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Ginsenoside Rb1 Attenuates Acute Inflammatory Nociception by Inhibition of Neuronal ERK Phosphorylation by Regulation of the Nrf2 and NF-κB Pathways

  • Minhee Jang
    Affiliations
    Department of Convergence Medical Science, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea

    Department of Cancer Preventive Material Development, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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  • Min Jung Lee
    Affiliations
    Department of Convergence Medical Science, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea

    Brain Korea 21 Plus Program, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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  • Jong Hee Choi
    Affiliations
    Department of Convergence Medical Science, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea

    Brain Korea 21 Plus Program, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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  • Eun-Jeong Kim
    Affiliations
    Department of Convergence Medical Science, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea

    Brain Korea 21 Plus Program, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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  • Seung-Yeol Nah
    Affiliations
    Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
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  • Hak-Jae Kim
    Affiliations
    Department of Clinical Pharmacology, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
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  • Sanghyun Lee
    Affiliations
    Department of Integrative Plant Science, Chung-Ang University, Anseong, Republic of Korea
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  • Sang Won Lee
    Affiliations
    Department of Medicinal Crop Research Institute, National Institute of Horticultural & Herbal Science, Rural Development Administration, Eumseong, Republic of Korea
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  • Young Ock Kim
    Affiliations
    Department of Medicinal Crop Research Institute, National Institute of Horticultural & Herbal Science, Rural Development Administration, Eumseong, Republic of Korea
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  • Ik-Hyun Cho
    Correspondence
    Address reprint requests to Ik-Hyun Cho, DVM, PhD, Department of Convergence Medical Science, Brain Korea 21 Plus Program, Institute of Korean Medicine, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
    Affiliations
    Department of Convergence Medical Science, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea

    Brain Korea 21 Plus Program, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea

    Institute of Oriental Medicine, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea
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Published:November 05, 2015DOI:https://doi.org/10.1016/j.jpain.2015.10.007

      Highlights

      • Intrathecal introduction of ginsenoside-Rb1 (Rb1) decreased nociceptive behavior.
      • Rb1 decreased activation of the proto-oncogene c-Fos in the spinal dorsal horn.
      • Rb1 inhibited neuronal extracellular signal-regulated kinase phosphorylation.
      • Rb1 activated the nuclear factor erythroid 2-related factor 2 pathway.
      • Rb1 inhibited the nuclear factor kappa B pathway.

      Abstract

      Ginsenoside-Rb1 (Rb1) has anti-inflammatory effects. However, the potential antinociceptive value of Rb1 for the treatment of acute inflammatory nociception is still unknown. In this study, we examined whether Rb1 has any antinociceptive effects on acute inflammatory nociception in Sprague Dawley rats given intrathecal (i.t.) introduction of Rb1 (2, 10, and 50 μg) 20 minutes before injection of formalin (5%, 50 μL) into the plantar surface of the hind paws. I.t. introduction of Rb1 significantly decreased nociceptive behavior during phase II (16–60 minutes), but not phase I (0–10 minutes), after formalin stimulation, corresponding to the reduced activation of c-Fos in the L4 to L5 spinal dorsal horn after formalin stimulation. Rb1 also reduced the phosphorylation of extracellular signal-regulated kinase in the neurons, but not the microglia and astrocytes. Microscopic examination of the microglia and astrocytes revealed no morphological changes due to formalin stimulation and i.t. introduction of Rb1. Interestingly, Rb1 activated the nuclear factor erythroid 2-related factor 2 pathway and inhibited nuclear factor kappa B pathways.

      Perspective

      Our findings indicate that i.t. introduction of Rb1 might effectively inhibit formalin-induced acute inflammatory nociception by inhibition of neuronal extracellular signal-regulated kinase phosphorylation, which is thought to regulate the nuclear factor erythroid 2-related factor 2 nuclear factor kappa B pathways in the spinal dorsal horn, which suggests therapeutic potential for suppression of acute inflammatory pain.

      Key words

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      References

        • Cho I.H.
        Effects of Panax ginseng in neurodegenerative diseases.
        J Ginseng Res. 2012; 36: 342-353
        • Cho I.H.
        • Chung Y.M.
        • Park C.K.
        • Park S.H.
        • Lee H.
        • Kim D.
        • Piao Z.G.
        • Choi S.Y.
        • Lee S.J.
        • Park K.
        • Kim J.S.
        • Jung S.J.
        • Oh S.B.
        Systemic administration of minocycline inhibits formalin-induced inflammatory pain in rat.
        Brain Res. 2006; 1072: 208-214
        • Cho I.H.
        • Lee M.J.
        • Jang M.
        • Gwak N.G.
        • Lee K.Y.
        • Jung H.S.
        Minocycline markedly reduces acute visceral nociception via inhibiting neuronal ERK phosphorylation.
        Mol Pain. 2012; 8: 13
        • Cho J.
        • Park W.
        • Lee S.
        • Ahn W.
        • Lee Y.
        Ginsenoside-Rb1 from Panax ginseng C.A. Meyer activates estrogen receptor-alpha and -beta, independent of ligand binding.
        J Clin Endocrinol Metab. 2004; 89: 3510-3515
        • Coggeshall R.E.
        Fos, nociception and the dorsal horn.
        Prog Neurobiol. 2005; 77: 299-352
        • Copple I.M.
        The Keap1-Nrf2 cell defense pathway–a promising therapeutic target?.
        Adv Pharmacol. 2012; 63: 43-79
        • Curran T.
        • Morgan J.I.
        Fos: An immediate-early transcription factor in neurons.
        J Neurobiol. 1995; 26: 403-412
        • Egea J.
        • Rosa A.O.
        • Lorrio S.
        • del Barrio L.
        • Cuadrado A.
        • López M.G.
        Haeme oxygenase-1 overexpression via nAChRs and the transcription factor Nrf2 has antinociceptive effects in the formalin test.
        Pain. 2009; 146: 75-83
        • Fang J.Q.
        • Fang J.F.
        • Liang Y.
        • Du J.Y.
        Electroacupuncture mediates extracellular signal-regulated kinase 1/2 pathways in the spinal cord of rats with inflammatory pain.
        BMC Complement Altern Med. 2014; 14: 285
        • Fu K.Y.
        • Light A.R.
        • Maixner W.
        Relationship between nociceptor activity, peripheral edema, spinal microglial activation and long-term hyperalgesia induced by formalin.
        Neuroscience. 2000; 101: 1127-1135
        • Fu K.Y.
        • Light A.R.
        • Matsushima G.K.
        • Maixner W.
        Microglial reactions after subcutaneous formalin injection into the rat hind paw.
        Brain Res. 1999; 825: 59-67
        • Galan A.
        • Cervero F.
        • Laird J.M.
        Extracellular signaling-regulated kinase-1 and -2 (ERK 1/2) mediate referred hyperalgesia in a murine model of visceral pain.
        Brain Res Mol Brain Res. 2003; 116: 126-134
        • Gao Y.
        • Chu S.F.
        • Li J.P.
        • Zuo W.
        • Wen Z.L.
        • He W.B.
        • Yan J.Q.
        • Chen N.H.
        Do glial cells play an anti-oxidative role in Huntington's disease?.
        Free Radic Res. 2014; 48: 1135-1144
        • Guo Y.J.
        • Shi X.D.
        • Fu D.
        • Yang Y.
        • Wang Y.P.
        • Dai R.P.
        Analgesic effects of the COX-2 inhibitor parecoxib on surgical pain through suppression of spinal ERK signaling.
        Exp Ther Med. 2013; 6: 275-279
        • Hashimoto R.
        • Yu J.
        • Koizumi H.
        • Ouchi Y.
        • Okabe T.
        Ginsenoside Rb1 prevents MPP(+)-induced apoptosis in PC12 cells by stimulating estrogen receptors with consequent activation of ERK1/2, Akt and inhibition of SAPK/JNK, p38 MAPK.
        Evid Based Complement Alternat Med. 2012; 2012: 693717
        • Hou Y.L.
        • Tsai Y.H.
        • Lin Y.H.
        • Chao J.C.
        Ginseng extract and ginsenoside Rb1 attenuate carbon tetrachloride-induced liver fibrosis in rats.
        BMC Complement Altern Med. 2014; 14: 415
        • Hu J.F.
        • Song X.Y.
        • Chu S.F.
        • Chen J.
        • Ji H.J.
        • Chen X.Y.
        • Yuan Y.H.
        • Han N.
        • Zhang J.T.
        • Chen N.H.
        Inhibitory effect of ginsenoside Rg1 on lipopolysaccharide-induced microglial activation in mice.
        Brain Res. 2011; 1374: 8-14
        • Hunt S.P.
        • Pini A.
        • Evan G.
        Induction of c-fos-like protein in spinal cord neurons following sensory stimulation.
        Nature. 1987; 328: 632-634
        • Hwang Y.P.
        • Jeong H.G.
        Ginsenoside Rb1 protects against 6-hydroxydopamine-induced oxidative stress by increasing heme oxygenase-1 expression through an estrogen receptor-related PI3K/Akt/Nrf2-dependent pathway in human dopaminergic cells.
        Toxicol Appl Pharmacol. 2010; 242: 18-28
        • Jang M.
        • Lee M.J.
        • Cho I.H.
        Ethyl pyruvate ameliorates 3-nitropropionic acid-induced striatal toxicity through anti-neuronal cell death and anti-inflammatory mechanisms.
        Brain Behav Immun. 2014; 38: 151-165
        • Jang M.
        • Lee M.J.
        • Kim C.S.
        • Cho I.H.
        Korean red ginseng extract attenuates 3-nitropropionic acid-induced Huntington’s-like symptoms.
        Evid Based Complement Alternat Med. 2013; 2013: 237207
        • Ji R.R.
        • Baba H.
        • Brenner G.J.
        • Woolf C.J.
        Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity.
        Nat Neurosci. 1999; 2: 1114-1119
        • Ji R.R.
        • Befort K.
        • Brenner G.J.
        • Woolf C.J.
        ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity.
        J Neurosci. 2002; 22: 478-485
        • Ji R.R.
        • Gereau 4th, R.W.
        • Malcangio M.
        • Strichartz G.R.
        MAP kinase and pain.
        Brain Res Rev. 2009; 60: 135-148
        • Joh E.H.
        • Lee I.A.
        • Jung I.H.
        • Kim D.H.
        Ginsenoside Rb1 and its metabolite compound K inhibit IRAK-1 activation–the key step of inflammation.
        Biochem Pharmacol. 2011; 82: 278-286
        • Joshi G.
        • Johnson J.A.
        The Nrf2-ARE pathway: A valuable therapeutic target for the treatment of neurodegenerative diseases.
        Recent Pat CNS Drug Discov. 2012; 7: 218-229
        • Juge N.
        • Mithen R.F.
        • Traka M.
        Molecular basis for chemoprevention by sulforaphane: A comprehensive review.
        Cell Mol Life Sci. 2007; 64: 1105-1127
        • Ke L.
        • Guo W.
        • Xu J.
        • Zhang G.
        • Wang W.
        • Huang W.
        Ginsenoside Rb1 attenuates activated microglia-induced neuronal damage.
        Neural Regen Res. 2014; 9: 252-259
        • Kim H.J.
        • Kim P.
        • Shin C.Y.
        A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system.
        J Ginseng Res. 2013; 37: 8-29
        • Landis S.C.
        • Amara S.G.
        • Asadullah K.
        • Austin C.P.
        • Blumenstein R.
        • Bradley E.W.
        • Crystal R.G.
        • Darnell R.B.
        • Ferrante R.J.
        • Fillit H.
        • Finkelstein R.
        • Fisher M.
        • Gendelman H.E.
        • Golub R.M.
        • Goudreau J.L.
        • Gross R.A.
        • Gubitz A.K.
        • Hesterlee S.E.
        • Howells D.W.
        • Huguenard J.
        • Kelner K.
        • Koroshetz W.
        • Krainc D.
        • Lazic S.E.
        • Levine M.S.
        • Macleod M.R.
        • McCall J.M.
        • Moxley 3rd, R.T.
        • Narasimhan K.
        • Noble L.J.
        • Perrin S.
        • Porter J.D.
        • Steward O.
        • Unger E.
        • Utz U.
        • Silberberg S.D.
        A call for transparent reporting to optimize the predictive value of preclinical research.
        Nature. 2012; 490: 187-191
        • Lee M.J.
        • Jang M.
        • Choi J.
        • Chang B.S.
        • Kim D.Y.
        • Kim S.H.
        • Kwak Y.S.
        • Oh S.
        • Lee J.H.
        • Chang B.J.
        • Nah S.Y.
        • Cho I.H.
        Korean red ginseng and ginsenoside-Rb1/-Rg1 alleviate experimental autoimmune encephalomyelitis by suppressing Th1 and Th17 cells and upregulating regulatory T.
        cells. Mol Neurobiol. 2015 Apr 7; ([Epub ahead of print])
        • Lee M.J.
        • Jang M.
        • Choi J.
        • Lee G.
        • Min H.J.
        • Chung W.S.
        • Kim J.I.
        • Jee Y.
        • Chae Y.
        • Kim S.H.
        • Lee S.J.
        • Cho I.H.
        Bee venom acupuncture alleviates experimental autoimmune encephalomyelitis by upregulating regulatory T cells and suppressing Th1 and Th17 responses.
        Mol Neurobiol. 2015 Jan 13; ([Epub ahead of print])
        • Lee M.J.
        • Jang M.
        • Jung H.S.
        • Kim S.H.
        • Cho I.H.
        Ethyl pyruvate attenuates formalin-induced inflammatory nociception by inhibiting neuronal ERK phosphorylation.
        Mol Pain. 2012; 8: 40
        • Li Q.Y.
        • Chen L.
        • Fu W.H.
        • Li Z.D.
        • Wang B.
        • Shi X.J.
        • Zhong M.K.
        Ginsenoside Rb1 inhibits proliferation and inflammatory responses in rat aortic smooth muscle cells.
        J Agric Food Chem. 2011; 59: 6312-6318
        • Li W.
        • Khor T.O.
        • Xu C.
        • Shen G.
        • Jeong W.S.
        • Yu S.
        • Kong A.N.
        Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis.
        Biochem Pharmacol. 2008; 76: 1485-1489
        • Ma W.
        • Quirion R.
        The ERK/MAPK pathway, as a target for the treatment of neuropathic pain.
        Expert Opin Ther Targets. 2005; 9: 699-713
        • Mestre C.
        • Pélissier T.
        • Fialip J.
        • Wilcox G.
        • Eschalier A.
        A method to perform direct transcutaneous intrathecal injection in rats.
        J Pharmacol Toxicol Methods. 1994; 32: 197-200
        • Negi G.
        • Kumar A.
        • Sharma S.S.
        Nrf2 and NF-kappaB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes.
        Curr Neurovasc Res. 2011; 8: 294-304
        • Ni N.
        • Liu Q.
        • Ren H.
        • Wu D.
        • Luo C.
        • Li P.
        • Wan J.B.
        • Su H.
        Ginsenoside Rb1 protects rat neural progenitor cells against oxidative injury.
        Molecules. 2014; 19: 3012-3024
        • Piao Z.G.
        • Cho I.H.
        • Park C.K.
        • Hong J.P.
        • Choi S.Y.
        • Lee S.J.
        • Lee S.
        • Park K.
        • Kim J.S.
        • Oh S.B.
        Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury.
        Pain. 2006; 121: 219-231
        • Rosa A.O.
        • Egea J.
        • Lorrio S.
        • Rojo A.I.
        • Cuadrado A.
        • López M.G.
        Nrf2-mediated haeme oxygenase-1 up-regulation induced by cobalt protoporphyrin has antinociceptive effects against inflammatory pain in the formalin test in mice.
        Pain. 2008; 137: 332-339
        • Seino D.
        • Tokunaga A.
        • Tachibana T.
        • Yoshiya S.
        • Dai Y.
        • Obata K.
        • Yamanaka H.
        • Kobayashi K.
        • Noguchi K.
        The role of ERK signaling and the P2X receptor on mechanical pain evoked by movement of inflamed knee joint.
        Pain. 2006; 123: 193-203
        • Smith H.S.
        The role of genomic oxidative-reductive balance as predictor of complex regional pain syndrome development: A novel theory.
        Pain Physician. 2010; 13: 79-90
        • Song Z.J.
        • Tang L.L.
        • Li G.L.
        Zhongguo Zhong Xi Yi Jie He Za Zhi. 2012; 32: 1380-1384
        • Sun Q.
        • Meng Q.T.
        • Jiang Y.
        • Xia Z.Y.
        Ginsenoside Rb1 attenuates intestinal ischemia reperfusion induced renal injury by activating Nrf2/ARE pathway.
        Molecules. 2012; 17: 7195-7205
        • Suzuki T.
        • Motohashi H.
        • Yamamoto M.
        Toward clinical application of the Keap1-Nrf2 pathway.
        Trends Pharmacol Sci. 2013; 34: 340-346
        • Svensson C.I.
        • Marsala M.
        • Westerlund A.
        • Calcutt N.A.
        • Campana W.M.
        • Freshwater J.D.
        • Catalano R.
        • Feng Y.
        • Protter A.A.
        • Scott B.
        • Yaksh T.L.
        Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing.
        J Neurochem. 2003; 86: 1534-1544
        • Taha R.
        • Blaise G.A.
        Update on the pathogenesis of complex regional pain syndrome: role of oxidative stress.
        Can J Anaesth. 2012; 59: 875-881
        • Thomas K.L.
        • Hunt S.P.
        The regional distribution of extracellularly regulated kinase-1 and -2 messenger RNA in the adult rat central nervous system.
        Neuroscience. 1993; 56: 741-757
        • Tjølsen A.
        • Berge O.G.
        • Hunskaar S.
        • Rosland J.H.
        • Hole K.
        The formalin test: An evaluation of the method.
        Pain. 1992; 51: 5-17
        • Watkins L.R.
        • Martin D.
        • Ulrich P.
        • Tracey K.J.
        • Maier S.F.
        Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat.
        Pain. 1997; 71: 225-235
        • Yuan Q.
        • Jiang Y.W.
        • Ma T.T.
        • Fang Q.H.
        • Pan L.
        Attenuating effect of Ginsenoside Rb1 on LPS-induced lung injury in rats.
        J Inflamm (Lond). 2014; 11: 40
        • Zhu J.
        • Jiang Y.
        • Wu L.
        • Lu T.
        • Xu G.
        • Liu X.
        Suppression of local inflammation contributes to the neuroprotective effect of ginsenoside Rb1 in rats with cerebral ischemia.
        Neuroscience. 2012; 202: 342-351
        • Zhuang Z.Y.
        • Gerner P.
        • Woolf C.J.
        • Ji R.R.
        ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model.
        Pain. 2005; 114: 149-159