hwang S, Lee CH, Kim SH (2007) Inhibition of glycogen synthase kinase-3 suppresses the onset of symptoms and disease progression of G93A-SOD1 mouse model of ALS. Exp Neurol 205(2):336–346PubMedGoogle Scholar
  66. 66.
    Takadera T, Ohyashiki T (2004) Glycogen synthase kinase-3 inhibitors prevent caspase-dependent apoptosis induced by ethanol in cultured rat cortical neurons. Eur J Pharmacol 499(3):239–245PubMedGoogle Scholar
  67. 67.
    Martinez A, Castro A, Dorronsoro I, Alonso M (2002) Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev 22(4):373–384PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical ResearchKorea Institute of Oriental MedicineDaejeonRepublic of Korea

Personalised recommendations