Skip to main content
Log in

Brain Protection Conferred by Long-Term Administration of 2-(2-Benzofuranyl)-2-Imidazoline Against Experimental Autoimmune Encephalomyelitis

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Our previous studies showed that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a ligand to type 2 imidazoline receptor, was protective against brain and spinal cord injury caused by experimental autoimmune encephalomyelitis (EAE). In the present study, we investigated the effect of long-term administration of 2-BFI and the dose-dependent response relationship of long-term administration of 2-BFI with neuroprotection. Treatment with 2-BFI at doses of 5, 10, and 20 mg/kg for 14 days significantly reduced hind limb paralysis and the severity of EAE compared with the EAE control group. Long-term use of 2-BFI was not only safe to mice, but also dose-dependently reduced the expression of inflammatory cytokines, including TNF-α, Interferon-γ and Interleukin-17A, compared with the EAE control group. Expressions of neuronal injury markers, including cytochrome c, AIF and β-APP, were also reduced significantly in response to long-term 2-BFI treatment. Together, these results provided new evidence to demonstrate that 2-BFI is a safe and effective candidate for further development as a therapeutic drug for treatment of multiple sclerosis.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Aranami T, Yamamura T (2008) Th17 Cells and autoimmune encephalomyelitis (EAE/MS). Allergol Int 57:115–120

    Article  PubMed  CAS  Google Scholar 

  2. Callado LF, Martin-Gomez JI, Ruiz J, Garibi JM, Meana JJ (2004) Imidazoline I(2) receptor density increases with the malignancy of human gliomas. J Neurol Neurosurg Psychiatry 75:785–787

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  3. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:1237–1240

    Article  PubMed  CAS  Google Scholar 

  4. Cua DJ, Hutchins B, LaFace DM, Stohlman SA, Coffman RL (2001) Central nervous system expression of IL-10 inhibits autoimmune encephalomyelitis. J Immunol 166:602–608

    Article  PubMed  CAS  Google Scholar 

  5. Gilad GM, Salame K, Rabey JM, Gilad VH (1996) Agmatine treatment is neuroprotective in rodent brain injury models. Life Sci 58:L-6

  6. Han Z, Cheng ZH, Liu S, Yang JL, Xiao MJ, Zheng RY, Hou ST (2012) Neurovascular protection conferred by 2-BFI treatment during rat cerebral ischemia. Biochem Biophys Res Commun 424:544–548

    Article  PubMed  CAS  Google Scholar 

  7. Han Z, Yang JL, Jiang SX, Hou ST, Zheng RY (2013) Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection. PLoS One 8:e64894

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Han Z, Zhang HX, Tian JS, Zheng RY, Hou ST (2010) 2-(-2-benzofuranyl)-2-imidazoline induces Bcl-2 expression and provides neuroprotection against transient cerebral ischemia in rats. Brain Res 1361:86–92

    Article  PubMed  CAS  Google Scholar 

  9. Hoffman WE, Cheng MA, Thomas C, Baughman VL, Albrecht RF (1991) Clonidine decreases plasma catecholamines and improves outcome from incomplete ischemia in the rat. Anesth Analg 73:460–464

    PubMed  CAS  Google Scholar 

  10. Hosseini AR, King PR, Louis WJ, Gundlach AL (1997) [3H]2-(2-Benzofuranyl)-2-imidazoline, a highly selective radioligand for I2-imidazoline receptor binding sites. Studies in rabbit kidney membranes. Naunyn Schmiedebergs Arch Pharmacol 355:131–138

    Article  PubMed  CAS  Google Scholar 

  11. Jiang SX, Zheng RY, Zeng JQ, Li XL, Han Z, Hou ST (2010) Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I(2) receptor antagonists. Eur J Pharmacol 629:12–19

    Article  PubMed  CAS  Google Scholar 

  12. Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573

    Article  PubMed  CAS  Google Scholar 

  13. Korn T, Anderson AC, Bettelli E, Oukka M (2007) The dynamics of effector T cells and Foxp3+ regulatory T cells in the promotion and regulation of autoimmune encephalomyelitis. J Neuroimmunol 191:51–60

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517

    Article  PubMed  CAS  Google Scholar 

  15. Kroenke MA, Segal BM (2007) Th17 and Th1 responses directed against the immunizing epitope, as opposed to secondary epitopes, dominate the autoimmune repertoire during relapses of experimental autoimmune encephalomyelitis. J Neurosci Res 85:1685–1693

    Article  PubMed  CAS  Google Scholar 

  16. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Li F, Zhang ZX, Liu YF, Xu HQ, Hou ST, Zheng RY (2012) 2-BFI ameliorates EAE-induced mouse spinal cord damage: effective therapeutic time window and possible mechanisms. Brain Res 1483:13–19

    Article  PubMed  CAS  Google Scholar 

  18. Mann MK, Maresz K, Shriver LP, Tan Y, Dittel BN (2007) B cell regulation of CD4+ CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J Immunol 178:3447–3456

    Article  PubMed  CAS  Google Scholar 

  19. McGeachy MJ, Stephens LA, Anderton SM (2005) Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+ CD25+ regulatory cells within the central nervous system. J Immunol 175:3025–3032

    Article  PubMed  CAS  Google Scholar 

  20. Miyake M, Sasaki K, Ide K, Matsukura Y, Shijima K, Fujiwara D (2006) Highly oligomeric procyanidins ameliorate experimental autoimmune encephalomyelitis via suppression of Th1 immunity. J Immunol 176:5797–5804

    Article  PubMed  CAS  Google Scholar 

  21. O’Neill EJ, Day MJ, Wraith DC (2006) IL-10 is essential for disease protection following intranasal peptide administration in the C57BL/6 model of EAE. J Neuroimmunol 178:1–8

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Olmos G, Alemany R, Escriba PV, Garcia-Sevilla JA (1994) The effects of chronic imidazoline drug treatment on glial fibrillary acidic protein concentrations in rat brain. Br J Pharmacol 111:997–1002

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Olsson T (1995) Critical influences of the cytokine orchestration on the outcome of myelin antigen-specific T-cell autoimmunity in experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol Rev 144:245–268

    Article  PubMed  CAS  Google Scholar 

  24. Regunathan S, Feinstein DL, Reis DJ (1993) Expression of non-adrenergic imidazoline sites in rat cerebral cortical astrocytes. J Neurosci Res 34:681–688

    Article  PubMed  CAS  Google Scholar 

  25. Ruggiero DA, Regunathan S, Wang H, Milner TA, Reis DJ (1998) Immunocytochemical localization of an imidazoline receptor protein in the central nervous system. Brain Res 780:270–293

    Article  PubMed  CAS  Google Scholar 

  26. Samoilova EB, Horton JL, Chen Y (1998) Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery. Cell Immunol 188:118–124

    Article  PubMed  CAS  Google Scholar 

  27. Schif-Zuck S, Wildbaum G, Karin N (2006) Coadministration of plasmid DNA constructs encoding an encephalitogenic determinant and IL-10 elicits regulatory T cell-mediated protective immunity in the central nervous system. J Immunol 177:8241–8247

    Article  PubMed  CAS  Google Scholar 

  28. Schmidt-Weber CB, Akdis M, Akdis CA (2007) TH17 cells in the big picture of immunology. J Allergy Clin Immunol 120:247–254

    Article  PubMed  CAS  Google Scholar 

  29. Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747

    Article  PubMed  CAS  Google Scholar 

  30. Stern JN, Keskin DB, Zhang H, Lv H, Kato Z, Strominger JL (2008) Amino acid copolymer-specific IL-10-secreting regulatory T cells that ameliorate autoimmune diseases in mice. Proc Natl Acad Sci USA 105:5172–5176

    Article  PubMed Central  PubMed  Google Scholar 

  31. Stohlman SA, Pei L, Cua DJ, Li Z, Hinton DR (1999) Activation of regulatory cells suppresses experimental allergic encephalomyelitis via secretion of IL-10. J Immunol 163:6338–6344

    PubMed  CAS  Google Scholar 

  32. Wang P, Wang ZW, Lin FH, Han Z, Hou ST, Zheng RY (2011) 2-BFI attenuates experimental autoimmune encephalomyelitis-induced spinal cord injury with enhanced B-CK, CaATPase, but reduced calpain activity. Biochem Biophys Res Commun 406:152–157

    Article  PubMed  CAS  Google Scholar 

  33. Wang XS, Chen YY, Shang XF, Zhu ZG, Chen GQ, Han Z, Shao B, Yang HM, Xu HQ, Chen JF, Zheng RY (2009) Idazoxan attenuates spinal cord injury by enhanced astrocytic activation and reduced microglial activation in rat experimental autoimmune encephalomyelitis. Brain Res 1253:198–209

    Article  PubMed  CAS  Google Scholar 

  34. Wheeler RD, Owens T (2005) The changing face of cytokines in the brain: perspectives from EAE. Curr Pharm Des 11:1031–1037

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by research Grants from the National Natural Science Foundation of China (81070960) and Zhejiang Natural Science Foundation (Y2090923) and Zhejiang Provincial Key Discipline-Neurobiology (437201203).

Conflict of interest

Authors declare no competing financial interests exist concerning the content of this document.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Sheng-Tao Hou or Rong-Yuan Zheng.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, YB., Xia, NG., Zhang, YT. et al. Brain Protection Conferred by Long-Term Administration of 2-(2-Benzofuranyl)-2-Imidazoline Against Experimental Autoimmune Encephalomyelitis. Neurochem Res 40, 572–578 (2015). https://doi.org/10.1007/s11064-014-1502-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1502-0

Keywords

Navigation