Ropinirole inhibits inflammatory cytokine production in gingival epithelial cells and suppresses alveolar bone loss in an experimental rat model of periodontitis

Isozaki,Yuta; Sato,Tsuyoshi; Takagi,Rie; Ito,Ko; Usui,Michihiko; Kawano,Masaaki; Matsushita,Sho

doi:10.3892/etm.2022.11777

Ropinirole inhibits inflammatory cytokine production in gingival epithelial cells and suppresses alveolar bone loss in an experimental rat model of periodontitis

Authors:
- Yuta Isozaki
- Tsuyoshi Sato
- Rie Takagi
- Ko Ito
- Michihiko Usui
- Masaaki Kawano
- Sho Matsushita
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Affiliations: Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, Iruma, Saitama 350‑0495, Japan, Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, Iruma, Saitama 350‑0495, Japan, Division of Periodontology, Department of Cardiology and Periodontology, Kyushu Dental University, Kitakyusyu, Fukuoka 803‑8530, Japan
Published online on: December 29, 2022 https://doi.org/10.3892/etm.2022.11777
Article Number: 78

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Abstract

The present study explored whether the dopamine 2‑like receptor agonist, ropinirole, a drug used for treating Parkinson's disease, suppresses neutrophilic inflammation and alveolar bone loss in an experimental rat model of periodontitis. Periodontitis is a neutrophilic inflammatory disease caused by periodontal pathogens. An excessive T helper (Th)17 immune response is involved in the progression of periodontitis, and interleukin (IL)‑17 promotes the exacerbation of inflammation and alveolar bone destruction. Recent evidence has suggested that dopamine signaling plays a key role in Th17 cell differentiation, and that dopamine 2‑like receptor agonists suppress cytokine production from Th17 cells. We previously demonstrated that tannic acid, which is a dopamine 2‑like receptor agonist, inhibits alveolar bone resorption in an experimental model of periodontitis. The present study used a carrageenan‑induced rat model of periodontitis with or without ropinirole. Micro‑computed tomography analysis was performed. Cells of the murine gingival epithelial cell line GE1 were stimulated with carrageenan and IL‑17A in the presence or absence of ropinirole. The anti‑inflammatory effect of ropinirole was analyzed using reverse transcription‑ quantitative PCR and enzyme‑linked immunosorbent assay. Subsequently, in the carrageenan‑induced rat model of periodontitis, alveolar bone resorption was observed in the maxillary second molar by micro‑computed tomography analysis. Intriguingly, ropinirole suppressed the alveolar bone destruction. The expression levels of C‑X‑C motif chemokine ligand 1 (CXCL1) and IL‑17 receptor A (IL‑17RA) in GE1 cells were increased by carrageenan, and CXCL1 expression in GE1 cells was upregulated under IL‑17A stimulation. Moreover, ropinirole inhibited CXCL1 and IL‑17RA expression in GE1 cells in the presence of IL‑17A and carrageenan. Finally, haloperidol promoted CXCL1 expression in GE1 cells in the presence of carrageenan. Overall, these findings suggested that ropinirole suppressed neutrophilic inflammation and alveolar bone destruction in periodontitis by inhibiting CXCL1 expression in gingival epithelial cells through the dopamine 2‑like receptor. Thus, ropinirole shows promise as a drug for the treatment of periodontitis.

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1	Hirschfeld J: Neutrophil subsets in periodontal health and disease: A mini review. Front Immunol. 10(3001)2019.PubMed/NCBI View Article : Google Scholar
2	Takahashi N, Okui T, Tabeta K and Yamazaki K: Effect of interleukin-17 on the expression of chemokines in gingival epithelial cells. Eur J Oral Sci. 119:339–344. 2011.PubMed/NCBI View Article : Google Scholar
3	Tipton DA, Cho S, Zacharia N and Dabbous MK: Inhibition of interleukin-17-stimulated interleukin-6 and -8 production by cranberry components in human gingival fibroblasts and epithelial cells. J Periodontal Res. 48:638–646. 2013.PubMed/NCBI View Article : Google Scholar
4	Dutzan N and Abusleme L: T helper 17 cells as pathogenic drivers of periodontitis. Adv Exp Med Biol. 1197:107–117. 2019.PubMed/NCBI View Article : Google Scholar
5	Rot A and von Andrian UH: Chemokines in innate and adaptive host defense: Basic chemokinese grammar for immune cells. Ann Rev Immunol. 22:891–928. 2004.PubMed/NCBI View Article : Google Scholar
6	Lindhe J and Nyman S: Scaling and granulation tissue removal in periodontal therapy. J Clin Periodontol. 12:374–388. 1985.PubMed/NCBI View Article : Google Scholar
7	Graziani F, Karapetsa D, Alonso B and Herrera D: Nonsurgical and surgical treatment of periodontitis: How many options for one disease? Periodontology. 75:152–188. 2000.PubMed/NCBI View Article : Google Scholar
8	Kitamura M, Akamatsu M, Machigashira M, Hara Y, Sakagami R, Hirofuji T, Hamachi T, Maeda K, Yokota M, Kido J, et al: FGF-2 stimulates periodontal regeneration: Results of a multi-center randomized clinical trial. J Dent Res. 90:35–40. 2011.PubMed/NCBI View Article : Google Scholar
9	da Costa LF, Amaral CD, Barbirato DD, Leão AT and Fogacci MF: Chlorhexidine mouthwash as an adjunct to mechanical therapy in chronic periodontitis: A meta-analysis. J Am Dent Assoc. 148:308–318. 2017.PubMed/NCBI View Article : Google Scholar
10	Matesanz-Pérez P, García-Gargallo M, Figuero E, Bascones-Martínez A, Sanz M and Herrera D: A systematic review on the effects of local antimicrobials as adjuncts to subgingival debridement, compared with subgingival debridement alone, in the treatment of chronic periodontitis. J Clin Periodontol. 40:227–241. 2013.PubMed/NCBI View Article : Google Scholar
11	Nakano K, Higashi T, Hashimoto K, Takagi R, Tanaka Y and Matsushita S: Antagonizing dopamine D1-like receptor inhibits Th17 cell differentiation: Preventive and therapeutic effects on experimental autoimmune encephalomyelitis. Biochem Biophys Res Commun. 373:286–291. 2008.PubMed/NCBI View Article : Google Scholar
12	Nakano K, Yamaoka K, Hanami K, Saito K, Sasaguri Y, Yanagihara N, Tanaka S, Katsuki I, Matsushita S and Tanaka Y: Dopamine induces IL-6-dependent IL-17 production via D1-like receptor on CD4 naive T cells and D1-like receptor antagonist SCH-23390 inhibits cartilage destruction in a human rheumatoid arthritis/SCID mouse chimera model. J Immunol. 186:3745–3752. 2011.PubMed/NCBI View Article : Google Scholar
13	Missale C, Nash SR, Robinson SW, Jaber M and Caron MG: Dopamine receptors: From structure to function. Physiol Rev. 78:189–225. 1998.PubMed/NCBI View Article : Google Scholar
14	Okada H, Inoue T, Hashimoto K, Suzuki H and Matsushita S: . D1-like receptor antagonist inhibits IL-17 expression and attenuates crescent formation in nephrotoxic serum nephritis. Am J Nephrol. 30:274–279. 2009.PubMed/NCBI View Article : Google Scholar
15	Hashimoto K, Inoue T, Higashi T, Takei S, Awata T, Katayama S, Takagi R, Okada H and Matsushita S: Dopamine D1-like receptor antagonist, SCH23390, exhibits a preventive effect on diabetes mellitus that occurs naturally in NOD mice. Biochem Biophys Res Comm. 383:460–463. 2009.PubMed/NCBI View Article : Google Scholar
16	Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C, Cosmi L, Lunardi C, Annunziato F, Romagnani S and Cassatella MA: Evidence for a cross-talk between human neutrophils and Th17 cells. Blood. 115:335–343. 2010.PubMed/NCBI View Article : Google Scholar
17	Matsuyama T, Kawano M, Takagi R, Nakagome K, Chikamatsu K and Matsushita S: Interleukin-8 produced by T cells is under the control of dopamine signaling. Clin Exp Neuroimmunol. 9:2571–2257. 2018.
18	Parrado AC, Canellada A, Gentile T and Rey-Roldán EB: Dopamine agonists upregulate IL-6 and IL-8 production in human keratinocytes. Neuroimmunomodulation. 19:359–366. 2012.PubMed/NCBI View Article : Google Scholar
19	Kawano M, Saika K, Takagi R, Matsui M and Matsushita S: Tannic acid acts as an agonist of the dopamine D2L receptor, regulates immune responses, and ameliorates experimentally induced colitis in mice. Brain Behav Immun Health. 5(100071)2020.PubMed/NCBI View Article : Google Scholar
20	Takagi R, Kawano M, Sato T and Matsushita S: Tannic acid, a dopamine receptor agonist, ameliorates periodontitis, atopic dermatitis and psoriasis in animal models. Curr Trends Immunol. 22:11–17. 2021.
21	Chen S, Zhang X, Yang D, Du Y, Li L, Li X, Ming M and Le W: D2/D3 receptor agonist ropinirole protects dopaminergic cell line against rotenone-induced apoptosis through inhibition of caspase- and JNK-dependent pathways. FEBS Lett. 582:603–610. 2008.PubMed/NCBI View Article : Google Scholar
22	Hatakeyama S, Ohara-Nemoto Y, Yanai N, Obinata M, Hayashi S and Satoh M: Establishment of gingival epithelial cell lines from transgenic mice harboring temperature sensitive simian virus 40 large T-antigen gene. J Oral Pathol Med. 30:296–304. 2001.PubMed/NCBI View Article : Google Scholar
23	Kirihara Y, Takechi M, Kurosaki K, Kobayashi Y, Saito Y and Takeuchi T: Effects of an anesthetic mixture of medetomidine, midazolam, and butorphanol in rats-strain difference and antagonism by atipamezole. Exp Anim. 65:27–36. 2016.PubMed/NCBI View Article : Google Scholar
24	Nakamura T, Ichii O, Irie T, Hosotani M, Dantsuka A, Nakamura S, Sato S, Sotozaki K, Kouguchi H, Yoshiyasu T, et al: Usefulness of an anesthetic mixture of medetomidine, midazolam, and butorphanol in cotton rats (Sigmodn hispidus). Jpn J Vet Res. 64:273–276. 2016.PubMed/NCBI
25	Bellini L, Banzato T, Contiero B and Zotti A: Evaluation of three medetomidine-based protocols for chemical restraint and sedation for non-painful procedures in companion rats (Rattus norvegicus). Vet J. 200:456–458. 2014.PubMed/NCBI View Article : Google Scholar
26	Yoshida K, Murakawa M and Hosono A: Effects of anesthetics on expression of dopamine and acetylcholine receptors in the rat brain in vivo. J Anesth. 36:436–440. 2022.PubMed/NCBI View Article : Google Scholar
27	Yamamoto H, Yokoyama M, Tamura H, Okumura S, Kawada E and Kuboyama N: Carrageenin-induced periodontitis as an experimental model in rats analyzed by micro-computerized tomography. J Hard Tissue Biol. 20:231–236. 2011.
28	Kanda Y: Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 48:452–458. 2013.PubMed/NCBI View Article : Google Scholar
29	Mukaida N, Harada A and Matsushima K: Interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1), chemokines essentially involved in inflammatory and immune reactions. Cytokine Growth Factor Rev. 9:9–23. 1998.PubMed/NCBI View Article : Google Scholar
30	Borthakur A, Bhattacharyya S, Dudeja PK and Tobacman JK: Carrageenan induces interleukin-8 production through distinct Bcl10 pathway in normal human colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol. 292:G829–G838. 2007.PubMed/NCBI View Article : Google Scholar
31	Mitani A, Niedbala W, Fujimura T, Mogi M, Miyamae S, Higuchi N, Abe A, Hishikawa T, Mizutani M, Ishihara Y, et al: Increased expression of interleukin (IL)-35 and IL-17, but not IL-27, in gingival tissues with chronic periodontitis. J Periodontol. 86:301–309. 2015.PubMed/NCBI View Article : Google Scholar
32	Franco R, Reyes-Resina I and Navarro G: Dopamine in health and disease: Much more than a neurotransmitter. Biomedicines. 9(109)2021.PubMed/NCBI View Article : Google Scholar
33	Nakagome K, Imamura M, Okada H, Kawahata K, Inoue T, Hashimoto K, Harada H, Higashi T, Takagi R, Nakano K, et al: Dopamine D1-like receptor antagonist attenuates Th17-mediated immune response and ovalbumin antigen-induced neutrophilic airway inflammation. J Immunol. 186:5975–5982. 2011.PubMed/NCBI View Article : Google Scholar
34	Lu JH, Liu YQ, Deng QW, Peng YP and Qiu YH: Dopamine D2 receptor is involved in alleviation of type II collagen-induced arthritis in mice. BioMed Res Int. 2015(496759)2015.PubMed/NCBI View Article : Google Scholar
35	Lieberknecht V, Junqueira SC, Cunha MP, Barbosa TA, de Souza LF, Coelho IS, Santos AR, Rodrigues AL, Dafré AL and Dutra RC: Pramipexole, a dopamine D2/D3 receptor-preferring agonist, prevents experimental autoimmune encephalomyelitis development in mice. Mol Neurobiol. 54:1033–1045. 2017.PubMed/NCBI View Article : Google Scholar
36	Cheng WC, Hughes FJ and Taams LS: The presence, function and regulation of IL-17 and Th17 cells in periodontitis. J Clin Periodontol. 41:541–549. 2014.PubMed/NCBI View Article : Google Scholar
37	Tsukasaki M, Komatsu N, Nagashima K, Nitta T, Pluemsakunthai W, Shukunami C, Iwakura Y, Nakashima T, Okamoto K and Takayanagi H: Host defense against oral microbiota by bone-damaging T cells. Nat Commun. 9(701)2018.PubMed/NCBI View Article : Google Scholar
38	Kuzel MD: Ropinirole: A dopamine agonist for the treatment of parkinson's disease. Am J Health Syst Pharm. 56:217–224. 1999.PubMed/NCBI View Article : Google Scholar
39	Pradeep AR, Singh SP, Martande SS, Raju AP, Rustagi T, Suke DK and Naik SB: Clinical evaluation of the periodontal health condition and oral health awareness in parkinson's disease patients. Gerodontology. 32:100–106. 2015.PubMed/NCBI View Article : Google Scholar
40	Schwarz J, Heimhilger E and Storch A: Increased periodontal pathology in parkinson's disease. J Neurol. 253:608–611. 2006.PubMed/NCBI View Article : Google Scholar
41	Einarsdóttir ER, Gunnsteinsdóttir H, Hallsdóttir MH, Sveinsson S, Jónsdóttir SR, Olafsson VG, Bragason TH, Saemundsson SR and Holbrook WP: Dental health of patients with parkinson's disease in Iceland. Spec Care Dentist. 29:123–127. 2009.PubMed/NCBI View Article : Google Scholar
42	Hanaoka A and Kashihara K: Increased frequencies of caries, periodontal disease and tooth loss in patients with parkinson's disease. J Clin Neurosci. 16:1279–1282. 2009.PubMed/NCBI View Article : Google Scholar
43	Armstrong MJ and Okun MS: Diagnosis and treatment of parkinson disease: A review. JAMA. 323:548–560. 2020.PubMed/NCBI View Article : Google Scholar
44	de Molon RS, Mascarenhas VI, de Avila ED, Finoti LS, Toffoli GB, Spolidorio DM, Scarel-Caminaga RM, Tetradis S and Cirelli JA: Long-term evaluation of oral gavage with periodontopathogens or ligature induction of experimental periodontal disease in mice. Clin Oral Invest. 20:1203–1216. 2016.PubMed/NCBI View Article : Google Scholar
45	Barth CR, Funchal GA, Luft C, de Oliveira JR, Porto BN and Donadio MV: Carrageenan-induced inflammation promotes ROS generation and neutrophil extracellular trap formation in a mouse model of peritonitis. Eur J Immunol. 46:964–970. 2016.PubMed/NCBI View Article : Google Scholar