Upper limb arthromyodynia can be treated with Notopterygium by down-regulating P2X3 to mediate PKC-induced inflammatory response

doi:10.5246/jcps.2022.03.014

Abstract

Abstract:

Rheumatoid arthritis (RA) is one of the most common refractory diseases in the world, and traditional Chinese medicine Notopterygium (NE) has been used in the treatment of upper limb pain for a long time. NE can significantly reduce the expression of inflammatory pain target P2X3 receptor in rats with upper-limb arthritis. To verify the relationship between the mechanism of NE for "upper limb paralysis" and the P2X3 receptor-mediated PKC inflammatory response pathway, UPLC was taken to measure the exact medicinal substance of ethyl acetate from NE. Sprague Dawley rats were randomly divided into a blank group, a model group, a live-action group, and a positive group. The joint cavity was removed after 21 d. Moreover, a model group, a live group, and a positive group were also set up with RA-FLS cells in our in vitro study. The expressions of P2X3 and PKC inflammation pathway indicators were detected by Western blotting analysis. A P2X3 inhibitor (A-317491) acted on RA-FLS cells, and a model group and a positive group were set. Then the protein expression of PKC was detected. NE reduced the expressions of P2X3, Rab7, PKC, and NF-κB at the protein level in both systems. NE and P2X3 receptor antagonists reduced the expressions of key proteins in the PKC pathway in RA-FLS cells to similar extents, and their effects were not additive. NE could effectively improve the "forelimb pain" of RA rats, with a mechanism closely related to the P2X3/Rab7/PKC/NF-κB pathway.

Key words: Notopterygium, P2X3 receptor, Protein kinase c, Inflammatory response pathway

Supporting:

Yingzheng Wang, Ce Yang, Cuiping Zhu, Qianqian Zhao, Xuehua Lu, Xiaoyu Su, Yinghao Wang. Upper limb arthromyodynia can be treated with Notopterygium by down-regulating P2X3 to mediate PKC-induced inflammatory response[J]. Journal of Chinese Pharmaceutical Sciences, 2022, 31(3): 163-175.

Figures/Tables 9

References 41

[1]	Choi, E.M.; Kim, Y.H. Hesperetin attenuates the highly reducing sugar-triggered inhibition of osteoblast differentiation. Cell Biol. Toxicol. 2008, 24, 225–231.
[2]	Malochet-Guinamand, S.; Lambert, C.; Gossec, L.; Soubrier, M.; Dougados, M. Evaluation of the implementation of guidelines on the treatment of osteoporosis in patients with rheumatoid arthritis. J. Rheumatol. 2020, 47, 6–14.
[3]	Hyndman, I.J. Rheumatoid arthritis: past, present and future approaches to treating the disease. Int. J. Rheum. Dis. 2017, 20, 417–419.
[4]	Guo, Q.; Wang, Y.X.; Xu, D.; Nossent, J.; Pavlos, N.J.; Xu, J.K. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018, 6, 15.
[5]	Linares, V.; Alonso, V.; Domingo, J.L. Oxidative stress as a mechanism underlying sulfasalazine-induced toxicity. Expert. Opin. Drug Saf. 2011, 10, 253–263.
[6]	van der Heijden, J.W.; Assaraf, Y.G.; Gerards, A.H.; Oerlemans, R.; Lems, W.F.; Scheper, R.J.; Dijkmans, B.A.; Jansen, G. Methotrexate analogues display enhanced inhibition of TNF-α production in whole blood from RA patients. Scand. J. Rheumatol. 2014, 43, 9–16.
[7]	Brown, P.M.; Pratt, A.G.; Isaacs, J.D. Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat. Rev. Rheumatol. 2016, 12, 731–742.
[8]	Yates, M.; Hamilton, L.E.; Elender, F.; Dean, L.; Doll, H.; MacGregor, A.J.; Thomas, J.; Gaffney, K. Is etanercept 25 Mg once weekly as effective as 50 Mg at maintaining response in patients with ankylosing spondylitis? A randomized control trial. J. Rheumatol. 2015, 42, 1177–1185.
[9]	Raimondo, M.G.; Biggioggero, M.; Crotti, C.; Becciolini, A.; Favalli, E.G. Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. Drug Des. Dev. Ther. 2017, 11, 1593–1603.
[10]	Jin, X.; Ding, C. Belimumab: an anti-BLyS human monoclonal antibody for rheumatoid arthritis. Expert. Opin. Biol. Ther. 2013, 13, 315–322.
[11]	Mélet, J.; Mulleman, D.; Goupille, P.; Ribourtout, B.; Watier, H.; Thibault, G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum. 2013, 65, 2783–2790.
[12]	Pisetsky, D.S. Advances in the treatment of rheumatoid arthritis. North Carol. Med. J. 2017, 78, 337–340.
[13]	Wang, Y.H.; Chen, Z.H.; Liu, C.; Lu, X.H.; Yang, C.; Qiu, S.P. Distributive differences of P2Xs between the forelimb and hind limb of adjuvant arthritis rats and intervention by Notopterygh rhizoma et radix. Pharm. Biol. 2019, 57, 81–88.
[14]	Bi, J.P.; Li, P.; Xu, X.X.; Wang, T.; Li, F. Anti-rheumatoid arthritic effect of volatile components in notopterygium incisum in rats via anti-inflammatory and anti-angiogenic activities. Chin. J. Nat. Med. 2018, 16, 926–935.
[15]	Pan, T.; Cheng, T.F.; Jia, Y.R.; Li, P.; Li, F. Anti-rheumatoid arthritis effects of traditional Chinese herb couple in adjuvant-induced arthritis in rats. J. Ethnopharmacol. 2017, 205, 1–7.
[16]	Dunn, P.M.; Zhong, Y.; Burnstock, G. P2X receptors in peripheral neurons. Prog. Neurobiol. 2001, 65, 107–134.
[17]	North, R.A. P2X receptors. Phil. Trans. R. Soc. B 2016, 371, 20150427.
[18]	Li, J.J.; Liu, Z.X.; Zhang, Y.L.; Xue, G.Y. P2X receptors and trigeminal neuralgia. Neuroreport. 2019, 30, 725–729.
[19]	Burnstock, G.; Wood, J.N. Purinergic receptors: their role in nociception and primary afferent neurotransmission. Curr. Opin. Neurobiol. 1996, 6, 526–532.
[20]	Fabbretti, E. P2X3 receptors are transducers of sensory signals. Brain Res. Bull. 2019, 151, 119–124.
[21]	Xu, G.Y.; Huang, L.Y.M. Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. J. Neurosci. 2002, 22, 93–102.
[22]	Donnelly-Roberts, D.; McGaraughty, S.; Shieh, C.C.; Honore, P.; Jarvis, M.F. Painful purinergic receptors. J. Pharmacol. Exp. Ther. 2008, 324, 409–415.
[23]	Jarvis, M.F.; Khakh, B.S. ATP-gated P2X cation-channels. Neuropharmacology. 2009, 56, 208–215.
[24]	Wang, S.L.; Dai, Y.; Kobayashi, K.; Zhu, W.J.; Kogure, Y.; Yamanaka, H.; Wan, Y.; Zhang, W.S.; Noguchi, K. Potentiation of the P2X3 ATP receptor by PAR-2 in rat dorsal root Ganglia neurons, through protein kinase-dependent mechanisms, contributes to inflammatory pain. Eur. J. Neurosci. 2012, 36, 2293–2301.
[25]	Gu, Y.P.; Wang, C.Y.; Li, G.W.; Huang, L.Y.M. F-actin links Epac-PKC signaling to purinergic P2X3 receptor sensitization in dorsal root Ganglia following inflammation. Mol. Pain. 2016, 12, 174480691666055.
[26]	Chen, X.Q.; Wang, B.; Wu, C.B.; Pan, J.; Yuan, B.; Su, Y.Y.; Jiang, X.Y.; Zhang, X.; Bao, L. Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons. Cell Res. 2012, 22, 677–696.
[27]	Radstake, T.R.; van der Voort, R.; ten Brummelhuis, M.; de Waal Malefijt, M.; Looman, M.; Figdor, C.G.; van den Berg, W.B.; Barrera, P.; Adema, G.J. Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors. Ann. Rheum. Dis. 2005, 64, 359–367.
[28]	Abdel-Halim, M.; Darwish, S.S.; ElHady, A.K.; Hoppstädter, J.; Abadi, A.H.; Hartmann, R.W.; Kiemer, A.K.; Engel, M. Pharmacological inhibition of protein kinase C (PKC)ζ downregulates the expression of cytokines involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Eur. J. Pharm. Sci. 2016, 93, 405–409.
[29]	Chovanova, L.; Vlcek, M.; Krskova, K.; Penesova, A.; Radikova, Z.; Rovensky, J.; Cholujova, D.; Sedlak, J.; Imrich, R. Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears from patients with rheumatoid arthritis. Gen. Physiol. Biophys. 2013, 32, 395–404.
[30]	Tang, C.H.; Hsu, C.J.; Yang, W.H.; Fong, Y.C. Lipoteichoic acid enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, PKCδ and c-Src dependent pathways. Biochem. Pharmacol. 2010, 79, 1648–1657.
[31]	Ogata, N.; Yamamoto, H.; Kugiyama, K.; Yasue, H.; Miyamoto, E. Involvement of protein kinase C in superoxide anion-induced activation of nuclear factor-κB in human endothelial cells. Cardiovasc. Res. 2000, 45, 513–521.
[32]	Sun, W.X.; Liu, Y.; Zhou, W.; Li, H.W.; Yang, J.; Chen, Z.B. Shikonin inhibits TNF-α production through suppressing PKC-NF-κB-dependent decrease of IL-10 in rheumatoid arthritis-like cell model. J. Nat. Med. 2017, 71, 349–356.
[33]	Breedveld, F.C.; Weisman, M.H.; Kavanaugh, A.F.; Cohen, S.B.; Pavelka, K.; Vollenhoven, R.V.; Sharp, J.; Perez, J.L.; Spencer-Green, G.T. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006, 54, 26–37.
[34]	Smolen, J.S.; Aletaha, D.; Bijlsma, J.W.; Breedveld, F.C.; Boumpas, D.; Burmester, G.; Combe, B.; Cutolo, M.; de Wit, M.; Dougados, M.; Emery, P.; Gibofsky, A.; Gomez-Reino, J.J.; Haraoui, B.; Kalden, J.; Keystone, E.C.; Kvien, T.K.; McInnes, I.; Martin-Mola, E.; Montecucco, C.; Schoels, M.; van der Heijde, D.; T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann. Rheum. Dis. 2010, 69, 631–637.
[35]	Stannus, O.; Jones, G.; Cicuttini, F.; Parameswaran, V.; Quinn, S.; Burgess, J.; Ding, C. Circulating levels of IL-6 and TNF-α are associated with knee radiographic osteoarthritis and knee cartilage loss in older adults. Osteoarthr. Cartil. 2010, 18, 1441–1447.
[36]	Li, X.; Yuan, F.L.; Lu, W.G.; Zhao, Y.Q.; Li, C.W.; Li, J.P.; Xu, R.S. The role of interleukin-17 in mediating joint destruction in rheumatoid arthritis. Biochem. Biophys. Res. Commun. 2010, 397, 131–135.
[37]	Du, B.Y.; Zhu, M.; Li, Y.L.; Li, G.; Xi, X.Y. The prostaglandin E2 increases the production of IL-17 and the expression of costimulatory molecules on γδ T cells in rheumatoid arthritis. Scand. J. Immunol. 2020, 91, e12872.
[38]	Teixeira, J.M.; Bobinski, F.; Parada, C.A.; Sluka, K.A.; Tambeli, C.H. P2X3 and P2X2/3 receptors play a crucial role in articular hyperalgesia development through inflammatory mechanisms in the knee joint experimental synovitis. Mol. Neurobiol. 2017, 54, 6174–6186.
[39]	Burnstock, G. Physiology and pathophysiology of purinergic neurotransmission. Physiol. Rev. 2007, 87, 659–797.
[40]	Kobayashi, K.; Fukuoka, T.; Yamanaka, H.; Dai, Y.; Obata, K.; Tokunaga, A.; Noguchi, K. Differential expression patterns of mRNAs for P2X receptor subunits in neurochemically characterized dorsal root ganglion neurons in the rat. J. Comp. Neurol. 2005, 481, 377–390.
[41]	Gao, Y.; Xu, C.S.; Liang, S.D.; Zhang, A.X.; Mu, S.N.; Wang, Y.X.; Wan, F. Effect of tetramethylpyrazine on primary afferent transmission mediated by P2X3 receptor in neuropathic pain states. Brain Res. Bull. 2008, 77, 27–32.