The Effects of Cyclosporine and Tacrolimus on Gingiva and Alveolar Bone of Rats

Yıl 2021, Cilt: 11 Sayı: 3, 516 - 522, 27.09.2021

Ural Karaduman Burcu Karaduman , İlhami Çelik , Mihtikar Gürsel

https://doi.org/10.33808/clinexphealthsci.835833

Öz

Objective: Cyclosporine A (CsA) and tacrolimus (Tac) are immunosuppressive drugs which is frequently used in organ transplantation. CsA can cause various side effects including gingival overgrowth (GO) and osteopenia. Tac has similar side effects to CsA but with different incidences. The aim of the present study was to evaluate and compare the effects of CsA and Tac on GO and alveolar bone resorption in rats.
Methods: Sixty mature male rats were randomly and equally allocated into six groups, as follows: Control-I, Control-II, CsA-I, CsA-II, Tac-I and Tac-II. The Control-I and Control-II groups received, subcutaneously, 1 ml/kg 0.9% NaCl, while the CsA-I and CsA-II groups received 10 mg/kg CsA daily, and the Tac-I and Tac-II groups 1.5 mg/kg Tac daily. The Control-I, CsA-I and Tac-I groups were sacrificed on the 16th day and other groups on the 31st day. Histological and histomorphometric analysis of the buccal gingiva and tartrate-resistant acid phosphatase (TRAP) enzyme histochemistry of the alveolar bone were performed in the right mandibular segment of each animal.
Results: GO was significantly greater in the groups administered CsA compared to the other groups (P<0.05). The gingival parameters in the Tac groups were quite similar to those in the control group (P>0.05). CsA caused a significant increase in TRAP positivity (P<0.05), while Tac had no significant effect on TRAP (P>0.05).
Conclusions: Our results showed that Tac does not seem to cause GO and alveolar bone resorption. However, the deleterious side effects of Tac on the gingival tissues of rats may be time-related.

Anahtar Kelimeler

Bone Resorption, , Cyclosporine A,, Gingival Overgrowth, Tacrolimus, Tartrate-Resistant Acid Phosphatase

Destekleyen Kurum

Selcuk University Scientific Research Projects Coordinatorship

Proje Numarası

09202006

Kaynakça

• Dongari-Bagtzolou A, Cutler C. Drug-Associated Gingival Enlargement. J Periodontol [Internet]. 2004;75:1424–31. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16945041
• Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y, Nickeleit V, Ryffel B. The side-effects of ciclosporine-A and tacrolimus. Clin Nephrol. 1998 Jun;49(6):356–63.
• Spencer CM, Goa KL, Gillis JC. Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation. Vol. 54, Drugs. Springer International Publishing; 1997. p. 925–75.
• Prabhu A, Mehta DS. A Morphologic Comparison of Gingival Changes Influenced by Cyclosporin and Tacrolimus in Rats: An Experimental Study. J Periodontol. 2006 Feb;77(2):265–70.
• Spolidorio LC, Holzhausen M, Spolidorio DMP, Nassar CA, Nassar PO, Muscará MN. Cyclosporin But Not Tacrolimus Significantly Increases Salivary Cytokine Contents in Rats. J Periodontol. 2005 Sep;76(9):1520–5.
• Martins L, Ventura A, Branco A, Carvalho MJ, Henriques AC, Dias L, et al. Cyclosporine versus tacrolimus in kidney transplantation: Are there differences in nephrotoxicity? In: Transplantation Proceedings. 2004. p. 877–9.
• James JA, Jamal S, Hull PS, Macfarlane T V., Campbell BA, Johnson RWG, et al. Tacrolimus is not associated with gingival overgrowth in renal transplant patients. J Clin Periodontol. 2001;28(9):848–52.
• Lima RB, Benini V, Sens YAS. Gingival Overgrowth in Renal Transplant Recipients: A Study Concerning Prevalence, Severity, Periodontal, and Predisposing Factors. Transplant Proc. 2008 Jun;40(5):1425–8.
• de Oliveira Costa F, Diniz Ferreira S, de Miranda Cota LO, da Costa JE, Aguiar MA. Prevalence, Severity, and Risk Variables Associated With Gingival Overgrowth in Renal Transplant Subjects Treated Under Tacrolimus or Cyclosporin Regimens. J Periodontol. 2006 Jun;77(6):969–75.
• Bader G, Lejeune S, Messner M. Reduction of Cyclosporine-Induced Gingival Overgrowth Following a Change to Tacrolimus. A Case History Involving a Liver Transplant Patient. J Periodontol. 1998 Jun;69(6):729–32.
• Andia DC, Nassar CA, Nassar PO, Guimarães MR, Cerri PS, Spolidorio LC. Treatment with tacrolimus enhances alveolar bone formation and decreases osteoclast number in the maxillae: A histomorphometric and ultrastructural study in rats. Histol Histopathol. 2008;23(10):1177–84.
• Kanda J, Izumo N, Furukawa M, Shimakura T, Yamamoto N, Takahashi HE, et al. Effects of the calcineurin inhibitors cyclosporine and tacrolimus on bone metabolism in rats. Biomed Res. 2018;39(3):131–9.
• Spolidorio LC, Nassar PO, Nassar CA, Spolidorio DMP, Muscará MN. Conversion of immunosuppressive monotherapy from cyclosporin A to tacrolimus reverses bone loss in rats. Calcif Tissue Int. 2007 Aug;81(2):114–23.
• Guimarães MR, Nassar PO, Andia DC, Nassar CA, Spolidorio DMP, Rossa C, et al. Protective effects of Tacrolimus, a calcineurin inhibitor, in experimental periodontitis in rats. Arch Oral Biol. 2007 Sep;52(9):882–8.
• Karaduman B, Uraz A, Altan GNN, Tuncer BBB, Alkan, Gönen S, et al. Changes of tumor necrosis factor-α, interleukin-10, and tartrate-resistant acid phosphatase5b in the crevicular fluid in relation to orthodontic movement. Eur J Inflamm. 2015 Apr 1;13(1):3–13.
• Sevc J, Goldberg D, van Gorp S, Leerink M, Juhas S, Juhasova J, et al. Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: Effect on spinally grafted human neural precursor survival. Exp Neurol. 2013 Oct;248:85–99.
• Wassef R, Cohen Z, Langer B. Pharmacokinetic profiles of cyclosporine in rats: Influence of route of administration and dosage. Transplantation. 1985;40(5):489–93.
• Culling, CFA.; Allison, RT.; Barr W. Cellular Pathology Technique. Cellular Pathology Technique. Elsevier; 1985.
• Berglundh T, Lindhe J, Sterrett JD. Clinical and structural characteristics of periodontal tissues in young and old dogs. J Clin Periodontol. 1991;18(8):616–23.
• Fischer RG, Klinge B. Clinical and histological evaluation of ligature‐induced periodontal breakdown in domestic ferrets immunosuppressed by Cyclosporin‐A. J Clin Periodontol. 1994;21(4):240–9.
• Cole AA, Walters LM. Tartrate-resistant acid phosphatase in bone and cartilage following decalcification and cold-embedding in plastic. J Histochem Cytochem. 1987;35(2):203–6.
• Martín-Fernández M, Rubert M, Montero M, de la Piedra C. Effects of Cyclosporine, Tacrolimus, and Rapamycin on Osteoblasts. Transplant Proc. 2017 Nov 1;49(9):2219–24.
• Rubert M, Montero M, Guede D, Caeiro JR, Martín-Fernández M, Díaz-Curiel M, et al. Sirolimus and tacrolimus rather than cyclosporine A cause bone loss in healthy adult male rats. Bone Reports. 2015 Jun 1;2:74–81.
• Dos Santos RL, Pithon MM, Lacerda MCM, Ruellas ACDO, Maia LC. Does the use of tacrolimus influence alveolar bone metabolism? Vol. 10, International Journal of Endocrinology and Metabolism. 2012. p. 429–34.
• Duarte PM, Nogueira Filho GR, Sallum EA, Toledo S de, Sallum AW, Nociti FH. The Effect of an Immunosuppressive Therapy and Its Withdrawal on Bone Healing Around Titanium Implants. A Histometric Study in Rabbits. J Periodontol. 2001 Oct;72(10):1391–7.
• Ishida H, Kondoh T, Kataoka M, Nishikawa S, Nakagawa T, Morisaki I, et al. Factors Influencing Nifedipine-Induced Gingival Overgrowth in Rats. J Periodontol. 1995 May;66(5):345–50.
• Rapone B, Ferrara E, Santacroce L, Cesarano F, Arazzi M, Di Liberato L, et al. Periodontal microbiological status influences the occurrence of cyclosporine-a and tacrolimus- induced gingival overgrowth. Antibiotics. 2019 Sep 1;8(3).
• Paixão CG, Sekiguchi RT, Saraiva L, Pannuti CM, Silva HT, Medina-Pestana JO, et al. Gingival Overgrowth Among Patients Medicated With Cyclosporin A and Tacrolimus Undergoing Renal Transplantation: A Prospective Study. J Periodontol. 2011 Feb;82(2):251–8.
• Pamuk F, Cetinkaya BO, Ayas B, Keles GC, Gacar A. Evaluation of gingival alterations in rats medicated with cyclosporine A, tacrolimus and sirolimus: A stereological study. J Periodontal Res. 2015 Oct 1;50(5):629–36.
• Nassar CA, Nassar PO, Andia DC, Guimarães MR, Spolidorio LC. The effects of up to 240 days of tacrolimus therapy on the gingival tissues of rats - A morphological evaluation. Oral Dis. 2008 Jan;14(1):67–72.