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Brain ischemic preconditioning protects against moderate, not severe, transient global cerebral ischemic injury

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Abstract

Ischemic preconditioning (IPC) in the brain increases ischemic tolerance to subsequent ischemic insults. In this study, we examined whether IPC protects neurons and attenuates microgliosis or not in the hippocampus following severe transient global cerebral ischemia (TCI) in gerbils. Gerbils were assigned to 8 groups; 5- and 15-min sham operated groups, 5-min and 15-min TCI operated groups, IPC plus 5- and 15-min sham operated groups, and IPC plus 5- and 15-min TCI operated groups. IPC was induced by subjecting animals to 2-min transient ischemia 1 day before 5-min TCI for a typical transient ischemia and 15-min TCI for severe transient ischemia. Neuronal damage was examined by cresyl violet staining and Fluoro-Jade B histofluorescence staining. In addition, microglial activation was examined using immunohistochemistry for Iba-1 (a marker for microglia). Delayed neuronal death and microgliosis was found in the CA1 alone in the 5-min TCI operated group at 5 days post-ischemia, and, in the 15-min TCI operated group, neuronal death and microgliosis was shown in all CA areas (CA1–3) and the dentate gyrus. IPC displayed neuroprotection and attenuated microglial activation in the 5-min TCI operated group. However, in the 15-min TCI operated group, IPC did not show neuroprotection and not attenuate microglial activation. Our present findings indicate that IPC hardly protect against severe transient cerebral ischemic injury.

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References

  • Barron KD (1995) The microglial cell. A historical review. J Neurol Sci 134(Suppl):57–68

    Article  PubMed  Google Scholar 

  • Beresewicz M, Kowalczyk JE, Zablocka B (2008) Kalirin-7, a protein enriched in postsynaptic density, is involved in ischemic signal transduction. Neurochem Res 33:1789–1794

    Article  PubMed  CAS  Google Scholar 

  • Bertolino G, De Araujo FL, Souza HC, Coimbra NC, De Araujo JE (2013) Neuropathology and behavioral impairments after bilateral global ischemia surgery and exposure to static magnetic field: evidence in the motor cortex, the hippocampal CA1 region and the neostriatum. Int J Radiat Biol 89:595–601

    Article  PubMed  CAS  Google Scholar 

  • 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. https://doi.org/10.1038/sj.jcbfm.9600058

    Article  PubMed  CAS  Google Scholar 

  • Dave KR, Lange-Asschenfeldt C, Raval AP, Prado R, Busto R, Saul I, Perez-Pinzon MA (2005) Ischemic preconditioning ameliorates excitotoxicity by shifting glutamate/gamma-aminobutyric acid release and biosynthesis. J Neurosci Res 82:665–673

    Article  PubMed  CAS  Google Scholar 

  • Dhodda VK, Sailor KA, Bowen KK, Vemuganti R (2004) Putative endogenous mediators of preconditioning-induced ischemic tolerance in rat brain identified by genomic and proteomic analysis. J Neurochem 89:73–89

    Article  PubMed  CAS  Google Scholar 

  • Durukan A, Tatlisumak T (2010) Preconditioning-induced ischemic tolerance: a window into endogenous gearing for cerebroprotection. Exp Transl Stroke Med 2:2

    Article  PubMed  PubMed Central  Google Scholar 

  • Edwards RJ, Saurin AT, Rakhit RD, Marber MS (2000) Therapeutic potential of ischaemic preconditioning. Br J Clin Pharmacol 50:87–97

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Feng Z, Davis DP, Sasik R, Patel HH, Drummond JC, Patel PM (2007) Pathway and gene ontology based analysis of gene expression in a rat model of cerebral ischemic tolerance. Brain Res 1177:103–123

    Article  PubMed  CAS  Google Scholar 

  • Gidday JM (2006) Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 7:437–448

    Article  PubMed  CAS  Google Scholar 

  • Hailer NP, Jarhult JD, Nitsch R (1996) Resting microglial cells in vitro: analysis of morphology and adhesion molecule expression in organotypic hippocampal slice cultures. Glia 18:319–331

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto M, Nitta A, Fukumitsu H, Nomoto H, Shen L, Furukawa S (2005) Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages. J Neurosci Res 79:476–487

    Article  PubMed  CAS  Google Scholar 

  • Hwang IK, Yoo KY, Kim DW, Choi SY, Kang TC, Kim YS, Won MH (2006) Ionized calcium-binding adapter molecule 1 immunoreactive cells change in the gerbil hippocampal CA1 region after ischemia/reperfusion. Neurochem Res 31:957–965

    Article  PubMed  CAS  Google Scholar 

  • Hwang IK, Yoo KY, Kim do H, Lee BH, Kwon YG, Won MH (2007) Time course of changes in pyridoxal 5′-phosphate (vitamin B6 active form) and its neuroprotection in experimental ischemic damage. Exp Neurol 206:114–125

    Article  PubMed  CAS  Google Scholar 

  • Hwang IK et al (2008) Differential changes in pyridoxine 5′-phosphate oxidase immunoreactivity and protein levels in the somatosensory cortex and striatum of the ischemic gerbil brain. Neurochem Res 33:1356–1364

    Article  PubMed  CAS  Google Scholar 

  • Hye Kim I et al (2016) Time interval after ischaemic preconditioning affects neuroprotection and gliosis in the gerbil hippocampal CA1 region induced by transient cerebral ischaemia. Neurol Res 38:210–219

    Article  PubMed  CAS  Google Scholar 

  • Kim IH et al (2013) Neuroprotection of a novel synthetic caffeic acid-syringic acid hybrid compound against experimentally induced transient cerebral ischemic damage. Planta Med 79:313–321

    Article  PubMed  CAS  Google Scholar 

  • Kim IH et al (2014) Comparison of neuroprotective effects of extract and fractions from Agarum clathratum against experimentally induced transient cerebral ischemic damage. Pharm Biol 52:335–343

    Article  PubMed  Google Scholar 

  • Kirino T, Sano K (1984) Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol 62:201–208

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kirino T, Nakagomi T, Kanemitsu H, Tamura A (1996) Ischemic tolerance. Adv Neurol 71:505–511

    PubMed  CAS  Google Scholar 

  • Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318

    Article  PubMed  CAS  Google Scholar 

  • Laurenzi MA, Arcuri C, Rossi R, Marconi P, Bocchini V (2001) Effects of microenvironment on morphology and function of the microglial cell line BV-2. Neurochem Res 26:1209–1216

    Article  PubMed  CAS  Google Scholar 

  • Lee JC et al (2013) Effects of transient cerebral ischemia on the expression of DNA methyltransferase 1 in the gerbil hippocampal CA1 region. Neurochem Res 38:74–81

    Article  PubMed  CAS  Google Scholar 

  • Lee JC et al (2014a) Transient ischemia-induced change of CCR7 immunoreactivity in neurons and its new expression in astrocytes in the gerbil hippocampus. J Neurol Sci 336:203–210

    Article  PubMed  CAS  Google Scholar 

  • Lee JC et al (2014b) Effect of transient cerebral ischemia on the expression of receptor for advanced glycation end products (RAGE) in the gerbil hippocampus proper. Neurochem Res 39:1553–1563

    Article  PubMed  CAS  Google Scholar 

  • Lee JC et al (2014c) Ischemic preconditioning-induced neuroprotection against transient cerebral ischemic damage via attenuating ubiquitin aggregation. J Neurol Sci 336:74–82

    Article  PubMed  CAS  Google Scholar 

  • Lee JC et al (2015) Ischemic preconditioning protects hippocampal pyramidal neurons from transient ischemic injury via the attenuation of oxidative damage through upregulating heme oxygenase-1. Free Radic Biol Med 79:78–90

    Article  PubMed  CAS  Google Scholar 

  • Lee JC et al (2016) Neuroprotection of ischemic preconditioning is mediated by Thioredoxin 2 in the hippocampal CA1 region following a subsequent transient cerebral ischemia. Brain Pathol 27(3):276–291

    Article  PubMed  CAS  Google Scholar 

  • Lehotsky J, Burda J, Danielisova V, Gottlieb M, Kaplan P, Saniova B (2009) Ischemic tolerance: the mechanisms of neuroprotective strategy. Anat Rec 292:2002–2012. https://doi.org/10.1002/ar.20970

    Article  Google Scholar 

  • Lehrmann E, Kiefer R, Finsen B, Diemer NH, Zimmer J, Hartung HP (1995) Cytokines in cerebral ischemia: expression of transforming growth factor beta-1 (TGF-beta 1) mRNA in the postischemic adult rat hippocampus. Exp Neurol 131:114–123

    Article  PubMed  CAS  Google Scholar 

  • Lin CS, Polsky K, Nadler JV, Crain BJ (1990) Selective neocortical and thalamic cell death in the gerbil after transient ischemia. Neuroscience 35:289–299

    Article  PubMed  CAS  Google Scholar 

  • Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Kato H, Nakata N, Kogure K (1992) Protection of rat hippocampus against ischemic neuronal damage by pretreatment with sublethal ischemia. Brain Res 586:121–124

    Article  PubMed  CAS  Google Scholar 

  • Lorrio S, Sobrado M, Arias E, Roda JM, Garcia AG, Lopez MG (2007) Galantamine postischemia provides neuroprotection and memory recovery against transient global cerebral ischemia in gerbils. J Pharmacol Exp Ther 322:591–599

    Article  PubMed  CAS  Google Scholar 

  • Lu YZ, Lin CH, Cheng FC, Hsueh CM (2005) Molecular mechanisms responsible for microglia-derived protection of Sprague-Dawley rat brain cells during in vitro ischemia. Neurosci Lett 373:159–164

    Article  PubMed  CAS  Google Scholar 

  • Malek M, Duszczyk M, Zyszkowski M, Ziembowicz A, Salinska E (2013) Hyperbaric oxygen and hyperbaric air treatment result in comparable neuronal death reduction and improved behavioral outcome after transient forebrain ischemia in the gerbil. Exp Brain Res 224:1–14

    Article  PubMed  CAS  Google Scholar 

  • Miao Y, Zhang W, Lin Y, Lu X, Qiu Y (2010) Neuroprotective effects of ischemic preconditioning on global brain ischemia through up-regulation of acid-sensing ion channel 2a. Int J Mol Sci 11:140–153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M, van Melle G (2000) Do transient ischemic attacks have a neuroprotective effect? Neurology 54:2089–2094

    Article  PubMed  CAS  Google Scholar 

  • Nakajima T, Ochi S, Oda C, Ishii M, Ogawa K (2011) Ischemic preconditioning attenuates of ischemia-induced degradation of spectrin and tau: implications for ischemic tolerance. Neurol Sci 32:229–239

    Article  PubMed  Google Scholar 

  • Nakamura H, Katsumata T, Nishiyama Y, Otori T, Katsura K, Katayama Y (2006) Effect of ischemic preconditioning on cerebral blood flow after subsequent lethal ischemia in gerbils. Life Sci 78:1713–1719

    Article  PubMed  CAS  Google Scholar 

  • Nakano M, Ueda H, Li JY, Matsumoto M, Yanagihara T (1998) Measurement of regional N-acetylaspartate after transient global ischemia in gerbils with and without ischemic tolerance: an index of neuronal survival. Ann Neurol 44:334–340

    Article  PubMed  CAS  Google Scholar 

  • Nishi S et al (1993) Ischemic tolerance due to the induction of HSP70 in a rat ischemic recirculation model. Brain Res 615:281–288

    Article  PubMed  CAS  Google Scholar 

  • Ohk TG et al (2012) Neuronal damage using Fluoro-jade B histofluorescence and gliosis in the striatum after various durations of transient cerebral ischemia in gerbils. Neurochem Res 37:826–834

    Article  PubMed  CAS  Google Scholar 

  • Perez-Pinzon MA (2004) Neuroprotective effects of ischemic preconditioning in brain mitochondria following cerebral ischemia. J Bioenerg Biomembr 36:323–327

    Article  PubMed  CAS  Google Scholar 

  • Schmued LC, Hopkins KJ (2000) Fluoro-jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 874:123–130

    Article  PubMed  CAS  Google Scholar 

  • Schwartz M, Butovsky O, Bruck W, Hanisch UK (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74

    Article  PubMed  CAS  Google Scholar 

  • Selakovic V, Korenic A, Radenovic L (2011) Spatial and temporal patterns of oxidative stress in the brain of gerbils submitted to different duration of global cerebral ischemia. Int J Dev Neurosci 29:645–654

    Article  PubMed  CAS  Google Scholar 

  • Stagliano NE, Perez-Pinzon MA, Moskowitz MA, Huang PL (1999) Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 19:757–761

    Article  PubMed  CAS  Google Scholar 

  • Stenzel-Poore MP et al (2003) Effect of ischaemic preconditioning on genomic response to cerebral ischaemia: similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 362:1028–1037

    Article  PubMed  CAS  Google Scholar 

  • Stenzel-Poore MP, Stevens SL, King JS, Simon RP (2007) Preconditioning reprograms the response to ischemic injury and primes the emergence of unique endogenous neuroprotective phenotypes: a speculative synthesis. Stroke 38:680–685

    Article  PubMed  Google Scholar 

  • Tanaka H, Calderone A, Jover T, Grooms SY, Yokota H, Zukin RS, Bennett MV (2002) Ischemic preconditioning acts upstream of GluR2 down-regulation to afford neuroprotection in the hippocampal CA1. Proc Natl Acad Sci U S A 99:2362–2367

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tang Y, Pacary E, Freret T, Divoux D, Petit E, Schumann-Bard P, Bernaudin M (2006) Effect of hypoxic preconditioning on brain genomic response before and following ischemia in the adult mouse: identification of potential neuroprotective candidates for stroke. Neurobiol Dis 21:18–28

    Article  PubMed  CAS  Google Scholar 

  • Toyoda T, Kassell NF, Lee KS (1997) Induction of ischemic tolerance and antioxidant activity by brief focal ischemia. Neuroreport 8:847–851

    Article  PubMed  CAS  Google Scholar 

  • Wegener S et al (2004) Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study. Stroke 35:616–621

    Article  PubMed  Google Scholar 

  • Weih M, Kallenberg K, Bergk A, Dirnagl U, Harms L, Wernecke KD, Einhaupl KM (1999) Attenuated stroke severity after prodromal TIA: a role for ischemic tolerance in the brain? Stroke 30:1851–1854

    Article  PubMed  CAS  Google Scholar 

  • Yan BC et al (2013) Neuroprotective effect of a new synthetic aspirin-decursinol adduct in experimental animal models of ischemic stroke. PLoS One 8:e74886

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yu DK et al (2012) Neuronal damage in hippocampal subregions induced by various durations of transient cerebral ischemia in gerbils using Fluoro-jade B histofluorescence. Brain Res 1437:50–57

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Mr. Seung Uk Lee for his technical help in this study. This research was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (NRF-2015M3A9B6066835), and by the Bio-Synergy Research Project (NRF-2015M3A9C4076322) of the Ministry of Science, ICT and Future Planning through the National Research Foundation.

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  1. Co-firsts: Jae-Chul Lee and Bich-Na Shin have contributed equally to this article.

Authors and Affiliations

  1. Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea

    Jae-Chul Lee, Bich-Na Shin, Jeong Hwi Cho, Tae-Kyeong Lee & Moo-Ho Won

  2. Famenity Company, Gwacheon, 13837, Republic of Korea

    In Hye Kim, YooHun Noh & Sung-Su Kim

  3. Department of Obstetrics and Gynecology, School of Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea

    Hyang-Ah Lee

  4. Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea

    Young-Myeong Kim

  5. Department of Anesthesiology and Pain Medicine, Chungju Hospital, Konkuk University School of Medicine, Chungju, 27376, Republic of Korea

    Hyeyoung Kim

  6. Department of Emergency Medicine, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, 24341, Republic of Korea

    Hyeyoung Kim, Jun Hwi Cho & Myoung Cheol Shin

  7. Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, Republic of Korea

    Joon Ha Park & Ji Hyeon Ahn

  8. Department of Food Science and Nutrition, Hallym University, Chuncheon, 24252, Republic of Korea

    Il Jun Kang

  9. Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea

    In Koo Hwang

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  1. Jae-Chul Lee
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Correspondence to Moo-Ho Won or Myoung Cheol Shin.

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Lee, JC., Shin, BN., Cho, J.H. et al. Brain ischemic preconditioning protects against moderate, not severe, transient global cerebral ischemic injury. Metab Brain Dis 33, 1193–1201 (2018). https://doi.org/10.1007/s11011-018-0231-5

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