DOI QR코드

DOI QR Code

The Effect of GCSB-5 a New Herbal Medicine on Changes in Pain Behavior and Neuroglial Activation in a Rat Model of Lumbar Disc Herniation

  • Cho, Hee Kyung (Department of Physical Medicine and Rehabilitation, College of Medicine, Catholic University of Daegu) ;
  • Kim, So-Yeon (Medical Devices Clinical Trial Center, College of Medicine, Yeungnam University) ;
  • Choi, Mi Jung (Medical Devices Clinical Trial Center, College of Medicine, Yeungnam University) ;
  • Baek, Seung Ok (Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University) ;
  • Kwak, Sang Gyu (Department of Medical Statistics, College of Medicine, Catholic University of Daegu) ;
  • Ahn, Sang Ho (Medical Devices Clinical Trial Center, College of Medicine, Yeungnam University)
  • Received : 2015.09.11
  • Accepted : 2016.02.10
  • Published : 2016.03.01

Abstract

Objective : Lumbar disc herniation can induce sciatica by mechanical compression and/or chemical irritation. The aim of this study was to compare the effects of GCSB-5 (Shinbaro$^{(R)}$) and NSAIDs on pain-related behavior and on the expressions of microglia, astrocytes, CGRP, TRPV1, IL-6, and CX3CL1 in a rat model of lumbar disc herniation. Methods : 112 male Sprague-Dawley rats underwent implantation of nucleus pulposus to a dorsal root ganglion (DRG). Rats were divided into five groups as follows; a saline group (the vehicle control group) (n=27), a 10 mg/kg aceclofenac group (the aceclofenac group) (n=22), and 100, 300 or 600 mg/kg GCSB-5 groups (the GCSB-5 100, 300, or 600 groups) (n=21 for each group). Rats were tested for mechanical allodynia at 3 days after surgery and at 1 day, 3 days, 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, and 56 days after treatment commencement. Immunohistochemical staining of microglia (Iba1), astrocytes (GFAP), CGRP, and TRPV1, and PCR for IL-6 and CX3CL1 were performed on spinal dorsal horns and DRGs at 56 days after medication commencement. Results : After 56 days of GCSB-5 300 administration, mechanical withdrawal thresholds were significantly increased (p<0.05), and immunohistochemical expressions of Iba1, GFAP, CGRP, and TRPV1 were reduced than other groups, but this difference was not statistically significant. Conclusion : These results indicate GCSB-5 reduces mechanical allodynia and downregulates neuroglial activity and the expressions of CGRP and TRPV1 in the spinal segments of a rat model of lumbar disc herniation.

Keywords

References

  1. Ahn SH, Cho YW, Ahn MW, Jang SH, Sohn YK, Kim HS : mRNA expression of cytokines and chemokines in herniated lumbar intervertebral discs. Spine (Phila Pa 1976) 27 : 911-917, 2002 https://doi.org/10.1097/00007632-200205010-00005
  2. Anzai H, Hamba M, Onda A, Konno S, Kikuchi S : Epidural application of nucleus pulposus enhances nociresponses of rat dorsal horn neurons. Spine (Phila Pa 1976) 27 : E50-E55, 2002 https://doi.org/10.1097/00007632-200202010-00003
  3. Aoki Y, Rydevik B, Kikuchi S, Olmarker K : Local application of disc-related cytokines on spinal nerve roots. Spine (Phila Pa 1976) 27 : 1614-1617, 2002 https://doi.org/10.1097/00007632-200208010-00004
  4. Brisby H, Byrod G, Olmarker K, Miller VM, Aoki Y, Rydevik B : Nitric oxide as a mediator of nucleus pulposus-induced effects on spinal nerve roots. J Orthop Res 18 : 815-820, 2000 https://doi.org/10.1002/jor.1100180520
  5. Burke JG, Watson RW, McCormack D, Dowling FE, Walsh MG, Fitzpatrick JM : Spontaneous production of monocyte chemoattractant protein-1 and interleukin-8 by the human lumbar intervertebral disc. Spine (Phila Pa 1976) 27 : 1402-1407, 2002 https://doi.org/10.1097/00007632-200207010-00006
  6. Chen Y, Willcockson HH, Valtschanoff JG : Influence of the vanilloid receptor TRPV1 on the activation of spinal cord glia in mouse models of pain. Exp Neurol 220 : 383-390, 2009 https://doi.org/10.1016/j.expneurol.2009.09.030
  7. Chung HJ, Lee HS, Shin JS, Lee SH, Park BM, Youn YS, et al. : Modulation of acute and chronic inflammatory processes by a traditional medicine preparation GCSB-5 both in vitro and in vivo animal models. J Ethnopharmacol 130 : 450-459, 2010 https://doi.org/10.1016/j.jep.2010.05.020
  8. Cuellar JM, Montesano PX, Carstens E : Role of TNF-alpha in sensitization of nociceptive dorsal horn neurons induced by application of nucleus pulposus to L5 dorsal root ganglion in rats. Pain 110 : 578-587, 2004 https://doi.org/10.1016/j.pain.2004.03.029
  9. Ding M, Hart RP, Jonakait GM : Tumor necrosis factor-alpha induces substance P in sympathetic ganglia through sequential induction of interleukin-1 and leukemia inhibitory factor. J Neurobiol 28 : 445-454, 1995 https://doi.org/10.1002/neu.480280405
  10. Ge WH, Guo JY, Shen YJ, Chen ML, Shi SL, Han YH, et al. : [Effects of volatie oil of Schizonepeta tenuifolia Briq herb and Saposhnikovia divaricata Schischke root on proinflammatory cytokine expression and regulation]. Zhongguo Zhong Yao Za Zhi 32 : 1777-1179, 2007
  11. Hatashita S, Sekiguchi M, Kobayashi H, Konno S, Kikuchi S : Contralateral neuropathic pain and neuropathology in dorsal root ganglion and spinal cord following hemilateral nerve injury in rats. Spine (Phila Pa 1976) 33 : 1344-1351, 2008 https://doi.org/10.1097/BRS.0b013e3181733188
  12. Hong ND, Rho YS, Kim JW, Won DH, Kim NJ, Cho BS : Studies on the general pharmacological activities of Eucommia ulmoides Oliver. Korean J Pharmacogn 19 : 102-110, 1988
  13. Hua XY, Chen P, Fox A, Myers RR : Involvement of cytokines in lipopolysaccharide-induced facilitation of CGRP release from capsaicin-sensitive nerves in the trachea : studies with interleukin-1beta and tumor necrosis factor-alpha. J Neurosci 16 : 4742-4748, 1996 https://doi.org/10.1523/JNEUROSCI.16-15-04742.1996
  14. Ida Y, Satoh Y, Katsumata M, Nagasao M, Hirai Y, Kajimoto T, et al. : Two novel oleanolic acid saponins having a sialyl Lewis X mimetic structure from Achyranthes fauriei root. Bioorg Med Chem Lett 8 : 2555-2558, 1998 https://doi.org/10.1016/S0960-894X(98)00457-0
  15. Igarashi T, Kikuchi S, Shubayev V, Myers RR : 2000 Volvo Award winner in basic science studies : exogenous tumor necrosis factor-alpha mimics nucleus pulposus-induced neuropathology. Molecular, histologic, and behavioral comparisons in rats. Spine (Phila Pa 1976) 25 : 2975-2980, 2000 https://doi.org/10.1097/00007632-200012010-00003
  16. Ito T, Ohtori S, Inoue G, Koshi T, Doya H, Ozawa T, et al. : Glial phosphorylated p38 MAP kinase mediates pain in a rat model of lumbar disc herniation and induces motor dysfunction in a rat model of lumbar spinal canal stenosis. Spine (Phila Pa 1976) 32 : 159-167, 2007 https://doi.org/10.1097/01.brs.0000251437.10545.e9
  17. Kallakuri S, Takebayashi T, Ozaktay AC, Chen C, Yang S, Wooley PH, et al. : The effects of epidural application of allografted nucleus pulposus in rats on cytokine expression, limb withdrawal and nerve root discharge. Eur Spine J 14 : 956-964, 2005 https://doi.org/10.1007/s00586-004-0773-6
  18. Kang JD, Georgescu HI, McIntyre-Larkin L, Stefanovic-Racic M, Donaldson WF 3rd, Evans CH : Herniated lumbar intervertebral discs spontaneously produce matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2. Spine (Phila Pa 1976) 21 : 271-277, 1996 https://doi.org/10.1097/00007632-199602010-00003
  19. Kang JD, Stefanovic-Racic M, McIntyre LA, Georgescu HI, Evans CH : Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases. Spine (Phila Pa 1976) 22 : 1065-1073, 1997 https://doi.org/10.1097/00007632-199705150-00003
  20. Kawakami M, Tamaki T, Hashizume H, Weinstein JN, Meller ST : The role of phospholipase A2 and nitric oxide in pain-related behavior produced by an allograft of intervertebral disc material to the sciatic nerve of the rat. Spine (Phila Pa 1976) 22 : 1074-1079, 1997 https://doi.org/10.1097/00007632-199705150-00004
  21. Kayama S, Konno S, Olmarker K, Yabuki S, Kikuchi S : Incision of the anulus fibrosus induces nerve root morphologic, vascular, and functional changes. An experimental study. Spine (Phila Pa 1976) 21 : 2539-2543, 1996 https://doi.org/10.1097/00007632-199611150-00002
  22. Kim BH, Park KS, Chang IM : Elucidation of anti-inflammatory potencies of Eucommia ulmoides bark and Plantago asiatica seeds. J Med Food 12 : 764-769, 2009 https://doi.org/10.1089/jmf.2008.1239
  23. Kim DS, Figueroa KW, Li KW, Boroujerdi A, Yolo T, Luo ZD : Profiling of dynamically changed gene expression in dorsal root ganglia post peripheral nerve injury and a critical role of injury-induced glial fibrillary acidic protein in maintenance of pain behaviors [corrected]. Pain 143 : 114-122, 2009 https://doi.org/10.1016/j.pain.2009.02.006
  24. Kim HW, Kwon YB, Ham TW, Roh DH, Yoon SY, Han HJ, et al. : The antinociceptive and anti-inflammatory effect of ethylacetate extracts from Bang-Poong (Radix ledebouriellae) on the Freund's adjuvant-induced arthritis in rats. J Vet Sci 3 : 343-349, 2002
  25. Kim JK, Park SW, Kang JW, Kim YJ, Lee SY, Shin J, et al. : Effect of GCSB-5, a herbal formulation, on monosodium iodoacetate-induced ssteoarthritis in rats. Evid Based Complement Alternat Med 2012 : 730907, 2012
  26. Kim SJ, Kim WR, Kim HS, Park HW, Cho YW, Jang SH, et al. : Abnormal spontaneous activities on needle electromyography and their relation with pain behavior and nerve fiber pathology in a rat model of lumbar disc herniation. Spine (Phila Pa 1976) 36 : E1562-E1567, 2011 https://doi.org/10.1097/BRS.0b013e318210aa10
  27. Lappin SC, Randall AD, Gunthorpe MJ, Morisset V : TRPV1 antagonist, SB-366791, inhibits glutamatergic synaptic transmission in rat spinal dorsal horn following peripheral inflammation. Eur J Pharmacol 540 : 73-81, 2006 https://doi.org/10.1016/j.ejphar.2006.04.046
  28. Marchand F, Perretti M, McMahon SB : Role of the immune system in chronic pain. Nat Rev Neurosci 6 : 521-532, 2005
  29. Norimoto M, Sakuma Y, Suzuki M, Orita S, Yamauchi K, Inoue G, et al. : Up-regulation of pain behavior and glial activity in the spinal cord after compression and application of nucleus pulposus onto the sciatic nerve in rats. Asian Spine J 8 : 549-556, 2014 https://doi.org/10.4184/asj.2014.8.5.549
  30. Ohtori S, Takahashi K, Aoki Y, Doya H, Ozawa T, Saito T, et al. : Spinal neural cyclooxygenase-2 mediates pain caused in a rat model of lumbar disk herniation. J Pain 5 : 385-391, 2004 https://doi.org/10.1016/j.jpain.2004.06.004
  31. Ohtori S, Takahashi K, Moriya H, Myers RR : TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury : studies in murine DRG and spinal cord. Spine (Phila Pa 1976) 29 : 1082-1088, 2004 https://doi.org/10.1097/00007632-200405150-00006
  32. Olmarker K, Brisby H, Yabuki S, Nordborg C, Rydevik B : The effects of normal, frozen, and hyaluronidase-digested nucleus pulposus on nerve root structure and function. Spine (Phila Pa 1976) 22 : 471-475; discussion 476, 1997 https://doi.org/10.1097/00007632-199703010-00001
  33. Olmarker K, Larsson K : Tumor necrosis factor alpha and nucleus-pulposus-induced nerve root injury. Spine (Phila Pa 1976) 23 : 2538-2544, 1998 https://doi.org/10.1097/00007632-199812010-00008
  34. Olmarker K, Rydevik B, Nordborg C : Autologous nucleus pulposus induces neurophysiologic and histologic changes in porcine cauda equina nerve roots. Spine (Phila Pa 1976) 18 : 1425-1432, 1993 https://doi.org/10.1097/00007632-199318110-00005
  35. Park HW, Ahn SH, Kim SJ, Seo JM, Cho YW, Jang SH, et al. : Changes in spinal cord expression of fractalkine and its receptor in a rat model of disc herniation by autologous nucleus pulposus. Spine (Phila Pa 1976) 36 : E753-E760, 2011 https://doi.org/10.1097/BRS.0b013e3181ef610b
  36. Patwardhan AM, Scotland PE, Akopian AN, Hargreaves KM : Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia. Proc Natl Acad Sci U S A 106 : 18820-18824, 2009 https://doi.org/10.1073/pnas.0905415106
  37. Rand N, Reichert F, Floman Y, Rotshenker S : Murine nucleus pulposus-derived cells secrete interleukins-1-beta, -6, and -10 and granulocyte-macrophage colony-stimulating factor in cell culture. Spine (Phila Pa 1976) 22 : 2598-2601; discussion 2602, 1997 https://doi.org/10.1097/00007632-199711150-00002
  38. Sekiguchi M, Otoshi K, Kikuchi S, Konno S : Analgesic effects of prostaglandin E2 receptor subtype EP1 receptor antagonist : experimental study of application of nucleus pulposus. Spine (Phila Pa 1976) 36 : 1829-1834, 2011 https://doi.org/10.1097/BRS.0b013e3181fa1fca
  39. Spicarova D, Palecek J : The role of the TRPV1 endogenous agonist N-Oleoyldopamine in modulation of nociceptive signaling at the spinal cord level. J Neurophysiol 102 : 234-243, 2009 https://doi.org/10.1152/jn.00024.2009
  40. Takahashi H, Suguro T, Okazima Y, Motegi M, Okada Y, Kakiuchi T : Inflammatory cytokines in the herniated disc of the lumbar spine. Spine (Phila Pa 1976) 21 : 218-224, 1996 https://doi.org/10.1097/00007632-199601150-00011
  41. Takeda M, Tanimoto T, Kadoi J, Nasu M, Takahashi M, Kitagawa J, et al. : Enhanced excitability of nociceptive trigeminal ganglion neurons by satellite glial cytokine following peripheral inflammation. Pain 129 : 155-166, 2007 https://doi.org/10.1016/j.pain.2006.10.007
  42. Tsuda M, Inoue K, Salter MW : Neuropathic pain and spinal microglia : a big problem from molecules in "small" glia. Trends Neurosci 28 : 101-107, 2005 https://doi.org/10.1016/j.tins.2004.12.002
  43. Vane J, Botting R : Inflammation and the mechanism of action of anti-inflammatory drugs. FASEB J 1 : 89-96, 1987 https://doi.org/10.1096/fasebj.1.2.3111928
  44. Wang CC, Chen LG, Yang LL : Inducible nitric oxide synthase inhibitor of the Chinese herb I. Saposhnikovia divaricata (Turcz.) Schischk. Cancer Lett 145 : 151-157, 1999 https://doi.org/10.1016/S0304-3835(99)00248-7
  45. Watkins LR, Maier SF : Beyond neurons : evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82 : 981-1011, 2002 https://doi.org/10.1152/physrev.00011.2002
  46. Watkins LR, Maier SF : Glia : a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2 : 973-985, 2003 https://doi.org/10.1038/nrd1251
  47. Watkins LR, Martin D, Ulrich P, Tracey KJ, Maier SF : Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 71 : 225-235, 1997 https://doi.org/10.1016/S0304-3959(97)03369-1
  48. Yabuki S, Kikuchi S, Olmarker K, Myers RR : Acute effects of nucleus pulposus on blood flow and endoneurial fluid pressure in rat dorsal root ganglia. Spine (Phila Pa 1976) 23 : 2517-2523, 1998 https://doi.org/10.1097/00007632-199812010-00006
  49. Zhu J, Gao X, Xie WL, Jin YZ, Sun WJ : [Effect of geniposide on serum IL-1beta and TNF-alpha of rheumatoid arthritis rats]. Zhongguo Zhong Yao Za Zhi 30 : 708-711, 2005

Cited by

  1. The Efficacy of Shinbaro for the Preventive Treatment of Migraine: A Pilot Study vol.2019, pp.None, 2019, https://doi.org/10.1155/2019/2363420
  2. Effects of SHINBARO2 on Rat Models of Lumbar Spinal Stenosis vol.2019, pp.None, 2016, https://doi.org/10.1155/2019/7651470
  3. AMP-Activated Protein Kinase Activation in Dorsal Root Ganglion Suppresses mTOR/p70S6K Signaling and Alleviates Painful Radiculopathies in Lumbar Disc Herniation Rat Model vol.44, pp.15, 2016, https://doi.org/10.1097/brs.0000000000003005
  4. A Case of Dural Ectasia with Low Back Pain and Sciatica Treated with Integrative Korean Medical Treatment vol.36, pp.3, 2016, https://doi.org/10.13045/jar.2019.00164
  5. Natural Products as Sources of Novel Drug Candidates for the Pharmacological Management of Osteoarthritis: A Narrative Review vol.27, pp.6, 2016, https://doi.org/10.4062/biomolther.2019.139
  6. Dexamethasone Suppresses Radicular Pain Through Targeting the L‐PGDS/PI3K/Akt Pathway in Rats With Lumbar Disc Herniation vol.21, pp.1, 2016, https://doi.org/10.1111/papr.12934
  7. Inflammatory interactions between degenerated intervertebral discs and microglia: Implication of sphingosine‐1‐phosphate signaling vol.39, pp.7, 2021, https://doi.org/10.1002/jor.24827
  8. Network Pharmacological Dissection of the Mechanisms of Eucommiae Cortex-Achyranthis Radix Combination for Intervertebral Disc Herniation Treatment vol.16, pp.10, 2016, https://doi.org/10.1177/1934578x211055024