, Volume 22, Issue 11, pp 1353–1361 | Cite as

Remote ischemic preconditioning protects human neural stem cells from oxidative stress

  • Ayako Motomura
  • Mikiko Shimizu
  • Akira Kato
  • Kazuya Motomura
  • Akane Yamamichi
  • Hiroko Koyama
  • Fumiharu Ohka
  • Tomohide Nishikawa
  • Yusuke Nishimura
  • Masahito Hara
  • Tetsuya Fukuda
  • Yasuhiko Bando
  • Toshihide Nishimura
  • Toshihiko Wakabayashi
  • Atsushi Natsume
Short Communication


In previous clinical trials, we showed that remote ischemic preconditioning (rIPC) reduced myocardial damage in children undergoing treatment for congenital heart defects and postoperative renal failure in patients undergoing abdominal aortic aneurysm surgery. In rabbit experiments, pre-treatment with plasma and plasma dialysate (obtained using 15-kDa cut-off dialysis membrane) from donor rabbits subjected to rIPC similarly protected against cardiac infarction. However, the protective substances containing in rIPC plasma have been unknown. In the present study, we showed that rIPC plasma exerted anti-apoptotic and anti-oxidative effects on human neural stem cells under oxygen glucose deprivation (OGD) that mimics brain ischemia. Additionally, we applied the sample to the liquid chromatography integrated with mass spectrometry to identify candidate key molecules in the rIPC plasma and determine its role in protecting neural stem cells from OGD-induced cell death. Thioredoxin increased significantly after rIPC compared to pre-IPC. Pretreatment with thioredoxin, the antioxidant protein, markedly protected human neural stem cells from OGD-induced cell death. The effect of thioredoxin on brain ischemia in animals should be further evaluated. However, the present study first evaluated the effect of rIPC in the ischemic cellular model.


Remote ischemic preconditioning Oxygen glucose deprivation (OGD) Neural stem cells Oxidative stress 

Supplementary material

10495_2017_1425_MOESM1_ESM.pptx (1.1 mb)
Supplementary material 1 (PPTX 1134 KB)


  1. 1.
    Johnston SC, Mendis S, Mathers CD (2009) Global variation in stroke burden and mortality: estimates from monitoring, surveillance, and modelling. Lancet Neurol 8:345–354CrossRefPubMedGoogle Scholar
  2. 2.
    Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS (1999) Stroke. Neurologic and functional recovery the Copenhagen Stroke Study. Phys Med Rehabil Clin N Am 10:887–906PubMedGoogle Scholar
  3. 3.
    Roger VL, Go AS, Lloyd-Jones DM et al (2011) Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 123:e18–e209CrossRefPubMedGoogle Scholar
  4. 4.
    Seshadri S, Beiser A, Kelly-Hayes M et al (2006) The lifetime risk of stroke: estimates from the Framingham Study. Stroke 37:345–350CrossRefPubMedGoogle Scholar
  5. 5.
    Otani H (2008) Ischemic preconditioning: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 10:207–247CrossRefPubMedGoogle Scholar
  6. 6.
    Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136CrossRefPubMedGoogle Scholar
  7. 7.
    Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P (1993) Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893–899CrossRefPubMedGoogle Scholar
  8. 8.
    Shimizu M, Tropak M, Diaz RJ et al (2009) Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci 117:191–200CrossRefPubMedGoogle Scholar
  9. 9.
    Gidday JM (2006) Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 7:437–448CrossRefPubMedGoogle Scholar
  10. 10.
    Dave KR, Saul I, Prado R, Busto R, Perez-Pinzon MA (2006) Remote organ ischemic preconditioning protect brain from ischemic damage following asphyxial cardiac arrest. Neurosci Lett 404:170–175CrossRefPubMedGoogle Scholar
  11. 11.
    Jensen HA, Loukogeorgakis S, Yannopoulos F et al (2011) Remote ischemic preconditioning protects the brain against injury after hypothermic circulatory arrest. Circulation 123:714–721CrossRefPubMedGoogle Scholar
  12. 12.
    Malhotra S, Naggar I, Stewart M, Rosenbaum DM (2011) Neurogenic pathway mediated remote preconditioning protects the brain from transient focal ischemic injury. Brain Res 1386:184–190CrossRefPubMedGoogle Scholar
  13. 13.
    Zhao HG, Li WB, Li QJ et al (2004) Limb ischemic preconditioning attenuates apoptosis of pyramidal neurons in the CA1 hippocampus induced by cerebral ischemia-reperfusion in rats. Sheng Li Xue Bao 56:407–412PubMedGoogle Scholar
  14. 14.
    Wei D, Ren C, Chen X, Zhao H (2012) The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke. PLoS ONE 7:e30892CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cheung MM, Kharbanda RK, Konstantinov IE et al (2006) Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 47:2277–2282CrossRefPubMedGoogle Scholar
  16. 16.
    Ali ZA, Callaghan CJ, Lim E et al (2007) Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation 116:I98-105CrossRefPubMedGoogle Scholar
  17. 17.
    Hausenloy DJ, Mwamure PK, Venugopal V et al (2007) Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 370:575–579CrossRefPubMedGoogle Scholar
  18. 18.
    Kharbanda RK, Peters M, Walton B et al (2001) Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation 103:1624–1630CrossRefPubMedGoogle Scholar
  19. 19.
    Shimizu M, Saxena P, Konstantinov IE et al (2010) Remote ischemic preconditioning decreases adhesion and selectively modifies functional responses of human neutrophils. J Surg Res 158:155–161CrossRefPubMedGoogle Scholar
  20. 20.
    Kim SU (2004) Human neural stem cells genetically modified for brain repair in neurological disorders. Neuropathology 24:159–171CrossRefPubMedGoogle Scholar
  21. 21.
    Perkins DN, Pappin DJ, Creasy DM, Cottrell JS (1999) Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis 20:3551–3567CrossRefPubMedGoogle Scholar
  22. 22.
    Elias JE, Haas W, Faherty BK, Gygi SP (2005) Comparative evaluation of mass spectrometry platforms used in large-scale proteomics investigations. Nat Methods 2:667–675CrossRefPubMedGoogle Scholar
  23. 23.
    Patwardhan AJ, Strittmatter EF, Camp DG 2nd, Smith RD, Pallavicini MG. (2005) Comparison of normal and breast cancer cell lines using proteome, genome, and interactome data. J Proteome Res 4:1952–1960CrossRefPubMedGoogle Scholar
  24. 24.
    Brosch M, Swamy S, Hubbard T, Choudhary J (2008) Comparison of Mascot and X!Tandem performance for low and high accuracy mass spectrometry and the development of an adjusted Mascot threshold. Mol Cell Proteomics 7:962–970CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kawamura T, Nomura M, Tojo H et al (2010) Proteomic analysis of laser-microdissected paraffin-embedded tissues: (1) stage-related protein candidates upon non-metastatic lung adenocarcinoma. J Proteomics 73:1089–1099CrossRefPubMedGoogle Scholar
  26. 26.
    Nishimura T, Nomura M, Tojo H et al (2010) Proteomic analysis of laser-microdissected paraffin-embedded tissues: (2) MRM assay for stage-related proteins upon non-metastatic lung adenocarcinoma. J Proteomics 73:1100–1110CrossRefPubMedGoogle Scholar
  27. 27.
    Chamorro A, Dirnagl U, Urra X, Planas AM (2016) Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 15:869–881CrossRefPubMedGoogle Scholar
  28. 28.
    Schittek B (2012) The multiple facets of dermcidin in cell survival and host defense. J Innate Immun 4:349–360CrossRefPubMedGoogle Scholar
  29. 29.
    Leyton-Jaimes MF, Kahn J, Israelson A (2017) Macrophage migration inhibitory factor: a multifaceted cytokine implicated in multiple neurological diseases. Exp Neurol pii: S0014-4886(17):30160–0167Google Scholar
  30. 30.
    Li X, Rong Y, Zhang M et al (2009) Up-regulation of thioredoxin interacting protein (Txnip) by p38 MAPK and FOXO1 contributes to the impaired thioredoxin activity and increased ROS in glucose-treated endothelial cells. Biochem Biophys Res Commun 381:660–665CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Shalev A, Pise-Masison CA, Radonovich M et al (2002) Oligonucleotide microarray analysis of intact human pancreatic islets: identification of glucose-responsive genes and a highly regulated TGFbeta signaling pathway. Endocrinology 143:3695–3698CrossRefPubMedGoogle Scholar
  32. 32.
    Tsai NW, Chang YT, Huang CR et al (2014) Association between oxidative stress and outcome in different subtypes of acute ischemic stroke. Biomed Res Int 2014:256879PubMedPubMedCentralGoogle Scholar
  33. 33.
    Galley HF (2011) Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth 107:57–64CrossRefPubMedGoogle Scholar
  34. 34.
    Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13CrossRefPubMedGoogle Scholar
  35. 35.
    Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 95:11715–11720CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Guzy RD, Schumacker PT (2006) Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91:807–819CrossRefPubMedGoogle Scholar
  37. 37.
    Go YM, Jones DP (2013) The redox proteome. J Biol Chem 288:26512–26520CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Yoshioka J, Imahashi K, Gabel SA et al (2007) Targeted deletion of thioredoxin-interacting protein regulates cardiac dysfunction in response to pressure overload. Circ Res 101:1328–1338CrossRefPubMedGoogle Scholar
  39. 39.
    Berndt C, Lillig CH, Holmgren A (2007) Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. Am J Physiol Heart Circ Physiol 292:H1227–H1236CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Ayako Motomura
    • 1
  • Mikiko Shimizu
    • 2
  • Akira Kato
    • 1
  • Kazuya Motomura
    • 1
  • Akane Yamamichi
    • 1
  • Hiroko Koyama
    • 3
  • Fumiharu Ohka
    • 1
  • Tomohide Nishikawa
    • 1
  • Yusuke Nishimura
    • 1
  • Masahito Hara
    • 1
  • Tetsuya Fukuda
    • 4
  • Yasuhiko Bando
    • 4
  • Toshihide Nishimura
    • 5
    • 6
  • Toshihiko Wakabayashi
    • 1
  • Atsushi Natsume
    • 1
  1. 1.Department of NeurosurgeryNagoya University School of MedicineNagoyaJapan
  2. 2.Pediatric Cardiology, The Heart Institute of JapanTokyo Women’s Medical UniversityTokyoJapan
  3. 3.Division of Regeneration and Advanced Medical ScienceGifu University Graduate School of MedicineGifuJapan
  4. 4.Biosys Technologies, Inc.TokyoJapan
  5. 5.Department of Translational Medicine InformaticsSt. Marianna University School of MedicineKanagawaJapan
  6. 6.Center of Excellence in Biological and Medical Mass SpectrometryLund UniversityLundSweden

Personalised recommendations