Advertisement

Molecular Neurobiology

, Volume 48, Issue 3, pp 921–930 | Cite as

The Imbalanced Expression of Adenosine Receptors in an Epilepsy Model Corrected Using Targeted Mesenchymal Stem Cell Transplantation

  • Kang Huicong
  • Xue Zheng
  • Wang Furong
  • Tang Zhouping
  • Xu Feng
  • Hu Qi
  • Liu Xiaoyan
  • Huang Xiaojiang
  • Zhang Na
  • Xu Ke
  • Zeng Zheng
  • Zhu Suiqiang
Article

Abstract

Adenosine inhibits epileptic episodes by interacting with G-protein-coupled receptors. This study examined the mechanism by which the inhibitory effect of adenosine becomes impaired during epileptogenesis. Dynamic changes in adenosine A1 receptors (A1Rs) and A2a receptors (A2aRs) were investigated in a kindling model of epilepsy. RT-PCR, Western blotting, and immunofluorescence results indicated that expression of A1Rs was increased in the hippocampus 24 h after kindling, but progressively decreased 1 and 6 months after kindling. Opposite changes were seen in the expression of A2aRs. This bidirectional change resulted in an imbalance between A1Rs and A2aRs and dysregulation of the adenosine system. Autologous mesenchymal stem cell (MSC) transplantation was used to correct this disorder and avoid side effects of systematic adenosine therapy. Paramagnetic iron oxide particles were used to mark and track the MSCs in vivo using MRI. The results indicated that the transplanted cells migrated along the callosum and settled at the ependymal layer. The MSCs displayed a relatively long survival time, at least 3 months. The improved AR expression and EEG findings suggested that MSC transplantation was a potentially effective means of treating refractory epilepsy.

Keywords

Adenosine receptors Adenosine kinase Mesenchymal stem cells Epilepsy Transplantation 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81201006), Natural Science Foundation of Hubei Province (2011CDB201) and Science and Technology Research Plan Project of Wuhan City (201161038339-02).

Conflict of Interest

The authors declare that there were no conflicts of interest for any of the participating authors.

Supplementary material

12035_2013_8480_MOESM1_ESM.doc (94 kb)
ESM 1 (DOC 94 kb)

References

  1. 1.
    Boison D (2007) Adenosine as a modulator of brain activity. Drug News Perspect 20:607–611PubMedCrossRefGoogle Scholar
  2. 2.
    Gouder N, Fritschy JM, Boison D (2003) Seizure suppression by adenosine A1 receptor activation in a mouse model of pharmacoresistant epilepsy. Epilepsia 44:877–885PubMedCrossRefGoogle Scholar
  3. 3.
    Berman RF, Fredholm BB, Aden U, O’Connor WT (2000) Evidence for increased dorsal hippocampal adenosine release and metabolism during pharmacologically induced seizures in rats. Brain Res 872:44–53PubMedCrossRefGoogle Scholar
  4. 4.
    Sebastiao AM, Ribeiro JA (2009) Adenosine receptors and the central nervous system. Handb Exp Pharmacol 193:471–534PubMedCrossRefGoogle Scholar
  5. 5.
    Fredholm BB, Chen JF, Cunha RA, Svenningsson P, Vaugeois JM (2005) Adenosine and brain function. Int Rev Neurobiol 63:191–270PubMedCrossRefGoogle Scholar
  6. 6.
    Boison D, Chen JF, Fredholm BB (2010) Adenosine signalling and function in glial cells. Cell Death Differ 17:1071–1082PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Benarroch EE (2008) Adenosine and its receptors: multiple modulatory functions and potential therapeutic targets for neurologic disease. Neurology 70:231–236PubMedCrossRefGoogle Scholar
  8. 8.
    Xiang L, Huicong K, Xiaoyan L, Zhiguang L, Kai S, Chen X, Suiqiang Z (2012) Effect of adenosine A2A receptor antagonist ZM241385 on amygdala-kindled seizures and progression of amygdala kindling. J Huazhong Uni Sci Technol (Med Sci) 32:257–264CrossRefGoogle Scholar
  9. 9.
    Kang Huicong H, Qi LX et al (2009) The dynamic feature of adenosine receptors imbalance during kindling by lithium chloride–pilocarpine. Chin J Neurol 42:185–189Google Scholar
  10. 10.
    Seo J, Jung S, Lee SY, Yang H, Kim BS, Choi J, Bang M, Shin HS, Jeon D (2013) Early deficits in social behavior and cortical rhythms in pilocarpine-induced mouse model of temporal lobe epilepsy. Exp Neurol 241:38–44PubMedCrossRefGoogle Scholar
  11. 11.
    Glass M, Faull RLM, Bullock JY, Jansen K, Mee EW, Walker EB, Synek BJL, Dragunow M (1996) Loss of A1 adenosine receptors in human temporal lobe epilepsy. Brain Res 710:56–68PubMedCrossRefGoogle Scholar
  12. 12.
    Nelson R, Joana EC, Ana RC, Luisa VL, Antonio P, Catarina RO, Patricio SS, Alexandre M, Rodrigo AC (2003) Decrease of adenosine A1 receptor density and of adenosine neuromodulation in the hippocampus of kindled rats. Eur J Neurosci 18:820–828CrossRefGoogle Scholar
  13. 13.
    Pagonopoulou O, Efthimiadou A, Asimakopoulos B, Nikolettos NK (2006) Modulatory role of adenosine and its receptors in epilepsy: possible therapeutic approaches. Neurosci Res 56:14–20PubMedCrossRefGoogle Scholar
  14. 14.
    Pagonopoulou O, Angelatou F (1998) Time development and regional distribution of [3H] nitrobenzylthioinosine adenosine uptake sites binding in the mouse brain after acute pentylenetetrazol-induced seizures. J Neurosci Res 53:433–442PubMedCrossRefGoogle Scholar
  15. 15.
    Nelson R, Lisiane OP, Luísa VL, Catarina RO, Patrício S, Rodrigo AC (2005) Long-term effect of convulsive behavior on the density of adenosine A1 and A2A receptors in the rat cerebral cortex. Epilepsia 46(suppl 5):159–165Google Scholar
  16. 16.
    Vanore G, Giraldez L, Rodriguez LA, Girardi E (2001) Seizure activity produces differential changes in adenosine A1 receptors within rat hippocampus. Neurochem Res 26:225–230PubMedCrossRefGoogle Scholar
  17. 17.
    Wetherington JP, Lambert NA (2002) Differential desensitisation of responses mediated by presynaptic and postsynaptic A1 adenosine receptors. J Neurosci 22:1248–1255PubMedGoogle Scholar
  18. 18.
    Vianna EP, Ferreira AT, Doná F, Cavalheiro EA, da Silva Fernandes MJ (2005) Modulation of seizures and synaptic plasticity by adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats. Epilepsia 46(Suppl 5):166–173PubMedCrossRefGoogle Scholar
  19. 19.
    During MJ, Spencer DD (1992) Adenosine—a potential mediator of seizure arrest and postictal refractoriness. Ann Neurol 32:618–624PubMedCrossRefGoogle Scholar
  20. 20.
    Dunwiddie TV (1999) Adenosine and suppression of seizures. Adv Neurol 79:1001–1010PubMedGoogle Scholar
  21. 21.
    Güttinger M, Padrun V, Pralong WF, Boison D (2005) Seizure suppression and lack of adenosine A1 receptor desensitization after focal long-term delivery of adenosine by encapsulated myoblasts. Exp Neurol 193:53–64PubMedCrossRefGoogle Scholar
  22. 22.
    Ren G, Li T, Lan JQ, Wilz A, Simon RP, Boison D (2007) Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: a novel perspective for seizure control. Exp Neurol 208:26–37PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Güttinger M, Fedele D, Koch P, Padrun V, Pralong WF, Brüstle O, Boison D (2005) Suppression of kindled seizures by paracrine adenosine release from stem cell-derived brain implants. Epilepsia 46:1162–1169PubMedCrossRefGoogle Scholar
  24. 24.
    Rebola N, Coelho JE, Costenla AR, Lopes LV, Parada A, Oliveira CR, Soares-da-Silva P, de Mendonca A, Cunha RA (2003) Decrease of adenosine A1 receptor density and of adenosine neuromodulation in the hippocampus of kindled rats. Eur J Neurosci 18:820–828PubMedCrossRefGoogle Scholar
  25. 25.
    Güttinger M, Padrun V, Pralong WF, Boison D (2005) Seizure suppression and lack of adenosine A1 receptor desensitization after focal long-term delivery of adenosine by encapsulated myoblasts. Exp Neurol 193:53–64PubMedCrossRefGoogle Scholar
  26. 26.
    Dunwiddie TV, Diao L, Kim HO, Jiang JL, Jacobson KA (1997) Activation of hippocampal adenosine a3 receptors produces a desensitization of A1 receptor-mediated responses in rat hippocampus. J Neurosci 17:607–614PubMedGoogle Scholar
  27. 27.
    Takigawa T, Alzheimer C (2002) Phasic and tonic attenuation of epilepsy by inward rectifier K+ channels in rat hippocampal pyramidal cells. J Physiol 539:67–75PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Kang Huicong
    • 1
  • Xue Zheng
    • 1
  • Wang Furong
    • 1
  • Tang Zhouping
    • 1
  • Xu Feng
    • 1
  • Hu Qi
    • 1
  • Liu Xiaoyan
    • 1
  • Huang Xiaojiang
    • 1
  • Zhang Na
    • 1
  • Xu Ke
    • 1
  • Zeng Zheng
    • 1
  • Zhu Suiqiang
    • 1
  1. 1.Department of Neurology, Tongji Hospital Affiliated to Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations