Skip to main content
Log in

Modifications of gene expression detected in peripheral blood after brain ischemia treated with remote postconditioning

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

A stroke is an acute damage to a certain area of a nerve tissue of the brain. In developed countries, it ranks second among the most often causes of death and is also the leading cause of disability. Recent findings emphasize the significant neuroprotective effect of conditioning on the course and rate of recovery after ischemic attack; however the molecular mechanism of ischemic tolerance induced by conditioning is still not completely explored.

Methods and results

The purpose of this study is an identification of changes in gene expression induced by stimulation of reaction cascades after activation of the neuroprotective mechanism using an experimental rat model of global ischemia. The induction of neuroprotective cascades was stimulated by the application of early and delayed form of remote ischemic postconditioning. The quantitative qRT-PCR method was used to assess the rate of change in ADM, BDNF, CDKN1A, CREB, GADD45G, IL6, nNOS, and TM4SF1 gene expression levels 72 h after ischemic attack. The detected results confirm the neuroprotective effect of both forms of postconditioning. Participation of neuroprotection-related gene expression changes was observed once as an early one (CREB, GADD45G), once as a delayed one (ADM, IL6), or both (BDNF, CDKN1A, nNOS, TM4SF1) postconditioning forms, depending on the particular gene.

Conclusions

Our results characterize impact of ischemic tolerance on the molecular level. We predict ischemic tolerance to be consisted of complex combination of early and delayed remote postconditioning.

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

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

References

  1. Doeppner TR, Zechmeister B, Kaltwasser B, Jin F, Zheng X, Majid A, Venkataramani V, Bahr M, Hermann DM (2018) Very delayed remote ischemic post-conditioning induces sustained neurological recovery by mechanisms involving enhanced angioneurogenesis and peripheral immunosuppression reversal. Front Cell Neurosci 12:383

    Article  CAS  Google Scholar 

  2. Shi C-X, Ding Y-B, Jin FYJ, Li T, Ma J-H, Qiao L-Y, Pan W-Z, Li K-Z (2018) Effects of sevoflurane post-conditioning in cerebral ischemia-reperfusion injury via TLR4/NF-κB pathway in rats. Eur Rev Med Pharmacol Sci 22:1770–1775

    PubMed  Google Scholar 

  3. Doeppner TR, Doehring M, Kaltwasser B, Majid A, Lin F, Bahr M, Kilic E, Hermann DM (2017) Ischemic post-conditioning induces post-stroke neuroprotection via Hsp70-mediated proteasome inhibition and facilitates neural progenitor cell transplantation. Mol Neurobiol 54:6061–6073

    Article  CAS  Google Scholar 

  4. Howard DPJ, Gaziano L, Rothwell PM, Oxford Vascular S (2021) Risk of stroke in relation to degree of asymptomatic carotid stenosis: a population-based cohort study, systematic review, and meta-analysis. Lancet Neurol 20:193–202

    Article  Google Scholar 

  5. Kisrieva YS, Petushkova NA, Samenkova NF, Kuznetsova GP, Larina OV, Teryaeva NB, Zgoda VG, Karuzina II, Usachev DU, Belyaev AY (2018) Analysis of blood plasma protein composition in patients with cerebral ischemia. Bull Exp Biol Med 165:22–26

    Article  CAS  Google Scholar 

  6. Rothstein L, Jickling GC (2013) Ischemic stroke biomarkers in blood. Biomark Med 7:37–47

    Article  CAS  Google Scholar 

  7. Swyngedouw NE, Jickling GC (2017) RNA as a stroke biomarker. Future Neurol 12:71–78

    Article  CAS  Google Scholar 

  8. Barr TL, Conley Y, Ding J, Dillman A, Warach S, Singleton A, Matarin M (2010) Genomic biomarkers and cellular pathways of ischemic stroke by RNA gene expression profiling. Neurology 75:1009–1014

    Article  CAS  Google Scholar 

  9. Moore DF, Li H, Jeffries N, Wright V, Cooper RA Jr, Elkahloun A, Gelderman MP, Zudaire E, Blevins G, Yu H, Goldin E, Baird AE (2005) Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke: a pilot investigation. Circulation 111:212–221

    Article  CAS  Google Scholar 

  10. Stamova B, Xu H, Jickling G, Bushnell C, Tian Y, Ander BP, Zhan X, Liu D, Turner R, Adamczyk P, Khoury JC, Pancioli A, Jauch E, Broderick JP, Sharp FR (2010) Gene expression profiling of blood for the prediction of ischemic stroke. Stroke 41:2171–2177

    Article  Google Scholar 

  11. Tang Y, Xu H, Du X, Lit L, Walker W, Lu A, Ran R, Gregg JP, Reilly M, Pancioli A, Khoury JC, Sauerbeck LR, Carrozzella JA, Spilker J, Clark J, Wagner KR, Jauch EC, Chang DJ, Verro P, Broderick JP, Sharp FR (2006) Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study. J Cereb Blood Flow Metab 26:1089–1102

    Article  CAS  Google Scholar 

  12. Jickling GC, Stamova B, Ander BP, Zhan X, Liu D, Sison SM, Verro P, Sharp FR (2012) Prediction of cardioembolic, arterial, and lacunar causes of cryptogenic stroke by gene expression and infarct location. Stroke 43:2036–2041

    Article  CAS  Google Scholar 

  13. Jickling GC, Stamova B, Ander BP, Zhan X, Tian Y, Liu D, Xu H, Johnston SC, Verro P, Sharp FR (2011) Profiles of lacunar and nonlacunar stroke. Ann Neurol 70:477–485

    Article  Google Scholar 

  14. Jickling GC, Xu H, Stamova B, Ander BP, Zhan X, Tian Y, Liu D, Turner RJ, Mesias M, Verro P, Khoury J, Jauch EC, Pancioli A, Broderick JP, Sharp FR (2010) Signatures of cardioembolic and large-vessel ischemic stroke. Ann Neurol 68:681–692

    Article  Google Scholar 

  15. Jickling GC, Zhan X, Stamova B, Ander BP, Tian Y, Liu D, Sison SM, Verro P, Johnston SC, Sharp FR (2012) Ischemic transient neurological events identified by immune response to cerebral ischemia. Stroke 43:1006–1012

    Article  CAS  Google Scholar 

  16. Ramsay L, Quille ML, Orset C, de la Grange P, Rousselet E, Ferec C, Le Gac G, Genin E, Timsit S (2019) Blood transcriptomic biomarker as a surrogate of ischemic brain gene expression. Ann Clin Transl Neurol 6:1681–1695

    Article  CAS  Google Scholar 

  17. Pulsinelli WA, Brierley JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10:267–272

    Article  CAS  Google Scholar 

  18. Schmidt-Kastner R, Paschen W, Ophoff BG, Hossmann KA (1989) A modified four-vessel occlusion model for inducing incomplete forebrain ischemia in rats. Stroke 20:938–946

    Article  CAS  Google Scholar 

  19. Nemethova M, Talian I, Danielisova V, Tkacikova S, Bonova P, Bober P, Matiasova M, Sabo J, Burda J (2016) Delayed bradykinin postconditioning modulates intrinsic neuroprotective enzyme expression in the rat CA1 region after cerebral ischemia: a proteomic study. Metab Brain Dis 31:1391–1403

    Article  CAS  Google Scholar 

  20. Bonova P, Nemethova M, Matiasova M, Bona M, Gottlieb M (2016) Blood cells serve as a source of factor-inducing rapid ischemic tolerance in brain. Eur J Neurosci 44:2958–2965

    Article  Google Scholar 

  21. Ayers JD, Rota PA, Collins ML, Drew CP (2012) Alternatives to retroorbital blood collection in hispid cotton rats (Sigmodon hispidus). J Am Assoc Lab Anim Sci 51:239–245

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kang Y, Wu Z, Cai LuB (2018) Evaluation of reference genes for gene expression studies in mouse and N2a cell ischemic stroke models using quantitative real-time PCR. BMC Neurosci 19:3

    Article  Google Scholar 

  23. Yuan J (2009) Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis 14:469–477

    Article  Google Scholar 

  24. Chen J, Graham SH, Zhu RL, Simon RP (1996) Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab 16:566–577

    Article  CAS  Google Scholar 

  25. Kirino T, Tsujita Y, Tamura A (1991) Induced tolerance to ischemia in gerbil hippocampal neurons. J Cereb Blood Flow Metab 11:299–307

    Article  CAS  Google Scholar 

  26. Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K et al (1990) “Ischemic tolerance” phenomenon found in the brain. Brain Res 528:21–24

    Article  CAS  Google Scholar 

  27. Yunoki M, Kanda T, Suzuki K, Uneda A, Hirashita K, Yoshino K (2017) Ischemic tolerance of the brain and spinal cord: a review. Neurol Med Chir (Tokyo) 57:590–600

    Article  Google Scholar 

  28. Kakimoto M, Kawaguchi M, Sakamoto T, Inoue S, Furuya H, Nakamura M, Konishi N (2003) Evaluation of rapid ischemic preconditioning in a rabbit model of spinal cord ischemia. Anesthesiology 99:1112–1117

    Article  Google Scholar 

  29. Stetler RA, Leak RK, Gan Y, Li P, Zhang F, Hu X, Jing Z, Chen J, Zigmond MJ, Gao Y (2014) Preconditioning provides neuroprotection in models of CNS disease: paradigms and clinical significance. Prog Neurobiol 114:58–83

    Article  Google Scholar 

  30. Han D, Wang J, Wen L, Sun M, Liu H, Gao Y (2021) Remote limb ischemic postconditioning protects against ischemic stroke via modulating microglia/macrophage polarization in mice. J Immunol Res 2021:6688053

    Article  Google Scholar 

  31. McDonald MW, Dykes A, Jeffers MS, Carter A, Nevins R, Ripley A, Silasi G, Corbett D (2021) Remote ischemic conditioning and stroke recovery. Neurorehabil Neural Repair 35:545–549

    Article  Google Scholar 

  32. Seifert-Held T, Pekar T, Gattringer T, Simmet NE, Scharnagl H, Bocksrucker C, Lampl C, Storch MK, Stojakovic T, Fazekas F (2013) Plasma midregional pro-adrenomedullin improves prediction of functional outcome in ischemic stroke. PLoS One 8:e68768

    Article  CAS  Google Scholar 

  33. Wu H, Yang SF, Dai J, Qiu YM, Miao YF, Zhang XH (2015) Combination of early and delayed ischemic postconditioning enhances brain-derived neurotrophic factor production by upregulating the ERK-CREB pathway in rats with focal ischemia. Mol Med Rep 12:6427–6434

    Article  CAS  Google Scholar 

  34. Bejot Y, Mossiat C, Giroud M, Prigent-Tessier A, Marie C (2011) Circulating and brain BDNF levels in stroke rats Relevance to clinical studies. PLoS One 6:e29405

    Article  CAS  Google Scholar 

  35. Caracciolo L, Marosi M, Mazzitelli J, Latifi S, Sano Y, Galvan L, Kawaguchi R, Holley S, Levine MS, Coppola G, Portera-Cailliau C, Silva AJ, Carmichael ST (2018) CREB controls cortical circuit plasticity and functional recovery after stroke. Nat Commun 9:2250

    Article  CAS  Google Scholar 

  36. Zhang S, Wang J, Qu MJ, Wang K, Ma AJ, Pan XD, Zhu XY (2021) Novel insights into the potential diagnostic value of circulating exosomal IncRNA-related networks in large artery atherosclerotic stroke. Front Mol Biosci 8:682769

    Article  CAS  Google Scholar 

  37. Gertz K, Kronenberg G, Kalin RE, Baldinger T, Werner C, Balkaya M, Eom GD, Hellmann-Regen J, Krober J, Miller KR, Lindauer U, Laufs U, Dirnagl U, Heppner FL, Endres M (2012) Essential role of interleukin-6 in post-stroke angiogenesis. Brain 135:1964–1980

    Article  Google Scholar 

  38. Chen ZQ, Mou RT, Feng DX, Wang Z, Chen G (2017) The role of nitric oxide in stroke. Med Gas Res 7:194–203

    Article  CAS  Google Scholar 

  39. Lu XC, Williams AJ, Yao C, Berti R, Hartings JA, Whipple R, Vahey MT, Polavarapu RG, Woller KL, Tortella FC, Dave JR (2004) Microarray analysis of acute and delayed gene expression profile in rats after focal ischemic brain injury and reperfusion. J Neurosci Res 77:843–857

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by SK-VEGA 2/0054/20 Grant from Slovak Academy of Sciences.

Funding

This study was supported by the grant from the Slovak Scientific Grant Agency VEGA 2/0054/20.

Author information

Authors and Affiliations

Authors

Contributions

MF: Investigation, Formal analysis, Writing—Original Draft, Validation, Visualization. MN: Methodology, Investigation, Writing—Review & Editing. LM: Investigation, VS: Investigation, Methodology, Resources, Project administration, Writing—Review & Editing. PB: Resources, Writing—Review & Editing. IK: Resources, Writing—Review & Editing. MV: Resources, RM: Conceptualization, Methodology, Validation, Resources, Data Curation, Writing—Review and Editing, Supervision, Funding acquisition, Project administration.

Corresponding author

Correspondence to Vladimir Sihotsky.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare that are relevant to the content of this article.

Ethical approval

All experiments were approved by the Institutional Ethical Committee in accordance with current national legislation and EU Directive 2010/63/EU guidelines for animal experiments.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

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

Furman, M., Nemethova, M., Macakova, L. et al. Modifications of gene expression detected in peripheral blood after brain ischemia treated with remote postconditioning. Mol Biol Rep 49, 477–485 (2022). https://doi.org/10.1007/s11033-021-06899-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06899-5

Keywords

Navigation