Skip to main content

Advertisement

SpringerLink
Log in

Erythromycin pretreatment induces tolerance against focal cerebral ischemia through up-regulation of nNOS but not down-regulation of HIF-1α in rats

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

The purpose of this study was to determine whether the antibiotic erythromycin induces tolerance against focal cerebral ischemia, and the possible underlying mechanism including the involvement of neuronal nitric oxide synthase (nNOS) and hypoxia-inducible factor-1α (HIF-1α). In rat focal cerebral ischemia models, we found that erythromycin preconditioning could significantly decrease the cerebral infarct volume and brain edema. Meanwhile, the neurological deficits from day 4 through 7 after surgery were also remarkably decreased after erythromycin preconditioning. Moreover, erythromycin preconditioning induced significantly increased nNOS levels and decreased HIF-1α levels in both mRNA and protein expression. This study for the first time indicated that erythromycin preconditioning could induce focal brain ischemic tolerance and attenuate brain injury of subsequent transient focal cerebral ischemia. The potential mechanism may be due to up-regulation of nNOS, but the HIF-1α system was not involved.

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

Similar content being viewed by others

References

  1. Shamloo M, Wieloch T (1999) Changes in protein tyrosine phosphorylation in the rat brain after cerebral ischemia in a model of ischemic tolerance. J Cereb Blood Flow Metab 19(2):173–183

    Article  CAS  PubMed  Google Scholar 

  2. Chang S, Jiang X, Zhao C, Lee C, Ferriero DM (2008) Exogenous low dose hydrogen peroxide increases hypoxia-inducible factor-1alpha protein expression and induces preconditioning protection against ischemia in primary cortical neurons. Neurosci Lett 441(1):134–138

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Xiao-qian LIU, Rui SHENG, Zheng-hong QIN (2009) The neuroprotective mechanism of brain ischemic preconditioning. Acta Pharmacol Sin 30:1071–1080

    Article  Google Scholar 

  4. Atochin DN, Clark J, Demchenko IT, Moskowitz MA, Huang PL (2003) Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases. Stroke 34(5):1299–1303

    Article  CAS  PubMed  Google Scholar 

  5. Xu Q, Tang B, Zhang N, Song L, Zhang Z, Chen Y (2008) COX-2 or nNOS mediates cardioprotection during the final stage of the late phase of ischemic preconditioning. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 25(6):1411–1414

    CAS  PubMed  Google Scholar 

  6. Feng RF, Hu YY, Li WB, Liu HQ, Li QJ, Zhang M (2009) The role of NO resulted from neuronal nitric oxide synthase in the metabotropic glutamate receptor2/3 mediated-brain ischemic tolerance. Zhongguo Ying Yong Sheng Li Xue Za Zhi 25(2):182–185

    CAS  PubMed  Google Scholar 

  7. Mahfoudh-Boussaid A, Zaouali MA, Hadj-Ayed K, Miled AH, Saidane-Mosbahi D, Rosello-Catafau J, Ben Abdennebi H (2012) Ischemic preconditioning reduces endoplasmic reticulum stress and up-regulates hypoxia inducible factor-1α in ischemic kidney: the role of nitric oxide. J Biomed Sci 19:7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR (2000) Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol 48:285–296

    Article  CAS  PubMed  Google Scholar 

  9. Suzuki H, Tomida A, Tsuruo T (2001) Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 20(41):5779–5788

    Article  CAS  PubMed  Google Scholar 

  10. Brambrink AM, Koerner IP, Diehl K, Strobel G, Noppens R, Kempski O (2006) The antibiotic erythromycin induces tolerance against transient global cerebral ischemia in rats (pharmacologic preconditioning). Anesthesiology 104(6):1208–1215

    Article  CAS  PubMed  Google Scholar 

  11. Koerner IP, Gatting M, Noppens R, Kempski O, Brambrink AM (2007) Induction of cerebral ischemic tolerance by erythromycin preconditioning reprograms the transcriptional response to ischemia and suppresses inflammation. Anesthesiology 106(3):538–547

    Article  PubMed  Google Scholar 

  12. Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20(1):84–91

    Article  CAS  PubMed  Google Scholar 

  13. Shimakura A, Kamanaka Y, Ikeda Y, Kondo K, Suzuki Y, Umemura K (2000) Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion. Brain Res 858(1):55–60

    Article  CAS  PubMed  Google Scholar 

  14. Chen H, Xing B, Liu X, Zhan B, Zhou J, Zhu H, Chen Z (2008) Similarities between ozone oxidative preconditioning and ischemic preconditioning in renal ischemia/reperfusion injury. Arch Med Res 39(2):169–178

    Article  CAS  PubMed  Google Scholar 

  15. Nandagopal K, Dawson TM, Dawson VL (2001) Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J Pharmacol Exp Ther 297(2):474–478

    CAS  PubMed  Google Scholar 

  16. Lu XM, Zhang GX, Yu YQ, Kimura S, Nishiyama A, Matsuyoshi H, Shimizu J, Takaki M (2009) The opposite roles of nNOS in cardiac ischemia-reperfusion-induced injury and in ischemia preconditioning-induced cardioprotection in mice. J Physiol Sci 59(4):253–262

    Article  CAS  PubMed  Google Scholar 

  17. Andoh T, Chock PB, Chiueh CC (2002) Preconditioning-mediated neuroprotection: role of nitric oxide, cGMP, and new protein expression. Ann NY Acad Sci 962:1–7

    Article  CAS  PubMed  Google Scholar 

  18. Scorziello A, Santillo M, Adornetto A, Dell’aversano C, Sirabella R, Damiano S, Canzoniero LM, Renzo GF, Annunziato L (2007) NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via Ras/ERK1/2 pathway. J Neurochem 103(4):1472–1480

    Article  CAS  PubMed  Google Scholar 

  19. Kapinya KJ, Lowl D, Futterer C, Maurer M, Waschke KF, Isaev NK, Dirnagl U (2002) Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible NO synthase dependent. Stroke 33:1889–1898

    Article  CAS  PubMed  Google Scholar 

  20. Cho S, Park EM, Zhou P, Frys K, Ross ME, Iadecola C (2005) Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J Cereb Blood Flow Metab 25:493–501

    Article  CAS  PubMed  Google Scholar 

  21. Kawano T, Kunz A, Abe T, Girouard H, Anrather J, Zhou P, Iadecola C (2007) iNOS-derived NO and nox2-derived superoxide confer tolerance to excitotoxic brain injury through peroxynitrite. J Cereb Blood Flow Metab 27(8):1453–1462

    Article  CAS  PubMed  Google Scholar 

  22. Cai Z, Zhong H, Bosch-Marce M, Fox-Talbot K, Wang L, Wei C, Trush MA, Semenza GL (2008) Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1 alpha. Cardiovasc Res 77(3):463–470

    Article  CAS  PubMed  Google Scholar 

  23. Knudsen AR, Kannerup AS, Grønbæk H, Andersen KJ, Funch-Jensen P, Frystyk J, Flyvbjerg A, Mortensen FV (2011) Effects of ischemic pre- and postconditioning on HIF-1α, VEGF and TGF-β expression after warm ischemia and reperfusion in the rat liver. Comp Hepatol 10(1):3

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Sarkar K, Cai Z, Gupta R, Parajuli N, Fox-Talbot K, Darshan MS, Gonzalez FJ, Semenza GL (2012) Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning. Proc Natl Acad Sci USA 109(26):10504–10509

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Kalakech H, Tamareille S, Pons S, Godin-Ribuot D, Carmeliet P, Furber A, Martin V, Berdeaux A, Ghaleh B, Prunier F (2013) Role of hypoxia inducible factor-1α in remote limb ischemic preconditioning. J Mol Cell Cardiol S0022–2828(13):00292–00297

    Google Scholar 

  26. Schölzke MN, Schwaninger M (2007) Transcriptional regulation of neurogenesis: potential mechanisms in cerebral ischemia. J Mol Med 85:577–588

    Article  PubMed  Google Scholar 

  27. Tang B, Qu Y, Wang D, Mu D (2010) Targeting hypoxia inducible factor-1α: a novel mechanism of ginsenoside rg1 for brain repair after hypoxia/ischemia brain damage. CNS Neurol Disord Drug Targets 10:235–238

    Article  Google Scholar 

  28. Knudsen AR, Kannerup AS, Grønbæk H, Andersen KJ, Funch-Jensen P, Frystyk J, Flyvbjerg A, Mortensen FV (2011) Effects of ischemic pre- and postconditioning on HIF-1α, VEGF and TGF-β expression after warm ischemia and reperfusion in the rat liver. Comp Hepatol 10(1):3

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 30400463), the Natural Science Foundation of Liaoning Province (No. 20072099, No. 2013021075), and Technology Plan Project of Educational Department of Liaoning Province (No. 2006401013-3), Science and Technology Plan Project of Liaoning Province (No. 2012225070, No. 20131114).

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, First Affiliated Hospital of China Medical University, No. 155, North Nanjing Street, Heping District, Shenyang, 110001, Liaoning, People’s Republic of China

    Wei-cheng Lu, Guang-yu Li, Bo Qiu, Ri-miao Yang & Zong-ze Guo

  2. Department of Histology and Embryology, College of Basic Medicine, Shenyang Medical College, Shenyang, 110034, People’s Republic of China

    Hui Xie

Authors
  1. Wei-cheng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guang-yu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bo Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ri-miao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zong-ze Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zong-ze Guo.

Additional information

W. Lu and G. Li are the first two authors who contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, Wc., Li, Gy., Xie, H. et al. Erythromycin pretreatment induces tolerance against focal cerebral ischemia through up-regulation of nNOS but not down-regulation of HIF-1α in rats. Neurol Sci 35, 687–693 (2014). https://doi.org/10.1007/s10072-013-1584-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-013-1584-5

Keywords

Search

Navigation