Skip to main content

Advertisement

SpringerLink
Log in

Tacrolimus Decreases Cognitive Function by Impairing Hippocampal Synaptic Balance: a Possible Role of Klotho

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The influence of long-term tacrolimus treatment on cognitive function remains to be elucidated. Using a murine model of chronic tacrolimus neurotoxicity, we evaluated the effects of tacrolimus on cognitive function, synaptic balance, its regulating protein (Klotho), and oxidative stress in the hippocampus. Compared to vehicle-treated mice, tacrolimus-treated mice showed significantly decreased hippocampal-dependent spatial learning and memory function. Furthermore, tacrolimus caused synaptic imbalance, as demonstrated by decreased excitatory synapses and increased inhibitory synapses, and downregulated Klotho in a dose-dependent manner; the downregulation of Klotho was localized to excitatory hippocampal synapses. Moreover, tacrolimus increased oxidative stress and was associated with activation of the PI3K/AKT pathway in the hippocampus. These results indicate that tacrolimus impairs cognitive function via synaptic imbalance, and that these processes are associated with Klotho downregulation at synapses through tacrolimus-induced oxidative stress in the hippocampus.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

Abbreviations

BM:

Barnes maze

CNI:

Calcineurin inhibitor

DAB:

3,3-Diaminobenzidine tetrahydrochloride

DAPI:

4,6-Diamidino-2-phenylindole

OFT:

Open field test

PSD:

Postsynaptic density

RT-qPCR:

Reverse transcription quantitative polymerase chain reaction

TAC:

Tacrolimus

VH:

Vehicle

References

  1. Zivkovic S (2007) Neuroimaging and neurologic complications after organ transplantation. J Neuroimaging 17:110–123. https://doi.org/10.1111/j.1552-6569.2007.00097.x

    Article  PubMed  Google Scholar 

  2. Zivkovic SA, Abdel-Hamid H (2010) Neurologic manifestations of transplant complications. Neurol Clin 28:235–251. https://doi.org/10.1016/j.ncl.2009.09.011

    Article  PubMed  Google Scholar 

  3. Gijtenbeek JM, van den Bent MJ, Vecht CJ (1999) Cyclosporine neurotoxicity: a review. J Neurol 246:339–346. https://doi.org/10.1007/s004150050360

    Article  CAS  PubMed  Google Scholar 

  4. Clipstone NA, Crabtree GR (1992) Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357:695–697. https://doi.org/10.1038/357695a0

    Article  CAS  PubMed  Google Scholar 

  5. Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR (1989) Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science 246:1617–1620. https://doi.org/10.1126/science.2595372

    Article  CAS  PubMed  Google Scholar 

  6. Fischer G, Wittmann-Liebold B, Lang K, Kiefhaber T, Schmid FX (1989) Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337:476–478. https://doi.org/10.1038/337476a0

    Article  CAS  PubMed  Google Scholar 

  7. Flanagan WM, Corthesy B, Bram RJ, Crabtree GR (1991) Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352:803–807. https://doi.org/10.1038/352803a0

    Article  CAS  PubMed  Google Scholar 

  8. Harding MW, Galat A, Uehling DE, Schreiber SL (1989) A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 341:758–760. https://doi.org/10.1038/341758a0

    Article  CAS  PubMed  Google Scholar 

  9. Jain J, McCaffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL, Curran T, Rao A (1993) The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 365:352–355. https://doi.org/10.1038/365352a0

    Article  CAS  PubMed  Google Scholar 

  10. O’Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O’Neill EA (1992) FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature 357:692–694. https://doi.org/10.1038/357692a0

    Article  CAS  PubMed  Google Scholar 

  11. Shaw KT, Ho AM, Raghavan A, Kim J, Jain J, Park J, Sharma S, Rao A et al (1995) Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci U S A 92:11205–11209. https://doi.org/10.1073/pnas.92.24.11205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Siekierka JJ, Hung SH, Poe M, Lin CS, Sigal NH (1989) A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341:755–757. https://doi.org/10.1038/341755a0

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi N, Hayano T, Suzuki M (1989) Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin. Nature 337:473–475. https://doi.org/10.1038/337473a0

    Article  CAS  PubMed  Google Scholar 

  14. Tolou-Ghamari Z (2012) Nephro and neurotoxicity of calcineurin inhibitors and mechanisms of rejections: a review on tacrolimus and cyclosporin in organ transplantation. J Nephropathol 1:23–30. https://doi.org/10.5812/jnp.6

    Article  PubMed  PubMed Central  Google Scholar 

  15. Eichenbaum H, Otto T, Cohen NJ (1992) The hippocampus–what does it do? Behav Neural Biol 57:2–36. https://doi.org/10.1016/0163-1047(92)90724-i

    Article  CAS  PubMed  Google Scholar 

  16. Olton DS, Walker JA, Gage FH (1978) Hippocampal connections and spatial discrimination. Brain Res 139:295–308. https://doi.org/10.1016/0006-8993(78)90930-7

    Article  CAS  PubMed  Google Scholar 

  17. Kennedy MB (2013) Synaptic signaling in learning and memory. Cold Spring Harb Perspect Biol 8:a016824. https://doi.org/10.1101/cshperspect.a016824

    Article  PubMed  Google Scholar 

  18. Yoon HE, Yang CW (2009) Established and newly proposed mechanisms of chronic cyclosporine nephropathy. Korean J Intern Med 24:81–92. https://doi.org/10.3904/kjim.2009.24.2.81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang X, Michaelis EK (2010) Selective neuronal vulnerability to oxidative stress in the brain. Front Aging Neurosci 2:12. https://doi.org/10.3389/fnagi.2010.00012

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M et al (1997) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51. https://doi.org/10.1038/36285

    Article  CAS  PubMed  Google Scholar 

  21. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H et al (2005) Suppression of aging in mice by the hormone Klotho. Science 309:1829–1833. https://doi.org/10.1126/science.1112766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Abraham CR, Mullen PC, Tucker-Zhou T, Chen CD, Zeldich E (2016) Klotho is a neuroprotective and cognition-enhancing protein. Vitam Horm 101:215–238. https://doi.org/10.1016/bs.vh.2016.02.004

    Article  CAS  PubMed  Google Scholar 

  23. Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y (2004) Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 565:143–147. https://doi.org/10.1016/j.febslet.2004.03.090

    Article  CAS  PubMed  Google Scholar 

  24. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, Obuse C, Togashi K et al (2007) alpha-Klotho as a regulator of calcium homeostasis. Science 316:1615–1618. https://doi.org/10.1126/science.1135901

    Article  CAS  PubMed  Google Scholar 

  25. Li SA, Watanabe M, Yamada H, Nagai A, Kinuta M, Takei K (2004) Immunohistochemical localization of Klotho protein in brain, kidney, and reproductive organs of mice. Cell Struct Funct 29:91–99. https://doi.org/10.1247/csf.29.91

    Article  CAS  PubMed  Google Scholar 

  26. Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG (2005) The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 310:490–493. https://doi.org/10.1126/science.1114245

    Article  CAS  PubMed  Google Scholar 

  27. Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, Moe OW (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124–136. https://doi.org/10.1681/ASN.2009121311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hu MC, Shi M, Zhang J, Quinones H, Kuro-o M, Moe OW (2010) Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective. Kidney Int 78:1240–1251. https://doi.org/10.1038/ki.2010.328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S et al (2006) Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 281:6120–6123. https://doi.org/10.1074/jbc.C500457200

    Article  CAS  PubMed  Google Scholar 

  30. Kumata C, Mizobuchi M, Ogata H, Koiwa F, Nakazawa A, Kondo F, Kadokura Y, Kinugasa E et al (2010) Involvement of alpha-klotho and fibroblast growth factor receptor in the development of secondary hyperparathyroidism. Am J Nephrol 31:230–238. https://doi.org/10.1159/000274483

    Article  CAS  PubMed  Google Scholar 

  31. Kurosu H, Kuro OM (2009) The Klotho gene family as a regulator of endocrine fibroblast growth factors. Mol Cell Endocrinol 299:72–78. https://doi.org/10.1016/j.mce.2008.10.052

    Article  CAS  PubMed  Google Scholar 

  32. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S et al (2006) Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444:770–774. https://doi.org/10.1038/nature05315

    Article  CAS  PubMed  Google Scholar 

  33. Clinton SM, Glover ME, Maltare A, Laszczyk AM, Mehi SJ, Simmons RK, King GD (2013) Expression of klotho mRNA and protein in rat brain parenchyma from early postnatal development into adulthood. Brain Res 1527:1–14. https://doi.org/10.1016/j.brainres.2013.06.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, Nabeshima T (2003) Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 17:50–52. https://doi.org/10.1096/fj.02-0448fje

    Article  CAS  PubMed  Google Scholar 

  35. Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D et al (2014) Life extension factor klotho enhances cognition. Cell Rep 7:1065–1076. https://doi.org/10.1016/j.celrep.2014.03.076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Semba RD, Moghekar AR, Hu J, Sun K, Turner R, Ferrucci L, O’Brien R (2014) Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci Lett 558:37–40. https://doi.org/10.1016/j.neulet.2013.10.058

    Article  CAS  PubMed  Google Scholar 

  37. Jin J, Jin L, Lim SW, Yang CW (2016) Klotho deficiency aggravates tacrolimus-induced renal injury via the phosphatidylinositol 3-kinase-Akt-forkhead box protein O pathway. Am J Nephrol 43:357–365. https://doi.org/10.1159/000446447

    Article  CAS  PubMed  Google Scholar 

  38. Lim SW, Jin L, Luo K, Jin J, Shin YJ, Hong SY, Yang CW (2017) Klotho enhances FoxO3-mediated manganese superoxide dismutase expression by negatively regulating PI3K/AKT pathway during tacrolimus-induced oxidative stress. Cell Death Dis 8:e2972. https://doi.org/10.1038/cddis.2017.365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu H, Miyoshi M, Ogawa Y et al (2005) Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 280:38029–38034. https://doi.org/10.1074/jbc.M509039200

    Article  CAS  PubMed  Google Scholar 

  40. Yoon HE, Ghee JY, Piao S, Song JH, Han DH, Kim S, Ohashi N, Kobori H et al (2011) Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant 26:800–813. https://doi.org/10.1093/ndt/gfq537

    Article  CAS  PubMed  Google Scholar 

  41. Yoon HE, Lim SW, Piao SG, Song JH, Kim J, Yang CW (2012) Statin upregulates the expression of klotho, an anti-aging gene, in experimental cyclosporine nephropathy. Nephron Exp Nephrol 120:e123-133. https://doi.org/10.1159/000342117

    Article  CAS  PubMed  Google Scholar 

  42. Doi S, Zou Y, Togao O, Pastor JV, John GB, Wang L, Shiizaki K, Gotschall R et al (2011) Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 286:8655–8665. https://doi.org/10.1074/jbc.M110.174037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ikushima M, Rakugi H, Ishikawa K, Maekawa Y, Yamamoto K, Ohta J, Chihara Y, Kida I et al (2006) Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun 339:827–832. https://doi.org/10.1016/j.bbrc.2005.11.094

    Article  CAS  PubMed  Google Scholar 

  44. Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II et al (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317:803–806. https://doi.org/10.1126/science.1143578

    Article  CAS  PubMed  Google Scholar 

  45. Choi H, Park HH, Koh SH, Choi NY, Yu HJ, Park J, Lee YJ, Lee KY (2012) Coenzyme Q10 protects against amyloid beta-induced neuronal cell death by inhibiting oxidative stress and activating the P13K pathway. Neurotoxicology 33:85–90. https://doi.org/10.1016/j.neuro.2011.12.005

    Article  CAS  PubMed  Google Scholar 

  46. Lee YJ, Park KH, Park HH, Kim YJ, Lee KY, Kim SH, Koh SH (2009) Cilnidipine mediates a neuroprotective effect by scavenging free radicals and activating the phosphatidylinositol 3-kinase pathway. J Neurochem 111:90–100. https://doi.org/10.1111/j.1471-4159.2009.06297.x

    Article  CAS  PubMed  Google Scholar 

  47. Wang S, Chong ZZ, Shang YC, Maiese K (2012) Wnt1 inducible signaling pathway protein 1 (WISP1) blocks neurodegeneration through phosphoinositide 3 kinase/Akt1 and apoptotic mitochondrial signaling involving Bad, Bax, Bim, and Bcl-xL. Curr Neurovasc Res 9:20–31. https://doi.org/10.2174/156720212799297137

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hwang H, Ghee JY, Song JH, Piao S, Yang CW (2012) Comparison of adverse drug reaction profiles of two tacrolimus formulations in rats. Immunopharmacol Immunotoxicol 34:434–442. https://doi.org/10.3109/08923973.2011.618135

    Article  CAS  PubMed  Google Scholar 

  49. Jin J, Lim SW, Jin L, Yu JH, Kim HS, Chung BH, Yang CW (2017) Effects of metformin on hyperglycemia in an experimental model of tacrolimus- and sirolimus-induced diabetic rats. Korean J Intern Med 32:314–322. https://doi.org/10.3904/kjim.2015.394

    Article  CAS  PubMed  Google Scholar 

  50. Jin L, Lim SW, Jin J, Luo K, Ko EJ, Chung BH, Lin HL, Yang CW (2018) Effect of conversion to CTLA4Ig on tacrolimus-induced diabetic rats. Transplantation 102:e137–e146. https://doi.org/10.1097/TP.0000000000002048

    Article  CAS  PubMed  Google Scholar 

  51. Shin YJ, Chun YT, Lim SW, Luo K, Quan Y, Cui S, Ko EJ, Chung BH et al (2019) Influence of tacrolimus on depressive-like behavior in diabetic rats through brain-derived neurotrophic factor regulation in the hippocampus. Neurotox Res 36:396–410. https://doi.org/10.1007/s12640-019-00062-6

    Article  CAS  PubMed  Google Scholar 

  52. Song HK, Han DH, Song JH, Ghee JY, Piao SG, Kim SH, Yoon HE, Li C et al (2009) Influence of sirolimus on cyclosporine-induced pancreas islet dysfunction in rats. Am J Transplant 9:2024–2033. https://doi.org/10.1111/j.1600-6143.2009.02751.x

    Article  CAS  PubMed  Google Scholar 

  53. Damian JP, Acosta V, Da Cuna M, Ramirez I, Oddone N, Zambrana A, Bervejillo V, Benech JC (2014) Effect of resveratrol on behavioral performance of streptozotocin-induced diabetic mice in anxiety tests. Exp Anim 63:277–287. https://doi.org/10.1538/expanim.63.277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lee B, Sur B, Yeom M, Shim I, Lee H, Hahm DH (2014) L-tetrahydropalmatine ameliorates development of anxiety and depression-related symptoms induced by single prolonged stress in rats. Biomol Ther (Seoul) 22:213–222. https://doi.org/10.4062/biomolther.2014.032

    Article  CAS  Google Scholar 

  55. Pompl PN, Mullan MJ, Bjugstad K, Arendash GW (1999) Adaptation of the circular platform spatial memory task for mice: use in detecting cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer’s disease. J Neurosci Methods 87:87–95. https://doi.org/10.1016/s0165-0270(98)00169-1

    Article  CAS  PubMed  Google Scholar 

  56. Riew TR, Kim HL, Choi JH, Jin X, Shin YJ, Lee MY (2017) Progressive accumulation of autofluorescent granules in macrophages in rat striatum after systemic 3-nitropropionic acid: a correlative light- and electron-microscopic study. Histochem Cell Biol 148:517–528. https://doi.org/10.1007/s00418-017-1589-x

    Article  CAS  PubMed  Google Scholar 

  57. Anderson JS, Carandini M, Ferster D (2000) Orientation tuning of input conductance, excitation, and inhibition in cat primary visual cortex. J Neurophysiol 84:909–926. https://doi.org/10.1152/jn.2000.84.2.909

    Article  CAS  PubMed  Google Scholar 

  58. Atallah BV, Scanziani M (2009) Instantaneous modulation of gamma oscillation frequency by balancing excitation with inhibition. Neuron 62:566–577. https://doi.org/10.1016/j.neuron.2009.04.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Cline H (2005) Synaptogenesis: a balancing act between excitation and inhibition. Curr Biol 15:R203-205. https://doi.org/10.1016/j.cub.2005.03.010

    Article  CAS  PubMed  Google Scholar 

  60. Iascone DM, Li Y, Sumbul U, Doron M, Chen H, Andreu V, Goudy F, Blockus H et al (2020) Whole-neuron synaptic mapping reveals spatially precise excitatory/inhibitory balance limiting dendritic and somatic spiking. Neuron 106:566-578 e568. https://doi.org/10.1016/j.neuron.2020.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Okun M, Lampl I (2008) Instantaneous correlation of excitation and inhibition during ongoing and sensory-evoked activities. Nat Neurosci 11:535–537. https://doi.org/10.1038/nn.2105

    Article  CAS  PubMed  Google Scholar 

  62. Wehr M, Zador AM (2003) Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex. Nature 426:442–446. https://doi.org/10.1038/nature02116

    Article  CAS  PubMed  Google Scholar 

  63. Degaspari S, Tzanno-Martins CB, Fujihara CK, Zatz R, Branco-Martins JP, Viel TA, Buck Hde S, Orellana AM et al (2015) Altered KLOTHO and NF-kappaB-TNF-alpha signaling are correlated with nephrectomy-induced cognitive impairment in rats. PLoS ONE 10:e0125271. https://doi.org/10.1371/journal.pone.0125271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Park SJ, Shin EJ, Min SS, An J, Li Z, Hee Chung Y, HoonJeong J, Bach JH et al (2013) Inactivation of JAK2/STAT3 signaling axis and downregulation of M1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging. Neuropsychopharmacology 38:1426–1437. https://doi.org/10.1038/npp.2013.39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li Q, Vo HT, Wang J, Fox-Quick S, Dobrunz LE, King GD (2017) Klotho regulates CA1 hippocampal synaptic plasticity. Neuroscience 347:123–133. https://doi.org/10.1016/j.neuroscience.2017.02.006

    Article  CAS  PubMed  Google Scholar 

  66. Honda T, Hirakawa Y, Nangaku M (2019) The role of oxidative stress and hypoxia in renal disease. Kidney Res Clin Pract 38:414–426. https://doi.org/10.23876/j.krcp.19.063

    Article  PubMed  PubMed Central  Google Scholar 

  67. Kokkinaki M, Abu-Asab M, Gunawardena N, Ahern G, Javidnia M, Young J, Golestaneh N (2013) Klotho regulates retinal pigment epithelial functions and protects against oxidative stress. J Neurosci 33:16346–16359. https://doi.org/10.1523/JNEUROSCI.0402-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kuro-o M (2011) Klotho and the aging process. Korean J Intern Med 26:113–122. https://doi.org/10.3904/kjim.2011.26.2.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rakugi H, Matsukawa N, Ishikawa K, Yang J, Imai M, Ikushima M, Maekawa Y, Kida I et al (2007) Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine 31:82–87. https://doi.org/10.1007/s12020-007-0016-9

    Article  CAS  PubMed  Google Scholar 

  70. Emerling BM, Weinberg F, Liu JL, Mak TW, Chandel NS (2008) PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc Natl Acad Sci U S A 105:2622–2627. https://doi.org/10.1073/pnas.0706790105

    Article  PubMed  PubMed Central  Google Scholar 

  71. Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unterman T, Hay N (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14:458–470. https://doi.org/10.1016/j.ccr.2008.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Los M, Maddika S, Erb B, Schulze-Osthoff K (2009) Switching Akt: from survival signaling to deadly response. BioEssays 31:492–495. https://doi.org/10.1002/bies.200900005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lu Q, Zhai Y, Cheng Q, Liu Y, Gao X, Zhang T, Wei Y, Zhang F et al (2013) The Akt-FoxO3a-manganese superoxide dismutase pathway is involved in the regulation of oxidative stress in diabetic nephropathy. Exp Physiol 98:934–945. https://doi.org/10.1113/expphysiol.2012.068361

    Article  CAS  PubMed  Google Scholar 

  74. Lijnen PJ, van Pelt JF, Fagard RH (2010) Downregulation of manganese superoxide dismutase by angiotensin II in cardiac fibroblasts of rats: association with oxidative stress in myocardium. Am J Hypertens 23:1128–1135. https://doi.org/10.1038/ajh.2010.128

    Article  CAS  PubMed  Google Scholar 

  75. McDonald JW, Goldberg MP, Gwag BJ, Chi SI, Choi DW (1996) Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures. Ann Neurol 40:750–758. https://doi.org/10.1002/ana.410400511

    Article  CAS  PubMed  Google Scholar 

  76. Stoltenburg-Didinger G, Boegner F (1992) Glia toxicity in dissociation cell cultures induced by cyclosporine. Neurotoxicology 13:179–184 (https://www.ncbi.nlm.nih.gov/pubmed/1324448)

    CAS  PubMed  Google Scholar 

  77. Jin KB, Choi HJ, Kim HT, Hwang EA, Suh SI, Han SY, Nam SI, Park SB et al (2008) The production of reactive oxygen species in tacrolimus-treated glial cells. Transplant Proc 40:2680–2681. https://doi.org/10.1016/j.transproceed.2008.08.033

    Article  CAS  PubMed  Google Scholar 

  78. Gold BG (1997) FK506 and the role of immunophilins in nerve regeneration. Mol Neurobiol 15:285–306. https://doi.org/10.1007/BF02740664

    Article  CAS  PubMed  Google Scholar 

  79. Sander M, Lyson T, Thomas GD, Victor RG (1996) Sympathetic neural mechanisms of cyclosporine-induced hypertension. Am J Hypertens 9:121S-138S. https://doi.org/10.1016/0895-7061(96)00288-9

    Article  CAS  PubMed  Google Scholar 

  80. Arnold R, Pussell BA, Pianta TJ, Lin CS, Kiernan MC, Krishnan AV (2013) Association between calcineurin inhibitor treatment and peripheral nerve dysfunction in renal transplant recipients. Am J Transplant 13:2426–2432. https://doi.org/10.1111/ajt.12324

    Article  CAS  PubMed  Google Scholar 

  81. DiMartini A, Crone C, Fireman M, Dew MA (2008) Psychiatric aspects of organ transplantation in critical care. Crit Care Clin 24:949–981. x.https://doi.org/10.1016/j.ccc.2008.05.001

    Article  PubMed  PubMed Central  Google Scholar 

  82. Grimm M, Yeganehfar W, Laufer G, Madl C, Kramer L, Eisenhuber E, Simon P, Kupilik N et al (1996) Cyclosporine may affect improvement of cognitive brain function after successful cardiac transplantation. Circulation 94:1339–1345. https://doi.org/10.1161/01.cir.94.6.1339

    Article  CAS  PubMed  Google Scholar 

  83. Griva K, Hansraj S, Thompson D, Jayasena D, Davenport A, Harrison M, Newman SP (2004) Neuropsychological performance after kidney transplantation: a comparison between transplant types and in relation to dialysis and normative data. Nephrol Dial Transplant 19:1866–1874. https://doi.org/10.1093/ndt/gfh141

    Article  PubMed  Google Scholar 

  84. Martinez-Sanchis S, Bernal MC, Montagud JV, Candela G, Crespo J, Sancho A, Pallardo LM (2011) Effects of immunosuppressive drugs on the cognitive functioning of renal transplant recipients: a pilot study. J Clin Exp Neuropsychol 33:1016–1024. https://doi.org/10.1080/13803395.2011.595396

    Article  PubMed  Google Scholar 

  85. Padovan CS, Yousry TA, Schleuning M, Holler E, Kolb HJ, Straube A (1998) Neurological and neuroradiological findings in long-term survivors of allogeneic bone marrow transplantation. Ann Neurol 43:627–633. https://doi.org/10.1002/ana.410430511

    Article  CAS  PubMed  Google Scholar 

  86. Scherwath A, Schirmer L, Kruse M, Ernst G, Eder M, Dinkel A, Kunze S, Balck F et al (2013) Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study. Psychooncology 22:1509–1516. https://doi.org/10.1002/pon.3159

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the administrative and research staff in the Transplantation Research Center, The College of Medicine, The Catholic University of Korea.

Funding

This work was supported by the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (HI14C3417), and the Basic Science Research Program through a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education (NRF-2018R1D1A1B07044219) and the Ministry of Science, ICT & Future Planning (NRF-2020R1A2C2012711).

Author information

Authors and Affiliations

  1. Convergent Research Consortium for Immunologic Disease, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Yoo Jin Shin, Sun Woo Lim, Sheng Cui, Eun Jeong Ko, Byung Ha Chung & Chul Woo Yang

  2. Transplant Research Center, The College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Yoo Jin Shin, Sun Woo Lim, Sheng Cui, Eun Jeong Ko, Byung Ha Chung & Chul Woo Yang

  3. Department of Internal Medicine, Division of Nephrology, Seoul St. Mary’s Hospital, The College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea

    Eun Jeong Ko, Byung Ha Chung & Chul Woo Yang

  4. Integrative Research Support Center, Laboratory of Electron Microscope, The College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Korea

    Hong Lim Kim

  5. Department of Anatomy, Catholic Neuroscience Institute, The College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Korea

    Tae Ryong Riew & Mun Yong Lee

Authors
  1. Yoo Jin Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sun Woo Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sheng Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eun Jeong Ko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Byung Ha Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong Lim Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tae Ryong Riew
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mun Yong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chul Woo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YJ Shin, SW Lim, and CW Yang designed the research and wrote the manuscript; YJ Shin and C Sheng conducted the animal experiments; EJ Ko, TR Riew, and HL Kim performed the histological experiments; YJ Shin, BH Chung, MY Lee, and CW Yang analyzed the data and edited the manuscript.

Corresponding author

Correspondence to Chul Woo Yang.

Ethics declarations

Ethics Approval and Consent to Participate

This study was approved by the Institutional Animal Care and Use Committee (IACUC) of the School of Medicine, Catholic University of Korea (CUMC-2020–0110-02). Consent to participate is not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, Y.J., Lim, S.W., Cui, S. et al. Tacrolimus Decreases Cognitive Function by Impairing Hippocampal Synaptic Balance: a Possible Role of Klotho. Mol Neurobiol 58, 5954–5970 (2021). https://doi.org/10.1007/s12035-021-02499-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-021-02499-3

Keywords

Search

Navigation