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タクロリムスによる神経毒性の発現メカニズムの解明と予防薬の探索

張, イ WEI, ZHANG チョウ, イ 九州大学

2022.03.23

概要

Background
Calcineurin inhibitors (CNIs), including tacrolimus, are widely used as immunosuppressants in transplantation therapy and dramatically improve patient survival. However, apart from their benefits, neurological adverse events caused by CNIs are one of the major problems encountered in clinical practice. Common symptoms of CNI-related neurotoxicity include tremor or headache in mild cases and posterior reversible encephalopathy syndrome in severe cases. Although CNI dose reduction may relieve tremors, mild symptoms might still be experienced, negatively affecting patients’ quality of life. Moreover, dose reduction also increases the risk of rejection of transplanted organs, and it is preferable to prevent tremor while maintaining the therapeutic intensity of CNIs.
Although the mechanism of CNI-induced neurotoxicity has not yet been elucidated, several studies have reported and discussed these adverse events. First, CNIs are usually restricted from entering the brain through the blood–brain barrier (BBB); however, previous studies have shown that CNIs disrupt BBB function by inducing nitric oxide synthesis and increasing transforming growth factor-β1 levels in brain endothelial cells and pericytes, respectively. Moreover, CNIs transported into the brain directly influence the neurons. CNIs suppress brain-derived neurotrophic factor and tyrosine kinase receptor B expression in the rat brain, which play vital roles in neurogenesis, cell survival, and regulation of synaptic plasticity. However, the part of the brain which is damaged after CNIs are transported to the brain remains unclear. Additionally, there are no potential protective agents against these adverse events in clinical settings.
Therefore, the aims of this study are to investigate the pathological mechanisms of tacrolimus-induced neurotoxicity and explore potential neuroprotective drugs for this neurotoxicity.

Methods and Results
Chapter 1 Tacrolimus-induced cell damage in cultured SH-SY5Y cells and investigation for potential drugs
In order to explore potential drugs to protect against tacrolimus-induced neurotoxicity, I investigated tacrolimus toxicity in vitro by using SH-SY5Y cells and then sought drugs that protect against tacrolimus-induced cell death.The results revealed that treatment with tacrolimus decreased the cell viability in a concentration- dependent and time-dependent manner. Western blot analysis showed that the ratio of both cleaved poly ADP-ribose polymerase (PARP)/PARP and cleaved caspase 3/caspase 3 protein expression remarkably increased 3 h after tacrolimus (40 µM) treatment. Moreover, the percentage of Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells increased significantly at 3 and 6 h after its treatment. Combined with the result that superoxide dismutase (SOD) activity was considerably increased 3 h after tacrolimus treatment, suggesting that an imbalance of reactive oxygen species and antioxidant properties correlates with tacrolimus-related neurotoxicity. Five compounds [N-acetylcysteine (NAC), glutathione (GSH), MK801, cilnidipine, and ibudilast] were used to investigate their possible protective effects against tacrolimus-induced cell damage. Only ibudilast (100 µM) significantly suppressed both the decrease in cell viability and the increase in the expression level of cleaved PARP/PARP by tacrolimus. Thus, ibudilast exhibited protective effects against tacrolimus-induced cell damage in vitro. Next, I studied whether ibudilast showed protective effect against tacrolimus-induced neurotoxicity in rats.

Chapter 2 Protective effect of ibudilast on tacrolimus-induced neurotoxicity in a rat model
In this chapter, I investigated whether tacrolimus induced neurotoxicity in rats and whether ibudilast could be a protective agent against this neurotoxicity. I found that rats treated with tacrolimus (2.5 mg/kg) showed no chronic neurotoxic behavior until day 15, whereas those treated with tacrolimus (5.0 mg/kg) showed a significant increase in the neurotoxicity score on days 8 and 15. Moreover, tacrolimus concentrations in rat brains with neurotoxic symptoms were significantly higher than those in rat brains without neurotoxic symptoms. Histopathological studies revealed that tacrolimus penetrated the brain and caused neurotoxic events by damaging the cerebral cortex and CA1 area of the hippocampus. Co-administration of ibudilast significantly ameliorated tacrolimus-induced neurotoxic behavior and neuronal damage in the cerebral cortex and hippocampal CA1 regions (Figure 1). On the other hand, the brain/blood tacrolimus concentration ratio in the tacrolimus + ibudilast group was not different from that in the tacrolimus group.

Discussion
In Chapter 1, tacrolimus induced cell damage in cultured SH-SY5Y cells by activating the PARP and caspase 3 pathways. The increase of SOD activity at 3 h, accompanied with the activation of PARP and caspase 3, suggesting that an imbalance of the reactive oxygen species and antioxidant properties correlateswith tacrolimus-induced cell death. However, NAC, GSH, cilnidipine, and MK801 did not prevent tacrolimus-induced cell death. On the other hand, ibudilast, a clinically available nonselective phosphodiesterase inhibitor, suppressed both the decrease in cell viability and the increase in the expression level of cleaved PARP/PARP by tacrolimus. In Chapter 2, I successfully demonstrated that ibudilast had a protective effect against tacrolimus-induced neurotoxicity in a rat model. As ibudilast did not affect the translocation of tacrolimus into the brain, the mechanism is anticipated to be based on its protective effect on neuronal cells. In conclusion, this study demonstrated that tacrolimus caused dose-dependent neuronal cell death in the cerebral cortex and hippocampal CA1 region. Ibudilast showed a protective effect on both pathological neuronal death and neurotoxic behavior without affecting the transfer of tacrolimus into the brain.

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参考文献

1. Verghese, P. S., Pediatric kidney transplantation: a historical review. Pediatr Res 2017, 81, (1-2), 259-264.

2. Tolou-Ghamari, Z., Nephro and neurotoxicity of calcineurin inhibitors and mechanisms of rejections: A review on tacrolimus and cyclosporin in organ transplantation. J Nephropathol 2012, 1, (1), 23-30.

3. Thaunat, O.; Koenig, A.; Leibler, C.; Grimbert, P., Effect of Immunosuppressive Drugs on Humoral Allosensitization after Kidney Transplant. J Am Soc Nephrol 2016, 27, (7), 1890-900.

4. Mayer, A. D.; Dmitrewski, J.; Squifflet, J. P.; Besse, T.; Grabensee, B.; Klein, B.; Eigler, F. W.; Heemann, U.; Pichlmayr, R.; Behrend, M.; Vanrenterghem, Y.; Donck, J.; van Hooff, J.; Christiaans, M.; Morales, J. M.; Andres, A.; Johnson, R. W.; Short, C.; Buchholz, B.; Rehmert, N.; Land, W.; Schleibner, S.; Forsythe, J. L.; Talbot, D.; Pohanka, E.; et al., Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997, 64, (3), 436-43.

5. Kramer, B. K.; Montagnino, G.; Kruger, B.; Margreiter, R.; Olbricht, C. J.; Marcen, R.; Sester, U.; Kunzendorf, U.; Dietl, K. H.; Rigotti, P.; Ronco, C.; Horsch, S.; Banas, B.; Muhlbacher, F.; Arias, M.; European Tacrolimus versus Ciclosporin Microemulsion Renal Transplantation Study, G., Efficacy and safety of tacrolimus compared with ciclosporin-A in renal transplantation: 7-year observational results. Transpl Int 2016, 29, (3), 307-14.

6. Mazariegos, G. V.; Molmenti, E. P.; Kramer, D. J., Early complications after orthotopic liver transplantation. Surg Clin North Am 1999, 79, (1), 109-29.

7. Ardizzone, G.; Arrigo, A.; Schellino, M. M.; Stratta, C.; Valzan, S.; Skurzak, S.; Andruetto, P.; Panio, A.; Ballaris, M. A.; Lavezzo, B.; Salizzoni, M.; Cerutti, E., Neurological complications of liver cirrhosis and orthotopic liver transplant. Transplant Proc 2006, 38, (3), 789-92.

8. Ponticelli, C.; Campise, M. R., Neurological complications in kidney transplant recipients. J Nephrol 2005, 18, (5), 521-8.

9. Ocal, R.; Kibaroglu, S.; Derle, E.; Tanoglu, C.; Camkiran, A.; Pirat, A.; Can, U.; Sezgin, A., Neurologic Complications After Cardiac Transplant. Exp Clin Transplant 2016.

10. Dowling, M. R.; Li, S.; Dey, B. R.; McAfee, S. L.; Hock, H. R.; Spitzer, T. R.; Chen, Y. B.; Ballen, K. K., Neurologic complications after allogeneic hematopoietic stem cell transplantation: risk factors and impact. Bone Marrow Transplant 2018, 53, (2), 199-206.

11. Campagna, F.; Biancardi, A.; Cillo, U.; Gatta, A.; Amodio, P., Neurocognitive- neurological complications of liver transplantation: a review. Metab Brain Dis 2010, 25, (1), 115-24.

12. Veroux, P.; Veroux, M.; Puliatti, C.; Morale, W.; Cappello, D.; Valvo, M.; Macarone, M., Tacrolimus-induced neurotoxicity in kidney transplant recipients. Transplant Proc 2002, 34, (8), 3188-90.

13. Henry, M. L., Cyclosporine and tacrolimus (FK506): a comparison of efficacy and safety profiles. Clin Transplant 1999, 13, (3), 209-20.

14. Eidelman, B. H.; Abu-Elmagd, K.; Wilson, J.; Fung, J. J.; Alessiani, M.; Jain, A.; Takaya, S.; Todo, S. N.; Tzakis, A.; Van Thiel, D.; et al., Neurologic complications of FK 506. Transplant Proc 1991, 23, (6), 3175-8.

15. Wijdicks, E. F., Neurotoxicity of immunosuppressive drugs. Liver Transpl 2001, 7, (11), 937-42.

16. Erro, R.; Bacchin, R.; Magrinelli, F.; Tomei, P.; Geroin, C.; Squintani, G.; Lupo, A.; Zaza, G.; Tinazzi, M., Tremor induced by Calcineurin inhibitor immunosuppression: a single-centre observational study in kidney transplanted patients. J Neurol 2018, 265, (7), 1676-1683.

17. Zivkovic, S. A.; Abdel-Hamid, H., Neurologic manifestations of transplant complications. Neurol Clin 2010, 28, (1), 235-51.

18. Zhang, W.; Egashira, N.; Masuda, S., Recent Topics on The Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities. Int J Mol Sci 2019, 20, (13).

19. Steg, R. E.; Kessinger, A.; Wszolek, Z. K., Cortical blindness and seizures in a patient receiving FK506 after bone marrow transplantation. Bone Marrow Transplant 1999, 23, (9), 959-62.

20. Hodnett, P.; Coyle, J.; O'Regan, K.; Maher, M. M.; Fanning, N., PRES (posterior reversible encephalopathy syndrome), a rare complication of tacrolimus therapy. Emerg Radiol 2009, 16, (6), 493-6.

21. Kiemeneij, I. M.; de Leeuw, F. E.; Ramos, L. M.; van Gijn, J., Acute headache as a presenting symptom of tacrolimus encephalopathy. J Neurol Neurosurg Psychiatry 2003, 74, (8), 1126-7.

22. Lee, V. H.; Wijdicks, E. F.; Manno, E. M.; Rabinstein, A. A., Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol 2008, 65, (2),205-10.

23. Wu, Q.; Marescaux, C.; Wolff, V.; Jeung, M. Y.; Kessler, R.; Lauer, V.; Chen, Y., Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur Neurol 2010, 64, (3), 169-77.

24. Cruz, R. J., Jr.; DiMartini, A.; Akhavanheidari, M.; Iacovoni, N.; Boardman, J. F.; Donaldson, J.; Humar, A.; Bartynski, W. S., Posterior reversible encephalopathy syndrome in liver transplant patients: clinical presentation, risk factors and initial management. Am J Transplant 2012, 12, (8), 2228-36.

25. Alexander, S.; David, V. G.; Varughese, S.; Tamilarasi, V.; Jacob, C. K., Posterior reversible encephalopathy syndrome in a renal allograft recipient: A complication of immunosuppression? Indian J Nephrol 2013, 23, (2), 137-9.

26. Singh, N.; Bonham, A.; Fukui, M., Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation 2000, 69, (4), 467-72.

27. Kumar, S.; Fowler, M.; Gonzalez-Toledo, E.; Jaffe, S. L., Central pontine myelinolysis, an update. Neurol Res 2006, 28, (3), 360-6.

28. de Groen, P. C.; Aksamit, A. J.; Rakela, J.; Forbes, G. S.; Krom, R. A., Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N Engl J Med 1987, 317, (14), 861-6.

29. Kusztal, M.; Piotrowski, P.; Mazanowska, O.; Misiak, B.; Kantorska-Janiec, M.; Boratynska, M.; Klinger, M.; Kiejna, A., Catatonic episode after kidney transplantation. Gen Hosp Psychiatry 2014, 36, (3), 360 e3-5.

30. Sierra-Hidalgo, F.; Martinez-Salio, A.; Moreno-Garcia, S.; de Pablo-Fernandez, E.; Correas-Callero, E.; Ruiz-Morales, J., Akinetic mutism induced by tacrolimus. Clin Neuropharmacol 2009, 32, (5), 293-4.

31. Bottiger, Y.; Brattstrom, C.; Tyden, G.; Sawe, J.; Groth, C. G., Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients. Br J Clin Pharmacol 1999, 48, (3), 445-8.

32. Jin, B.; Kim, G. Y.; Cheon, S. M., Tacrolimus-induced neurotoxicity from bipolar disorder to status epilepticus under the therapeutic serum level: a case report. BMC Neurol 2021, 21, (1), 448.

33. Saner, F. H.; Sotiropoulos, G. C.; Gu, Y.; Paul, A.; Radtke, A.; Gensicke, J.; Kavuk, I.; Malago, M.; Broelsch, C. E., Severe neurological events following liver transplantation. Arch Med Res 2007, 38, (1), 75-9.

34. Lauerma, A. I.; Surber, C.; Maibach, H. I., Absorption of topical tacrolimus (FK506) in vitro through human skin: comparison with cyclosporin A. Skin Pharmacol 1997, 10, (5-6), 230-4.

35. Tanaka, K.; Hirai, M.; Tanigawara, Y.; Yasuhara, M.; Hori, R.; Ueda, K.; Inui, K., Effect of cyclosporin analogues and FK506 on transcellular transport of daunorubicin and vinblastine via P-glycoprotein. Pharm Res 1996, 13, (7), 1073-7.

36. Kochi, S.; Takanaga, H.; Matsuo, H.; Ohtani, H.; Naito, M.; Tsuruo, T.; Sawada, Y., Induction of apoptosis in mouse brain capillary endothelial cells by cyclosporin A and tacrolimus. Life Sci 2000, 66, (23), 2255-60.

37. Dohgu, S.; Yamauchi, A.; Nakagawa, S.; Takata, F.; Kai, M.; Egawa, T.; Naito, M.; Tsuruo, T.; Sawada, Y.; Niwa, M.; Kataoka, Y., Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in cocultures of mouse brain endothelial cells and rat astrocytes. Eur J Pharmacol 2004, 505, (1- 3), 51-9. 38. Kochi, S.; Takanaga, H.; Matsuo, H.; Naito, M.; Tsuruo, T.; Sawada, Y., Effect of cyclosporin A or tacrolimus on the function of blood-brain barrier cells. Eur J Pharmacol 1999, 372, (3), 287-95.

39. Fabulas-da Costa, A.; Aijjou, R.; Hachani, J.; Landry, C.; Cecchelli, R.; Culot, M., In vitro blood-brain barrier model adapted to repeated-dose toxicological screening. Toxicol In Vitro 2013, 27, (6), 1944-53.

40. Bellwon, P.; Culot, M.; Wilmes, A.; Schmidt, T.; Zurich, M. G.; Schultz, L.; Schmal, O.; Gramowski-Voss, A.; Weiss, D. G.; Jennings, P.; Bal-Price, A.; Testai, E.; Dekant, W., Cyclosporine A kinetics in brain cell cultures and its potential of crossing the blood-brain barrier. Toxicol In Vitro 2015, 30, (1 Pt A), 166-75.

41. Schultz, L.; Zurich, M. G.; Culot, M.; da Costa, A.; Landry, C.; Bellwon, P.; Kristl, T.; Hormann, K.; Ruzek, S.; Aiche, S.; Reinert, K.; Bielow, C.; Gosselet, F.; Cecchelli, R.; Huber, C. G.; Schroeder, O. H.; Gramowski-Voss, A.; Weiss, D. G.; Bal-Price, A., Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models. Toxicol In Vitro 2015, 30, (1 Pt A), 138-65.

42. Illsinger, S.; Goken, C.; Brockmann, M.; Thiemann, I.; Bednarczyk, J.; Schmidt, K. H.; Lucke, T.; Hoy, L.; Janzen, N.; Das, A., Effect of tacrolimus on energy metabolism in human umbilical endothelial cells. Ann Transplant 2011, 16, (2), 68-75.

43. Palacin, M.; Coto, E.; Llobet, L.; Pacheu-Grau, D.; Montoya, J.; Ruiz-Pesini, E., FK506 affects mitochondrial protein synthesis and oxygen consumption in human cells. Cell Biol Toxicol 2013, 29, (6), 407-14.

44. Zini, R.; Simon, N.; Morin, C.; Thiault, L.; Tillement, J. P., Tacrolimus decreases in vitro oxidative phosphorylation of mitochondria from rat forebrain. Life Sci 1998, 63, (5), 357-68.

45. Jin, K. B.; Choi, H. J.; Kim, H. T.; Hwang, E. A.; Suh, S. I.; Han, S. Y.; Nam, S. I.; Park, S. B.; Kim, H. C.; Ha, E. Y.; Mun, K. C., The production of reactive oxygen species in tacrolimus-treated glial cells. Transplant Proc 2008, 40, (8), 2680-1.

46. Jin, K. B.; Hwang, E. A.; Han, S. Y.; Park, S. B.; Kim, H. C.; Ha, E. Y.; Suh, S. I.; Mun, K. C., Effects of tacrolimus on antioxidant status and oxidative stress in glioma cells. Transplant Proc 2008, 40, (8), 2740-1.

47. Asai, A.; Qiu, J.; Narita, Y.; Chi, S.; Saito, N.; Shinoura, N.; Hamada, H.; Kuchino, Y.; Kirino, T., High level calcineurin activity predisposes neuronal cells to apoptosis. J Biol Chem 1999, 274, (48), 34450-8.

48. Baumgartel, K.; Mansuy, I. M., Neural functions of calcineurin in synaptic plasticity and memory. Learn Mem 2012, 19, (9), 375-84.

49. Dumont, F. J., FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem 2000, 7, (7), 731-48.

50. De Weerdt, A.; Claeys, K. G.; De Jonghe, P.; Ysebaert, D.; Chapelle, T.; Roeyen, G.; Jorens, P. G., Tacrolimus-related polyneuropathy: case report and review of the literature. Clin Neurol Neurosurg 2008, 110, (3), 291-4.

51. Xu, X.; Su, B.; Barndt, R. J.; Chen, H.; Xin, H.; Yan, G.; Chen, L.; Cheng, D.; Heitman, J.; Zhuang, Y.; Fleischer, S.; Shou, W., FKBP12 is the only FK506 binding protein mediating T-cell inhibition by the immunosuppressant FK506. Transplantation 2002, 73, (11), 1835-8.

52. Lyons, W. E.; Steiner, J. P.; Snyder, S. H.; Dawson, T. M., Neuronal regeneration enhances the expression of the immunophilin FKBP-12. J Neurosci 1995, 15, (4), 2985-94.

53. Steiner, J. P.; Dawson, T. M.; Fotuhi, M.; Glatt, C. E.; Snowman, A. M.; Cohen, N.; Snyder, S. H., High brain densities of the immunophilin FKBP colocalized with calcineurin. Nature 1992, 358, (6387), 584-7.

54. Yokogawa, K.; Takahashi, M.; Tamai, I.; Konishi, H.; Nomura, M.; Moritani, S.; Miyamoto, K.; Tsuji, A., P-glycoprotein-dependent disposition kinetics of tacrolimus: studies in mdr1a knockout mice. Pharm Res 1999, 16, (8), 1213-8.

55. Yu, J. J.; Zhang, Y.; Wang, Y.; Wen, Z. Y.; Liu, X. H.; Qin, J.; Yang, J. L., Inhibition of calcineurin in the prefrontal cortex induced depressive-like behavior through mTOR signaling pathway. Psychopharmacology (Berl) 2013, 225, (2), 361-72.

56. Wang, Y.; Ge, Y. H.; Wang, Y. X.; Liu, T.; Law, P. Y.; Loh, H. H.; Chen, H. Z.; Qiu, Y., Modulation of mTOR Activity by mu-Opioid Receptor is Dependent upon the Association of Receptor and FK506-Binding Protein 12. CNS Neurosci Ther 2015, 21, (7), 591-8.

57. Ayas, M.; Al-Jefri, A.; Al-Seraihi, A., In cyclosporine induced neurotoxicity, is tacrolimus an appropriate substitute or is it out of the frying pan and into the fire? Pediatr Blood Cancer 2008, 50, (2), 426; author reply 427.

58. Chang, G. Y.; Saadi, A.; Schmahmann, J. D., Pearls & Oy-sters: Tacrolimus neurotoxicity presenting as an isolated brainstem lesion. Neurology 2016, 87, (13), 1423.

59. Arnold, R.; Pussell, B. A.; Pianta, T. J.; Lin, C. S.; Kiernan, M. C.; Krishnan, A. V., Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients. Am J Transplant 2013, 13, (9), 2426-32.

60. Serkova, N. J.; Christians, U.; Benet, L. Z., Biochemical mechanisms of cyclosporine neurotoxicity. Mol Interv 2004, 4, (2), 97-107.

61. Chen, C. C.; Hsu, L. W.; Huang, L. T.; Huang, T. L., Chronic administration of cyclosporine A changes expression of BDNF and TrkB in rat hippocampus and midbrain. Neurochem Res 2010, 35, (7), 1098-104.

62. Taylor, A. L.; Watson, C. J.; Bradley, J. A., Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005, 56, (1), 23-46.

63. Wijdicks, E. F.; Wiesner, R. H.; Dahlke, L. J.; Krom, R. A., FK506-induced neurotoxicity in liver transplantation. Ann Neurol 1994, 35, (4), 498-501.

64. Mueller, A. R.; Platz, K. P.; Bechstein, W. O.; Schattenfroh, N.; Stoltenburg- Didinger, G.; Blumhardt, G.; Christe, W.; Neuhaus, P., Neurotoxicity after orthotopic liver transplantation. A comparison between cyclosporine and FK506. Transplantation 1994, 58, (2), 155-70.

65. Csere, P.; Lill, R.; Kispal, G., Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p. FEBS Lett 1998, 441, (2), 266-70.

66. Chaudhary, R. K.; Dhakal, P.; Aryal, A.; Bhatt, V. R., Central nervous system complications after allogeneic hematopoietic stem cell transplantation. Future Oncol 2017, 13, (25), 2297-2312.

67. Morgan, J. C.; Kurek, J. A.; Davis, J. L.; Sethi, K. D., Insights into Pathophysiology from Medication-induced Tremor. Tremor Other Hyperkinet Mov (N Y) 2017, 7, 442-452.

68. McDonald, J. W.; Goldberg, M. P.; Gwag, B. J.; Chi, S. I.; Choi, D. W., Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures. Ann Neurol 1996, 40, (5), 750-8.

69. Brat, D. J.; Windebank, A. J.; Brimijoin, S., Emulsifier for intravenous cyclosporin inhibits neurite outgrowth, causes deficits in rapid axonal transport and leads to structural abnormalities in differentiating N1E.115 neuroblastoma. J Pharmacol Exp Ther 1992, 261, (2), 803-10.

70. Bavarsad Shahripour, R.; Harrigan, M. R.; Alexandrov, A. V., N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain Behav 2014, 4, (2), 108-22.

71. Ooi, S. L.; Green, R.; Pak, S. C., N-Acetylcysteine for the Treatment of Psychiatric Disorders: A Review of Current Evidence. Biomed Res Int 2018, 2018, 2469486.

72. Neuwelt, E. A.; Pagel, M. A.; Hasler, B. P.; Deloughery, T. G.; Muldoon, L. L., Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model. Cancer Res 2001, 61, (21), 7868-74.

73. Farr, S. A.; Poon, H. F.; Dogrukol-Ak, D.; Drake, J.; Banks, W. A.; Eyerman, E.; Butterfield, D. A.; Morley, J. E., The antioxidants alpha-lipoic acid and N- acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 2003, 84, (5), 1173-83.

74. Ross, E. K.; Gray, J. J.; Winter, A. N.; Linseman, D. A., Immunocal(R) and preservation of glutathione as a novel neuroprotective strategy for degenerative disorders of the nervous system. Recent Pat CNS Drug Discov 2012, 7, (3), 230-5.

75. Kovacic, P.; Somanathan, R., Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity. Oxid Med Cell Longev 2010, 3, (1), 13-22.

76. Gill, R.; Brazell, C.; Woodruff, G. N.; Kemp, J. A., The neuroprotective action of dizocilpine (MK-801) in the rat middle cerebral artery occlusion model of focal ischaemia. Br J Pharmacol 1991, 103, (4), 2030-6.

77. Hatfield, R. H.; Gill, R.; Brazell, C., The dose-response relationship and therapeutic window for dizocilpine (MK-801) in a rat focal ischaemia model. Eur J Pharmacol 1992, 216, (1), 1-7.

78. Takeda, K.; Yamagishi, R.; Masumiya, H.; Tanaka, H.; Shigenobu, K., Effect of cilnidipine on L- and T-type calcium currents in guinea pig ventricle and action potential in rabbit sinoatrial node. J Pharmacol Sci 2004, 95, (3), 398-401.

79. Yano, K.; Takimoto, S.; Motegi, T.; Tomono, T.; Hagiwara, M.; Idota, Y.; Morimoto, K.; Takahara, A.; Ogihara, T., Role of P-glycoprotein in regulating cilnidipine distribution to intact and ischemic brain. Drug Metab Pharmacokinet 2014, 29, (3), 254-8.

80. Takahara, A.; Konda, T.; Enomoto, A.; Kondo, N., Neuroprotective effects of a dual L/N-type Ca(2+) channel blocker cilnidipine in the rat focal brain ischemia model. Biol Pharm Bull 2004, 27, (9), 1388-91.

81. Takizawa, S.; Matsushima, K.; Fujita, H.; Nanri, K.; Ogawa, S.; Shinohara, Y., A selective N-type calcium channel antagonist reduces extracellular glutamate release and infarct volume in focal cerebral ischemia. J Cereb Blood Flow Metab 1995, 15, (4), 611-8.

82. Lu, C. W.; Lin, T. Y.; Huang, S. K.; Wang, S. J., Inhibition of glutamate release by cilnidipine in rat cerebrocortical nerve terminals (synaptosomes). Neuroreport 2017, 28, (9), 527-532.

83. Kishi, Y.; Ohta, S.; Kasuya, N.; Sakita, S.; Ashikaga, T.; Isobe, M., Ibudilast: a non-selective PDE inhibitor with multiple actions on blood cells and the vascular wall. Cardiovasc Drug Rev 2001, 19, (3), 215-25.

84. Rolan, P.; Hutchinson, M.; Johnson, K., Ibudilast: a review of its pharmacology, efficacy and safety in respiratory and neurological disease. Expert Opin Pharmacother 2009, 10, (17), 2897-904.

85. Egashira, N.; Goto, Y.; Takahashi, R.; Iba, H.; Yamamoto, S.; Watanabe, T.; Kubota, K.; Kawashiri, T.; Taniguchi, C.; Katsurabayashi, S.; Iwasaki, K., Ibudilast suppresses oxaliplatin-induced mechanical allodynia and neurodegeneration in rats. J Pharmacol Sci 2021, 147, (1), 114-117.

86. Fujita, M.; Tamano, R.; Yoneda, S.; Omachi, S.; Yogo, E.; Rokushima, M.; Shinohara, S.; Sakaguchi, G.; Hasegawa, M.; Asaki, T., Ibudilast produces anti- allodynic effects at the persistent phase of peripheral or central neuropathic pain in rats: Different inhibitory mechanism on spinal microglia from minocycline and propentofylline. Eur J Pharmacol 2018, 833, 263-274.

87. Mosieniak, G.; Figiel, I.; Kaminska, B., Cyclosporin A, an immunosuppressive drug, induces programmed cell death in rat C6 glioma cells by a mechanism that involves the AP-1 transcription factor. J Neurochem 1997, 68, (3), 1142-9.

88. Tominaga., Y.; Nakamura., Y.; Tsuji., K.; Shibata., T.; Kataoka., K., Ibudilast protects against neuronal damage induced by glutamate in cultured hippocampal neurons. Clin Exp Pharmacol Physiol 1996, 23, (6-7), 519-23.

89. Yanase, H.; Mitani, A.; Kataoka, K., Ibudilast reduces intracellular calcium elevation induced by in vitro ischaemia in gerbil hippocampal slices. Clin Exp Pharmacol Physiol 1996, 23, (4), 317-24.

90. Mizuno, T.; Kurotani, T.; Komatsu, Y.; Kawanokuchi, J.; Kato, H.; Mitsuma, N.; Suzumura, A., Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. Neuropharmacology 2004, 46, (3), 404-11.

91. Dohgu, S.; Nishioku, T.; Sumi, N.; Takata, F.; Nakagawa, S.; Naito, M.; Tsuruo, T.; Yamauchi, A.; Shuto, H.; Kataoka, Y., Adverse effect of cyclosporin A on barrier functions of cerebral microvascular endothelial cells after hypoxia- reoxygenation damage in vitro. Cell Mol Neurobiol 2007, 27, (7), 889-99.

92. Sakamoto, Y.; Makuuchi, M.; Harihara, Y.; Imamura, H.; Sato, H., Correlation between neurotoxic events and intracerebral concentration of tacrolimus in rats. Biol Pharm Bull 2000, 23, (8), 1008-10.

93. Tanaka, T.; Takeda, M.; Niigawa, H.; Hariguchi, S.; Nishimura, T., Phosphorylated neurofilament accumulation in neuronal perikarya by cyclosporin A injection in rat brain. Methods Find Exp Clin Pharmacol 1993, 15, (2), 77-87.

94. Famiglio, L.; Racusen, L.; Fivush, B.; Solez, K.; Fisher, R., Central nervous system toxicity of cyclosporine in a rat model. Transplantation 1989, 48, (2), 316-21.

95. Fu, R.; Tajima, S.; Shigematsu, T.; Zhang, M.; Tsuchimoto, A.; Egashira, N.; Ieiri, I.; Masuda, S., Establishment of an experimental rat model of tacrolimus-induced kidney injury accompanied by interstitial fibrosis. Toxicol Lett 2021, 341, 43-50.

96. Kishi, Y.; Ohta, S.; Kasuya, N.; Tatsumi, M.; Sawada, M.; Sakita, S.; Ashikaga, T.; Numano, F., Ibudilast modulates platelet-endothelium interaction mainly through cyclic GMP-dependent mechanism. J Cardiovasc Pharmacol 2000, 36, (1), 65-70.

97. Goodman, A. D.; Gyang, T.; Smith, A. D., 3rd, Ibudilast for the treatment of multiple sclerosis. Expert Opin Investig Drugs 2016, 25, (10), 1231-7.

98. Suzumura, A.; Ito, A.; Yoshikawa, M.; Sawada, M., Ibudilast suppresses TNF alpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS. Brain Res 1999, 837, (1-2), 203-12.

99. Suzumura, A.; Ito, A.; Mizuno, T., Phosphodiesterase inhibitors suppress IL-12 production with microglia and T helper 1 development. Mult Scler 2003, 9, (6), 574-8.

100. Kiebala, M.; Maggirwar, S. B., Ibudilast, a pharmacologic phosphodiesterase inhibitor, prevents human immunodeficiency virus-1 Tat-mediated activation of microglial cells. PLoS One 2011, 6, (4), e18633.

101. Takuma, K.; Lee, E.; Enomoto, R.; Mori, K.; Baba, A.; Matsuda, T., Ibudilast attenuates astrocyte apoptosis via cyclic GMP signalling pathway in an in vitro reperfusion model. Br J Pharmacol 2001, 133, (6), 841-8.

102. Wakita, H.; Tomimoto, H.; Akiguchi, I.; Lin, J. X.; Ihara, M.; Ohtani, R.; Shibata, M., Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat. Brain Res 2003, 992, (1), 53-9.

103. Lilius, T. O.; Rauhala, P. V.; Kambur, O.; Kalso, E. A., Modulation of morphine- induced antinociception in acute and chronic opioid treatment by ibudilast. Anesthesiology 2009, 111, (6), 1356-64.

104. Hutchinson, M. R.; Lewis, S. S.; Coats, B. D.; Skyba, D. A.; Crysdale, N. Y.; Berkelhammer, D. L.; Brzeski, A.; Northcutt, A.; Vietz, C. M.; Judd, C. M.; Maier, S. F.; Watkins, L. R.; Johnson, K. W., Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain Behav Immun 2009, 23, (2), 240-50.

105. Fujimoto, T.; Sakoda, S.; Fujimura, H.; Yanagihara, T., Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. J Neuroimmunol 1999, 95, (1-2), 35-42.

106. Ledeboer, A.; Hutchinson, M. R.; Watkins, L. R.; Johnson, K. W., Ibudilast (AV- 411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opin Investig Drugs 2007, 16, (7), 935-50.

107. Sanftner, L. M.; Gibbons, J. A.; Gross, M. I.; Suzuki, B. M.; Gaeta, F. C.; Johnson, K. W., Cross-species comparisons of the pharmacokinetics of ibudilast. Xenobiotica 2009, 39, (12), 964-77.

108. Kershner, R. P.; Fitzsimmons, W. E., Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation 1996, 62, (7), 920-6.

109. Yamauchi, A.; Ieiri, I.; Kataoka, Y.; Tanabe, M.; Nishizaki, T.; Oishi, R.; Higuchi, S.; Otsubo, K.; Sugimachi, K., Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002, 74, (4), 571-2.

110. Tanabe, M.; Ieiri, I.; Nagata, N.; Inoue, K.; Ito, S.; Kanamori, Y.; Takahashi, M.; Kurata, Y.; Kigawa, J.; Higuchi, S.; Terakawa, N.; Otsubo, K., Expression of P- glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 2001, 297, (3), 1137-43.

111. Goto, S.; Matsukado, Y.; Mihara, Y.; Inoue, N.; Miyamoto, E., The Distribution of Calcineurin in Rat Brain by Light and Electron Microscopic Immunohistochemistry and Enzyme-Immunoassay Brain Res 1986, 397, (1), 161- 172.

112. Wallace., R. W.; Tallant., E. A.; Cheung., W. Y., High levels of a heat-labile calmodulin-binding protein (CaM-BP80) in bovine neostriatum. Biochemistry 1980, 19, (9), 1831-7.

113. Morioka, M.; Nagahiro, S.; Fukunaga, K.; Miyamoto, E.; Ushio, Y., Calcineurin in the adult rat hippocampus: different distribution in CA1 and CA3 subfields. Neuroscience 1997, 78, (3), 673-84.

114. Nishiyama, K.; Numaga-Tomita, T.; Fujimoto, Y.; Tanaka, T.; Toyama, C.; Nishimura, A.; Yamashita, T.; Matsunaga, N.; Koyanagi, S.; Azuma, Y. T.; Ibuki, Y.; Uchida, K.; Ohdo, S.; Nishida, M., Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes. Br J Pharmacol 2019, 176, (18), 3723-3738.

115. Watanabe, T.; Zhang, N.; Liu, M.; Tanaka, R.; Mizuno, Y.; Urabe, T., Cilostazol protects against brain white matter damage and cognitive impairment in a rat model of chronic cerebral hypoperfusion. Stroke 2006, 37, (6), 1539-45.

116. Ye, Y. L.; Shi, W. Z.; Zhang, W. P.; Wang, M. L.; Zhou, Y.; Fang, S. H.; Liu, L. Y.; Zhang, Q.; Yu, Y. P.; Wei, E. Q., Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries. Eur J Pharmacol 2007, 557, (1), 23-31.

117. Li, Q.; Peng, Y.; Fan, L.; Xu, H.; He, P.; Cao, S.; Li, J.; Chen, T.; Ruan, W.; Chen, G., Phosphodiesterase-4 inhibition confers a neuroprotective efficacy against early brain injury following experimental subarachnoid hemorrhage in rats by attenuating neuronal apoptosis through the SIRT1/Akt pathway. Biomed Pharmacother 2018, 99, 947-955.

118. Thakur, T.; Sharma, S.; Kumar, K.; Deshmukh, R.; Sharma, P. L., Neuroprotective role of PDE4 and PDE5 inhibitors in 3-nitropropionic acid induced behavioral and biochemical toxicities in rats. Eur J Pharmacol 2013, 714, (1-3), 515-21.

119. Brunet, M.; van Gelder, T.; Asberg, A.; Haufroid, V.; Hesselink, D. A.; Langman, L.; Lemaitre, F.; Marquet, P.; Seger, C.; Shipkova, M.; Vinks, A.; Wallemacq, P.; Wieland, E.; Woillard, J. B.; Barten, M. J.; Budde, K.; Colom, H.; Dieterlen, M. T.; Elens, L.; Johnson-Davis, K. L.; Kunicki, P. K.; MacPhee, I.; Masuda, S.; Mathew, B. S.; Millan, O.; Mizuno, T.; Moes, D. A. R.; Monchaud, C.; Noceti, O.; Pawinski, T.; Picard, N.; van Schaik, R.; Sommerer, C.; Vethe, N. T.; de Winter, B.; Christians, U.; Bergan, S., Therapeutic Drug Monitoring of Tacrolimus- Personalized Therapy: Second Consensus Report. Ther Drug Monit 2019, 41, (3), 261-307.

120. Hammerstrom, A. E.; Howell, J.; Gulbis, A.; Rondon, G.; Champlin, R. E.; Popat, U., Tacrolimus-associated posterior reversible encephalopathy syndrome in hematopoietic allogeneic stem cell transplantation. Am J Hematol 2013, 88, (4), 301-5.

121. Wong, R.; Beguelin, G. Z.; de Lima, M.; Giralt, S. A.; Hosing, C.; Ippoliti, C.; Forman, A. D.; Kumar, A. J.; Champlin, R.; Couriel, D., Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2003, 122, (1), 128-34.

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