Yeungnam Univ J Med.  2019 May;36(2):105-108. 10.12701/yujm.2019.00108.

Impact of calcineurin inhibitors on rat glioma cells viability

Affiliations
  • 1Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea. mdjin922@gmail.com
  • 2Keimyung University Kidney Institute, Keimyung University School of Medicine, Daegu, Korea.
  • 3Department of Biochemistry, Keimyung University School of Medicine, Daegu, Korea.

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℃ 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.

Keyword

Calcineurin inhibitors; Glioma cell; Kidney transplantation; Neurotoxicity

MeSH Terms

Animals
Brain
Calcineurin Inhibitors*
Calcineurin*
Cell Survival
Cyclosporine
Glioma*
Humans
Kidney
Kidney Transplantation
Neurologic Manifestations
Rats*
Tacrolimus
Calcineurin
Calcineurin Inhibitors
Cyclosporine
Tacrolimus

Figure

  • Fig. 1. Comparison of morphological changes and cell viability in glioma cells according to the concentration of cyclosporine or tacrolimus by DMi1 inverted microscopic examination. (A) 0 mM/L cyclosporine, (B) 0 mM/L tacrolimus, (C) 0.25 mM/L cyclosporine, (D) 0.25 mM/L tacrolimus, (E) 0.5 mM/L cyclosporine, (F) 0.5 mM/L tacrolimus, (G) 2.5 mM/L cyclosporine, (H) 2.5 mM/L tacrolimus, (I) 5.0 mM/L cyclosporine, (J) 5.0 mM/L tacrolimus, (K) 10.0 mM/L, and (L) 10.0 mM/L tacrolimus (original magnification, ×400).


Reference

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.
Article
2. Malvezzi P, Rostaing L. The safety of calcineurin inhibitors for kidney-transplant patients. Expert Opin Drug Saf. 2015; 14:1531–46.
Article
3. Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol. 2003; 23:465–76.
Article
4. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009; 4:481–508.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
13. Chakkera HA, Mandarino LJ. Calcineurin inhibition and new-onset diabetes mellitus after transplantation. Transplantation. 2013; 95:647–52.
Article
14. Rosendal F, Bjarkam CR, Larsen M, Hansen HE, Madsen M, Sørensen JC, et al. Does chronic low-dose treatment with cyclosporine influence the brain? A histopathological study in pigs. Transplant Proc. 2005; 37:3305–8.
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.
Article
16. Thompson CB, June CH, Sullivan KM, Thomas ED. Association between cyclosporin neurotoxicity and hypomagnesaemia. Lancet. 1984; 2:1116–20.
Article
17. Gijtenbeek JM, van den Bent MJ, Vecht CJ. Cyclosporine neurotoxicity: a review. J Neurol. 1999; 246:339–46.
Article
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.
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.
Article
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.
Article
21. Folbergrová J, Li PA, Uchino H, Smith ML, Siesjö 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.
Article
22. Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. Biochim Biophys Acta. 1998; 1366:211–23.
Article
Full Text Links
  • YUJM
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr