Login Register Cart 0
Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Research Article

Yokukansan, a Japanese Herbal Medicine, Suppresses Substance P-Induced Production of Interleukin-6 and Interleukin-8 by Human U373 MG Glioblastoma Astrocytoma Cells

Author(s): Keisuke Yamaguchi, Sho Yamazaki, Seiichiro Kumakura, Akimasa Someya, Masako Iseki, Eiichi Inada and Isao Nagaoka*

Volume 20, Issue 7, 2020

Page: [1073 - 1080] Pages: 8

DOI: 10.2174/1871530320666200131103733

Price: $65

Abstract

Background: Yokukansan is a traditional Japanese herbal medicine that has an antiallodynic effect in patients with chronic pain. However, the mechanisms by which yokukansan inhibits neuropathic pain are unclear.

Objective: This study aimed to investigate the molecular effects of yokukansan on neuroinflammation in U373 MG glioblastoma astrocytoma cells, which express a functional high-affinity neurokinin 1 receptor (substance P receptor), and produce interleukin (IL)-6 and IL-8 in response to stimulation by substance P (SP).

Methods: We assessed the effect of yokukansan on the expression of ERK1/2, P38 MAPK, nuclear factor (NF)-κB, and cyclooxygenase-2 (COX-2) in U373 cells by western blot assay. Levels of IL-6 and IL-8 in conditioned medium obtained after stimulation of cells with SP for 24 h were measured by enzyme-linked immunosorbent assay. All experiments were conducted in triplicate. Results were analyzed by one-way ANOVA, and significance was accepted at p < 0.05.

Results: Yokukansan suppressed SP-induced production of IL-6 and IL-8 by U373 MG cells, and downregulated SP-induced COX-2 expression. Yokukansan also inhibited phosphorylation of ERK1/2 and p38 MAPK, as well as nuclear translocation of NF-κB, induced by SP stimulation of U373 MG cells.

Conclusion: Yokukansan exhibits anti-inflammatory activity by suppressing SP-induced production of IL-6 and IL-8 and downregulating COX-2 expression in U373 MG cells, possibly via inhibition of the activation of signaling molecules, such as ERK1/2, p38 MAPK, and NF-κB.

Keywords: Yokukansan, substance P, p38MAPK, NF-κB, NK-1 receptor, anti-inflammatory action.

« Previous Next »
Graphical Abstract

[1]
Yamaguchi, K.; Kumakura, S.; Murakami, T.; Someya, A.; Inada, E.; Nagaoka, I. Ketamine suppresses the substance P-induced production of IL-6 and IL-8 by human U373MG glioblastoma/astrocytoma cells. Int. J. Mol. Med., 2017, 39(3), 687-692.
[http://dx.doi.org/10.3892/ijmm.2017.2875] [PMID: 28204809]
[2]
Maeno, H.; Kiyama, H.; Tohyama, M. Distribution of the substance P receptor (NK-1 receptor) in the central nervous system. Brain Res. Mol. Brain Res., 1993, 18(1-2), 43-58.
[http://dx.doi.org/10.1016/0169-328X(93)90172-L] [PMID: 7683074]
[3]
Saffroy, M.; Beaujouan, J.C.; Torrens, Y.; Besseyre, J.; Bergström, L.; Glowinski, J. Localization of tachykinin binding sites (NK1, NK2, NK3 ligands) in the rat brain. Peptides, 1988, 9(2), 227-241.
[http://dx.doi.org/10.1016/0196-9781(88)90255-0] [PMID: 2836823]
[4]
Wolf, S.S.; Moody, T.W.; Quirion, R.; O’Donohue, T.L. Biochemical characterization and autoradiographic localization of central substance P receptors using [125I]physalaemin. Brain Res., 1985, 332(2), 299-307.
[http://dx.doi.org/10.1016/0006-8993(85)90598-0] [PMID: 2581653]
[5]
Lieb, K.; Schaller, H.; Bauer, J.; Berger, M.; Schulze-Osthoff, K.; Fiebich, B.L. Substance P and histamine induce interleukin-6 expression in human astrocytoma cells by a mechanism involving protein kinase C and nuclear factor-IL-6. J. Neurochem., 1998, 70(4), 1577-1583.
[http://dx.doi.org/10.1046/j.1471-4159.1998.70041577.x] [PMID: 9523575]
[6]
Lieb, K.; Fiebich, B.L.; Berger, M.; Bauer, J.; Schulze-Osthoff, K. The neuropeptide substance P activates transcription factor NF-kappa B and kappa B-dependent gene expression in human astrocytoma cells. J. Immunol., 1997, 159(10), 4952-4958.
[PMID: 9366421]
[7]
Kempuraj, D.; Thangavel, R.; Natteru, P.A.; Selvakumar, G.P.; Saeed, D.; Zahoor, H.; Zaheer, S.; Iyer, S.S.; Zaheer, A. Neuroinflammation Induces Neurodegeneration. J Neurol Neurosurg Spine, 2016, 1(1), 1003.
[PMID: 28127589]
[8]
Horuk, R.; Martin, A.W.; Wang, Z.; Schweitzer, L.; Gerassimides, A.; Guo, H.; Lu, Z.; Hesselgesser, J.; Perez, H.D.; Kim, J.; Parker, J.; Hadley, T.J.; Peiper, S.C. Expression of chemokine receptors by subsets of neurons in the central nervous system. J. Immunol., 1997, 158(6), 2882-2890.
[PMID: 9058825]
[9]
Kim, S.Y.; Bae, J.C.; Kim, J.Y.; Lee, H.L.; Lee, K.M.; Kim, D.S.; Cho, H.J. Activation of p38 MAP kinase in the rat dorsal root ganglia and spinal cord following peripheral inflammation and nerve injury. Neuroreport, 2002, 13(18), 2483-2486.
[http://dx.doi.org/10.1097/00001756-200212200-00021] [PMID: 12499853]
[10]
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(2), 478-485.
[http://dx.doi.org/10.1523/JNEUROSCI.22-02-00478.2002] [PMID: 11784793]
[11]
Eckert, R.L.; Kaartinen, M.T.; Nurminskaya, M.; Belkin, A.M.; Colak, G.; Johnson, G.V.; Mehta, K. Transglutaminase regulation of cell function. Physiol. Rev., 2014, 94(2), 383-417.
[http://dx.doi.org/10.1152/physrev.00019.2013] [PMID: 24692352]
[12]
Shi, Z.M.; Han, Y.W.; Han, X.H.; Zhang, K.; Chang, Y.N.; Hu, Z.M.; Qi, H.X.; Ting, C.; Zhen, Z.; Hong, W. Upstream regulators and downstream effectors of NF-κB in Alzheimer’s disease. J. Neurol. Sci., 2016, 366, 127-134.
[http://dx.doi.org/10.1016/j.jns.2016.05.022] [PMID: 27288790]
[13]
Ebisawa, S.; Andoh, T.; Shimada, Y.; Kuraishi, Y. Yokukansan Improves Mechanical Allodynia through the Regulation of Interleukin-6 Expression in the Spinal Cord in Mice with Neuropathic Pain. Evid. Based Complement. Alternat. Med., 2015, 2015870687
[http://dx.doi.org/10.1155/2015/870687] [PMID: 25866544]
[14]
Mizukami, K.; Asada, T.; Kinoshita, T.; Tanaka, K.; Sonohara, K.; Nakai, R.; Yamaguchi, K.; Hanyu, H.; Kanaya, K.; Takao, T.; Okada, M.; Kudo, S.; Kotoku, H.; Iwakiri, M.; Kurita, H.; Miyamura, T.; Kawasaki, Y.; Omori, K.; Shiozaki, K.; Odawara, T.; Suzuki, T.; Yamada, S.; Nakamura, Y.; Toba, K. A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia. Int. J. Neuropsychopharmacol., 2009, 12(2), 191-199.
[http://dx.doi.org/10.1017/S146114570800970X] [PMID: 19079814]
[15]
Suzuki, Y.; Mitsuhata, H.; Yuzurihara, M.; Kase, Y. Antiallodynic effect of herbal medicine yokukansan on peripheral neuropathy in rats with chronic constriction injury. Evid. Based Complement. Alternat. Med., 2012, 2012953459
[http://dx.doi.org/10.1155/2012/953459] [PMID: 22454692]
[16]
Yamaguchi, K.; Richardson, M.D.; Bigner, D.D.; Kwatra, M.M. Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCdelta. Cancer Chemother. Pharmacol., 2005, 56(6), 585-593.
[http://dx.doi.org/10.1007/s00280-005-1030-3] [PMID: 16012865]
[17]
Heuillet, E.; Ménager, J.; Fardin, V.; Flamand, O.; Bock, M.; Garret, C.; Crespo, A.; Fallourd, A.M.; Doble, A. Characterization of a human NK1 tachykinin receptor in the astrocytoma cell line U 373 MG. J. Neurochem., 1993, 60(3), 868-876.
[http://dx.doi.org/10.1111/j.1471-4159.1993.tb03231.x] [PMID: 7679727]
[18]
Nakao, K.; Fujiwara, A.; Komasawa, N.; Jin, D.; Kitano, M.; Matsunami, S.; Takai, S.; Ito, S.; Minami, T. Yokukansan Alleviates Cancer Pain by Suppressing Matrix Metalloproteinase-9 in a Mouse Bone Metastasis Model. Evid. Based Complement. Alternat. Med., 2019. 20192956920
[19]
Nakamura, Y.; Tajima, K.; Kawagoe, I.; Kanai, M.; Mitsuhata, H. Efficacy of traditional herbal medicine, Yokukansan on patients with neuropathic pain Masui, 2009, 58(10), 1248-1255.
[PMID: 19860227]
[20]
Tsuda, M.; Shigemoto-Mogami, Y.; Koizumi, S.; Mizokoshi, A.; Kohsaka, S.; Salter, M.W.; Inoue, K. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature, 2003, 424(6950), 778-783.
[http://dx.doi.org/10.1038/nature01786] [PMID: 12917686]
[21]
Seo, M.J.; Kim, S.J.; Kang, T.H.; Rim, H.K.; Jeong, H.J.; Um, J.Y.; Hong, S.H.; Kim, H.M. The regulatory mechanism of β-eudesmol is through the suppression of caspase-1 activation in mast cell-mediated inflammatory response. Immunopharmacol. Immunotoxicol., 2011, 33(1), 178-185.
[http://dx.doi.org/10.3109/08923973.2010.491082] [PMID: 20604677]
[22]
Kawakami, Z.; Kanno, H.; Ueki, T.; Terawaki, K.; Tabuchi, M.; Ikarashi, Y.; Kase, Y. Neuroprotective effects of yokukansan, a traditional Japanese medicine, on glutamate-mediated excitotoxicity in cultured cells. Neuroscience, 2009, 159(4), 1397-1407.
[http://dx.doi.org/10.1016/j.neuroscience.2009.02.004] [PMID: 19409210]
[23]
Arruda, J.L.; Colburn, R.W.; Rickman, A.J.; Rutkowski, M.D.; DeLeo, J.A. Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: potential role of IL-6 in neuropathic pain. Brain Res. Mol. Brain Res., 1998, 62(2), 228-235.
[http://dx.doi.org/10.1016/S0169-328X(98)00257-5] [PMID: 9813345]
[24]
Kumar, S.; Minnich, M.D.; Young, P.R. ST2/T1 protein functionally binds to two secreted proteins from Balb/c 3T3 and human umbilical vein endothelial cells but does not bind interleukin 1. J. Biol. Chem., 1995, 270(46), 27905-27913.
[http://dx.doi.org/10.1074/jbc.270.46.27905] [PMID: 7499265]
[25]
Lewis, M.; Tartaglia, L.A.; Lee, A.; Bennett, G.L.; Rice, G.C.; Wong, G.H.; Chen, E.Y.; Goeddel, D.V. Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc. Natl. Acad. Sci. USA, 1991, 88(7), 2830-2834.
[http://dx.doi.org/10.1073/pnas.88.7.2830] [PMID: 1849278]
[26]
Sims, J.E.; March, C.J.; Cosman, D.; Widmer, M.B.; MacDonald, H.R.; McMahan, C.J.; Grubin, C.E.; Wignall, J.M.; Jackson, J.L.; Call, S.M. cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science, 1988, 241(4865), 585-589.
[http://dx.doi.org/10.1126/science.2969618] [PMID: 2969618]
[27]
Imai, S.; Ikegami, D.; Yamashita, A.; Shimizu, T.; Narita, M.; Niikura, K.; Furuya, M.; Kobayashi, Y.; Miyashita, K.; Okutsu, D.; Kato, A.; Nakamura, A.; Araki, A.; Omi, K.; Nakamura, M.; James Okano, H.; Okano, H.; Ando, T.; Takeshima, H.; Ushijima, T.; Kuzumaki, N.; Suzuki, T.; Narita, M. Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. Brain, 2013, 136(Pt 3), 828-843.
[http://dx.doi.org/10.1093/brain/aws330] [PMID: 23364351]
[28]
Wang, X.M.; Hamza, M.; Wu, T.X.; Dionne, R.A. Upregulation of IL-6, IL-8 and CCL2 gene expression after acute inflammation: Correlation to clinical pain. Pain, 2009, 142(3), 275-283.
[http://dx.doi.org/10.1016/j.pain.2009.02.001] [PMID: 19233564]
[29]
Wang, F.; Xu, S.; Shen, X.; Guo, X.; Peng, Y.; Yang, J. Spinal macrophage migration inhibitory factor is a major contributor to rodent neuropathic pain-like hypersensitivity. Anesthesiology, 2011, 114(3), 643-659.
[http://dx.doi.org/10.1097/ALN.0b013e31820a4bf3] [PMID: 21293254]
[30]
Tang, H.B.; Li, Y.S.; Arihiro, K.; Nakata, Y. Activation of the neurokinin-1 receptor by substance P triggers the release of substance P from cultured adult rat dorsal root ganglion neurons. Mol. Pain, 2007, 3, 42.
[http://dx.doi.org/10.1186/1744-8069-3-42] [PMID: 18157919]
[31]
Yamamura, K.; Kato, S.; Kato, T.A.; Mizoguchi, Y.; Monji, A.; Kanba, S.; Furue, M.; Takeuchi, S. Anti-allergic mechanisms of Japanese herbal medicine, yokukansan on mast cells. J. Dermatol., 2014, 41(9), 808-814.
[http://dx.doi.org/10.1111/1346-8138.12578] [PMID: 25156212]

Rights & Permissions Print Cite
Article Metrics
15
© 2024 Bentham Science Publishers | Privacy Policy