Journal of Yeungnam Medical Science

Yeungnam University College of Medicine, Yeungnam University Institute Medical Science (영남대 의대 학술지 편집위원회)
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Impact of calcineurin inhibitors on rat glioma cells viability

  • Seong, Jeong Hun (Department of Internal Medicine, Keimyung University School of Medicine) ;
  • Park, Woo Yeong (Department of Internal Medicine, Keimyung University School of Medicine) ;
  • Paek, Jin Hyuk (Department of Internal Medicine, Keimyung University School of Medicine) ;
  • Park, Sung Bae (Department of Internal Medicine, Keimyung University School of Medicine) ;
  • Han, Seungyeup (Department of Internal Medicine, Keimyung University School of Medicine) ;
  • Mun, Kyo-Cheol (Department of Biochemistry, Keimyung University School of Medicine) ;
  • Jin, Kyubok (Department of Internal Medicine, Keimyung University School of Medicine)
  • Received : 2018.11.16
  • Accepted : 2019.01.16
  • Published : 2019.05.31
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Abstract

Background: Although kidney transplantation outcomes have improved dramatically after using calcineurin inhibitors (CNIs), CNI toxicity continues to be reported and the mechanism remains uncertain. Here, we investigated the neurotoxicity of CNIs by focusing on the viability of glioma cells. Methods: Glioma cells were treated with several concentrations of CNIs for 24 hours at $37^{\circ}C$ and their cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: Exposure to 0, 0.25, 0.5, 2.5, 5.0, and 10.0 mM concentrations respectively showed 100%, 64.3%, 61.3%, 68.1%, 62.4%, and 68.6% cell viability for cyclosporine and 100%, 38.6%, 40.8%, 43.7%, 37.8%, and 43.0% for tacrolimus. The direct toxic effect of tacrolimus on glioma cell viability was stronger than that of cyclosporine at the same concentration. Conclusion: CNIs can cause neurological side effects by directly exerting cytotoxic effects on brain cells. Therefore, we should carefully monitor the neurologic symptoms and level of CNIs in kidney transplant patients.

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References

  1. Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med 2002;346:580-90. https://doi.org/10.1056/NEJMra011295
  2. Malvezzi P, Rostaing L. The safety of calcineurin inhibitors for kidney-transplant patients. Expert Opin Drug Saf 2015;14:1531-46. https://doi.org/10.1517/14740338.2015.1083974
  3. Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol 2003;23:465-76. https://doi.org/10.1016/S0270-9295(03)00090-1
  4. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481-508. https://doi.org/10.2215/CJN.04800908
  5. Anghel D, Tanasescu R, Campeanu A, Lupescu I, Podda G, Bajenaru O. Neurotoxicity of immunosuppressive therapies in organ transplantation. Maedica (Buchar) 2013;8:170-5.
  6. Senzolo M, Ferronato C, Burra P. Neurologic complications after solid organ transplantation. Transpl Int 2009;22:269-78. https://doi.org/10.1111/j.1432-2277.2008.00780.x
  7. Besenski N, Rumboldt Z, Emovon O, Nicholas J, Kini S, Milutinovic J, et al. Brain MR imaging abnormalities in kidney transplant recipients. AJNR Am J Neuroradiol 2005;26:2282-9.
  8. Coley SC, Porter DA, Calamante F, Chong WK, Connelly A. Quantitative MR diffusion mapping and cyclosporine-induced neurotoxicity. AJNR Am J Neuroradiol 1999;20:1507-10.
  9. Schwartz RB, Bravo SM, Klufas RA, Hsu L, Barnes PD, Robson CD, et al. Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 1995;165:627-31. https://doi.org/10.2214/ajr.165.3.7645483
  10. Oh YL, Han SY, Mun KH, Choi HJ, Kim HY, Hwang EA, et al. Cyclosporine-induced apoptosis in osteosarcoma cells. Transplant Proc 2006;38:2237-9. https://doi.org/10.1016/j.transproceed.2006.06.025
  11. Han SY, Chang EJ, Choi HJ, Nam SI, Lee NH, Kwak CS, et al. Total antioxidant status and oxygen free radicals during hepatic regeneration. Transplant Proc 2006;38:2214-5. https://doi.org/10.1016/j.transproceed.2006.07.017
  12. Hoorn EJ, Walsh SB, McCormick JA, Zietse R, Unwin RJ, Ellison DH. Pathogenesis of calcineurin inhibitor-induced hypertension. J Nephrol 2012;25:269-75. https://doi.org/10.5301/jn.5000174
  13. Chakkera HA, Mandarino LJ. Calcineurin inhibition and new-onset diabetes mellitus after transplantation. Transplantation 2013;95:647-52. https://doi.org/10.1097/TP.0b013e31826e592e
  14. Rosendal F, Bjarkam CR, Larsen M, Hansen HE, Madsen M, Sorensen JC, et al. Does chronic low-dose treatment with cyclosporine influence the brain? A histopathological study in pigs. Transplant Proc 2005;37:3305-8. https://doi.org/10.1016/j.transproceed.2005.09.015
  15. Kiemeneij IM, de Leeuw FE, Ramos LM, van Gijn J. Acute headache as a presenting symptom of tacrolimus encephalopathy. J Neurol Neurosurg Psychiatry 2003;74:1126-7. https://doi.org/10.1136/jnnp.74.8.1126
  16. Thompson CB, June CH, Sullivan KM, Thomas ED. Association between cyclosporin neurotoxicity and hypomagnesaemia. Lancet 1984;2:1116-20.
  17. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol 1999;246:339-46. https://doi.org/10.1007/s004150050360
  18. Kou R, Greif D, Michel T. Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. J Biol Chem 2002;277:29669-73. https://doi.org/10.1074/jbc.M204519200
  19. Han SY, Mun KC, Choi HJ, Kwak CS, Bae JH, Suh SI, et al. Effects of cyclosporine and tacrolimus on the oxidative stress in cultured mesangial cells. Transplant Proc 2006;38:2240-1. https://doi.org/10.1016/j.transproceed.2006.06.078
  20. Jang YH, Lee YC, Park NH, Shin HY, Mun KC, Choi MS, et al. Polyphenol (-)-epigallocatechin gallate protection from ischemia/reperfusion-induced renal injury in normotensive and hypertensive rats. Transplant Proc 2006;38:2190-4. https://doi.org/10.1016/j.transproceed.2006.06.101
  21. Folbergrova J, Li PA, Uchino H, Smith ML, Siesjo BK. Changes in the bioenergetic state of rat hippocampus during 2.5 min of ischemia, and prevention of cell damage by cyclosporin A in hyperglycemic subjects. Exp Brain Res 1997;114:44-50. https://doi.org/10.1007/PL00005622
  22. Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta 1998;1366:211-23. https://doi.org/10.1016/S0005-2728(98)00114-5