Skip to main content
SpringerLink
Log in

Neuroprotective action of FK-506 (tacrolimus) after seizures induced with pilocarpine: quantitative and topographic elemental analysis of brain tissue

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

In the present work, X-ray fluorescence microscopy with a synchrotron source for the exciting radiation was applied for topographic and quantitative elemental analysis of rat brain tissue in pilocarpine-induced epilepsy and neuroprotection with FK-506. The mass per unit area of the elements P, S, Cl, K, Ca, Fe, Cu, Zn, Se, Br, and Rb was determined in four fields of the hippocampal formation (sectors 1 and 3 of Ammon’s horn–CA1, CA3; dentate gyrus; hilus of dentate gyrus) and the parietal cortex. The results obtained for epileptic rats treated with FK-506 (SNF) were compared with data obtained previously for epileptic rats (SNS) and a control group. Many statistically significant differences in elemental composition were observed between the SNF and SNS groups. Higher mass per unit area of P was noticed in CA1 and CA3 regions of the hippocampus of SNF rats in comparison with SNS rats. A similar relation was observed for K in all five brain areas analyzed. Also, Fe in CA3 and dentate gyrus, Cu in the parietal cortex, and Zn in CA3 and in the cortex were present at a higher level in the SNF group in comparison with the SNS group. The findings obtained in the present study suggest that the neuroprotective action of FK-506 in epileptic rat brain may involve not only the inhibition of calcineurin but also blockade of the K+ channels.

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

Similar content being viewed by others

References

  1. Loscher W (1997) Animal models of intractable epilepsy. Prog Neurobiol 53:239–258

    Article  CAS  PubMed  Google Scholar 

  2. Turski WA, Cavalheiro EA, Bortolotto ZA, Mello LM, Schwarz M, Turski L (1985) Seizures produced by pilocarpine in mice: a behavioral, electroencephalographic and morphological analysis. Brain Res 12:237–253

    Google Scholar 

  3. Covolan L, Mello LE (2000) Temporal profile of neuronal injury following pilocarpine or kainic acid-induced status epilepticus. Epilepsy Res 39:133–152

    Article  CAS  PubMed  Google Scholar 

  4. Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA (1989) Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse 3:154–171

    Article  CAS  PubMed  Google Scholar 

  5. Fujikawa DG (1996) The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Res 24:11–22

    Google Scholar 

  6. Bartynski WS, Zeigler Z, Spearman MP, Lin L, Shadduck RK, Lister J (2001) Etiology of cortical and white matter lesions in cyclosporin-A and FK-506 neurotoxicity. Am J Neuroradiol 22:1901–1914

    CAS  PubMed  Google Scholar 

  7. Uchino H, Minamikawa-Tachino R, Kristián T, Perkins G, Narazaki M, Siesjö BK, Shibasaki F (2002) Differential neuroprotection by cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition. Neurobiol Dis 10:219–223

    Article  CAS  PubMed  Google Scholar 

  8. Furuichi Y, Maeda M, Moriguchi A, Sawamoto T, Kawamura A, Matsuoka N, Mutoh S, Yanagihara T (2003) Tacrolimus, a potential neuroprotective agent, ameliorates ischemic brain damage and neurologic deficits after focal cerebral ischemia in nonhuman primates. J Cereb Blood Flow Metab 23:1183–1194

    Article  CAS  PubMed  Google Scholar 

  9. Setkowicz Z, Ciarach M (2007) Neuroprotectants FK-506 and cyclosporin A ameliorate the course of pilocarpine-induced seizures. Epilepsy Res 73:151–155

    Article  CAS  PubMed  Google Scholar 

  10. Chwiej J, Winiarski W, Ciarach M, Janeczko K, Lankosz M, Rickers K, Setkowicz Z (2008) The role of trace elements in the pathogenesis and progress of pilocarpine-induced epileptic seizures. J Biol Inorg Chem 13:1267–1274

    Article  CAS  PubMed  Google Scholar 

  11. Adams F, Janssens K, Snigirev A (1998) Microscopic X-ray fluorescence analysis and related methods with laboratory and synchrotron radiation sources. J Anal At Spectrom 13:319–331

    Article  CAS  Google Scholar 

  12. Janssens KH, Rindby A, Adams F (2000) Microscopic X-ray fluorescence analysis. Wiley, Chichester

    Google Scholar 

  13. Snigireva I, Snigirev A (2006) X-ray microanalytical techniques based on synchrotron radiation. J Environ Monit 8:33–42

    Article  CAS  PubMed  Google Scholar 

  14. Lankosz M, Holynska B, Pella PA (1993) Experimental verification of a Monte Carlo method for X-ray microfluorescence analysis of small particles. Xray Spectrom 22:54–57

    Article  CAS  Google Scholar 

  15. Setkowicz Z, Ciarach M, Guzik R, Janeczko K (2004) Different effects of neuroprotectants FK-506 and cyclosporin A on susceptibility to pilocarpine-induced seizures in rats with brain injured at different developmental stages. Epilepsy Res 61:63–72

    Article  CAS  PubMed  Google Scholar 

  16. Paxinos G, Watson C (1989) The rat brain in stereotaxic coordinates. Academic Press, Australia

    Google Scholar 

  17. Ralle M, Lutsenko S (2009) Quantitative imaging of metals and tissues. Biometals 22:197–205

    Article  CAS  PubMed  Google Scholar 

  18. Paunescu T, Vogt S, Maser J, Lai B, Woloschak G (2006) X-ray fluorescence microprobe imaging in biology and medicine. J Cell Biochem 99:1489–1502

    Article  Google Scholar 

  19. Fahrni CJ (2007) Biological applications of X-ray fluorescence microscopy: exploring the subcellular topography and speciation of transition metals. Curr Opin Chem Biol 11:121–127

    Article  CAS  PubMed  Google Scholar 

  20. Arii T, Kamiya T, Arii K, Ueda M, Nito C, Katsura KI, Katayama Y (2001) Neuroprotective effect of immunosuppressant FK506 in transient focal ischemia in rat: therapeutic time window for FK506 in transient focal ischemia. Neurol Res 23:755–760

    Article  CAS  PubMed  Google Scholar 

  21. Furuichi Y, Katsuta K, Maeda M, Ueyama N, Moriguchi A, Matsuoka N, Goto T, Yanagihara T (2003) Neuroprotective action of tacrolimus (FK506) in focal and global cerebral ischemia in rodents: dose dependency, therapeutic time window and long-term efficacy. Brain Res 965:137–145

    Article  CAS  PubMed  Google Scholar 

  22. Butscher SP, Henshall DC, Teramura Y, Iwasaki K, Sharkey J (1997) Neuroprotective actions of FK506 in experimental stroke: in vivo evidence against an antiexcitotoxic mechanism. J Neurosci 17:6939–6946

    Google Scholar 

  23. Toung TJ, Bhardway A, Dawson VL, Dawson TM, Trystman RJ, Hurn PD (1999) Neuroprotective FK506 does not alter in vivo nitric oxide production during ischemia and early reperfusion in rats. Stroke 30:1279–1285

    CAS  PubMed  Google Scholar 

  24. Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (1991) Calcineurin is a common target of cyclophilin–cyclosporin A and FKBP–FK506 complexes. Cell 66:807–815

    Article  CAS  PubMed  Google Scholar 

  25. Yakel JL (1997) Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription. Trends Pharmacol Sci 18:124–134

    Article  CAS  PubMed  Google Scholar 

  26. Klee CB, Ren H, Wang X (1998) Regulation of the calmodulin stimulated protein phosphatase, calcineurin. J Biol Chem 273:13367–13370

    Article  CAS  PubMed  Google Scholar 

  27. Hemenway CS, Heitman J (1999) Calcineurin: structure, function inhibition. Cell Biochem Biophys 30:115–151

    Article  CAS  PubMed  Google Scholar 

  28. Yu L, Haddy A, Rusnak F (1995) Evidence that calcineurin accommodates an active site binuclear center. J Am Chem Soc 117:10147–10734

    Article  CAS  Google Scholar 

  29. Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, Navia MA (1995) X-ray structure of calcineurin inhibited by the immunophilin–immunosuppressant FKBP12–FK506 complex. Cell 82:507–522

    Article  CAS  PubMed  Google Scholar 

  30. Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk CT, Kalish VJ, Tucker KD, Showalter RE, Moomow EW, Gastinel LN, Habuka N, Chen X, Maldonado F, Barker JE, Bacquet R, Villafranca JE (1995) Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex. Nature 378:641–644

    Article  CAS  PubMed  Google Scholar 

  31. Yu L, Golbeck J, Yao J, Rusnak F (1997) Spectroscopic and enzymatic characterization of the active site dinuclear metal center of calcineurin: implications for a mechanistic role. Biochemistry 36:10727–10734

    Article  CAS  PubMed  Google Scholar 

  32. Lieberman DN, Mody I (1994) Regulation of NMDA channel function by endogenous Ca(2+)-dependent phosphatase. Nature 369:235–239

    Article  CAS  PubMed  Google Scholar 

  33. Norris CM, Blalock EM, Chen KC, Porter NM, Landfield PW (2002) Calcineurin enhances L-type Ca(2+) channel activity in hippocampal neurons: increased effect with age in culture. Neuroscience 110:213–225

    Article  CAS  PubMed  Google Scholar 

  34. Terashima A, Nakai M, Hashimoto T, Kawamata T, Taniguchi T, Yasuda M, Maeda K, Tanaka C (1998) Single-channel activity of the Ca2+-dependent K+ channel is modulated by FK506 and rapamycin. Brain Res 786:255–258

    Article  CAS  PubMed  Google Scholar 

  35. Yu Y, Chen XQ, Cui YY, Hu GY (2007) Calcineurin-independent inhibition of the delayed rectifier K+ current by the immunosuppressant FK506 in rat hippocampal neurons. Brain Res 1148:62–68

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The research leading to these results received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 226716. This work was also supported by the Polish Ministry of Science and Higher Education and the following grants: 82/N-IA-SFS/2007/0, DESY-D-I-20070053 EC, DESY-D-II-20080009 EC, and N404 029 31/1636. J.C. is also grateful for support from the Foundation for Polish Science (Start Programme).

Author information

Authors and Affiliations

  1. Department of Applied Nuclear Methods, Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Kraków, Poland

    Joanna Chwiej, Marianna Marciszko & Mateusz Czyzycki

  2. Department of Neuroanatomy, Institute of Zoology, Jagiellonian University, Kraków, Poland

    Krzysztof Janeczko & Zuzanna Setkowicz

  3. Deutsches Elektronen-Synchrotron (DESY), Hamburg, Germany

    Karen Rickers

Authors
  1. Joanna Chwiej
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krzysztof Janeczko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marianna Marciszko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mateusz Czyzycki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karen Rickers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zuzanna Setkowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joanna Chwiej.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chwiej, J., Janeczko, K., Marciszko, M. et al. Neuroprotective action of FK-506 (tacrolimus) after seizures induced with pilocarpine: quantitative and topographic elemental analysis of brain tissue. J Biol Inorg Chem 15, 283–289 (2010). https://doi.org/10.1007/s00775-009-0597-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-009-0597-2

Keywords

Search

Navigation