Changes in Gene Expression After Brief Ischemic Insults as Potential Mediators of Induced Tolerance: Postischemic Temperature as a Variable Affecting the Stress Response

  • S. Suga
  • T. S. NowakJr


Recent studies have described the induction of tolerance to otherwise damaging ischemic insults following short priming challenges that do not themselves cause severe injury. This effect has been most convincingly demonstrated following brief 2-min ischemic insults in the gerbil [7, 8] after which vulnerability of CA1 neurons to a standard 5-min insult was reduced. Increased expression of the inducible 70-kDa heat shock/stress protein hsp72 in the protected neuron population correlated reasonably well with the time course of observed tolerance during 1 – 4 days of recirculation after the initial insult [7]. Parallel results have been obtained in vitro demonstrating reduced sensitivity of cultured neurons to glutamate toxicity following prior heat shock sufficient to induce hsp72 expression [11, 21]. Induced ischemic tolerance in vivo following hyperthermic stress has also been described [4, 9], although hsp72 expression in CA1 neurons after such insults has not been convincingly demonstrated [12]. Taken together the above studies suggest that the induced expression of hsp72 in otherwise vulnerable neurons may contribute to induced ishemic tolerance.


Ischemic Insult Cereb Blood Flow Hsp70 mRNA Ischemic Tolerance Gerbil Brain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Blake MJ, Nowak TS Jr, Holbrook NJ (1990) In vivo hyperthermia induces expression of HSP70 mRNA in brain regions controlling the neuroendocrine response to stress. Mol Brain Res 8: 89–92PubMedCrossRefGoogle Scholar
  2. 2.
    Buchan A, Pulsinelli WA (1990) Hypothermia but not the N-methyl-D–aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci 10: 311–316PubMedGoogle Scholar
  3. 3.
    Busto R, Dietrich WD, Globus MY-T, Valses I, Scheinberg P, Ginsberg MD (1987) Small differences in intrahemispheric brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7: 729–738PubMedCrossRefGoogle Scholar
  4. 4.
    Chopp M, Chen H, Ho K-L Dereski MO, Brown E, Hetzel FW, Welch KMA (1989) Transient hyperthermia protects against subsequent forebrain ischemic cell damage in the rat. Neurology 39: 1396–1398Google Scholar
  5. 5.
    Dienel GA, Pulsinelli WA, Duffy TE (1980) Regional protein synthesis in rat brain following acute hemispheric ischemia. J Neurochem 35: 1216–1226PubMedCrossRefGoogle Scholar
  6. 6.
    Ikeda J, Hirakawa K, Nowak TS Jr, Klatzo I (1990) Changes in rCBF and edema after transient cerebral ischemia. Ischemic threshold of postischemic hypoperfusion. No To Shinkei 42: 951–957Google Scholar
  7. 7.
    Kirino T, Tsujita Y, Tamura A (1991) Induced tolerance to ischemia in gerbil hippocampal neurons. J Cereb Blood Flow Metab 11: 299–307PubMedCrossRefGoogle Scholar
  8. 8.
    Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, Kamada T (1990) “Ischemic tolerance” phenomenon found in brain. Brain Res 528:21–24Google Scholar
  9. 9.
    Kitagawa K, Matsumoto M, Tagays M, Kuwabara K, Hata R, Handa N, Fukunaga R, Kimura K, Kamada T (1991) Hyperthermia-induced neuronal protection against ischemic injury in gerbils. J Cereb Blook Flow Metab 11: 449–452CrossRefGoogle Scholar
  10. 10.
    Kuroiwa T, Bonnekoh P, Hossmann K-A (1990) Prevention of postischemic hyperthermia prevents ischemic injury of CA1 neurons in gerbils. J Cereb Blood Flow Metab 10: 550–556PubMedCrossRefGoogle Scholar
  11. 11.
    Lowenstein DH, Chan PH, Miles MF (1991) The stress protein response in cultured neurons: characterization and evidence for a protective role in excitotoxicity. Neuron 7: 1053–1060PubMedCrossRefGoogle Scholar
  12. 12.
    Marini AM, Kozuka M, Lipsky RL, Nowak TS Jr (1990) 70-Kiladalton heat shock protein induction in cerebellar astrocytes and cerebellar granule cells in vitro: comparison with immunocytochemical localization after hyperthermia in vivo. J Neurochem 54: 1509–1516Google Scholar
  13. 13.
    Miller EK, Raese JD, Morrison-Bogorad M (1991) Expression of heat shock protein 70 and heat shock cognate 70 messenger RNAs in rat cortex and cerebellum after heat shock or amphetamine treatment. J Neurochem 56: 2060–2071PubMedCrossRefGoogle Scholar
  14. 14.
    Nowak TS Jr (1988) Effects of amphetamine on protein synthesis and energy metabolism in mouse brain: role of drug–induced hyperthermia. J Neurochem 50: 285–294PubMedCrossRefGoogle Scholar
  15. 15.
    Nowak TS Jr (1991) Localization of 70kDa stress protein mRNA induction in gerbil brain after ischemia. J Cereb Blood Flow Metab 11: 432–439PubMedCrossRefGoogle Scholar
  16. 16.
    Nowak TS Jr, Osborne OC (1991) Threshold ischemic duration for stess protein induction in gerbil brain ( Abstr ). Stroke 22: 131Google Scholar
  17. 17.
    Nowak TS Jr, Bond U, Schlesinger MJ (1990) Heat shock RNA levels, in brain and other tissues after hyperthermia and transient ischemia. J Neurochem 54: 451–458PubMedCrossRefGoogle Scholar
  18. 18.
    Nowak TS Jr, Osborne OC, Ikeda J (1992) Role of altered gene expression in development of neuronal changes after ischemia. In: Ito U, Kirino T, Kuroiwa T, Klatzo I (eds) Maturation phenomena in cerebral ischemia. Springer, Berlin, Heidelberg New York, pp 121– 128Google Scholar
  19. 19.
    Nowak TS Jr, Osborne OC, Suga S (1992) Changes in gene expression after transient ischemia as potential markers for excitotoxic pathology. In: Globus MY-T, Dietrich WD (eds) The role of neurotransmitters in brain injury. Plenum, New York, pp 227–232CrossRefGoogle Scholar
  20. 20.
    Nowak TS Jr, Osborne OC, Suga S (1993) Stress protein and proto-oncogene expression as indicators of neuronal pathophysiology after ischemia. Prog Brain Res 96: 195–208PubMedCrossRefGoogle Scholar
  21. 21.
    Rordorf G, Koroshetz WJ, Bonventre JV (1991) Heat shock protects cultured neurons from glutamate toxicity. Neuron 7: 1043–1051PubMedCrossRefGoogle Scholar
  22. 22.
    Roychoudhury R, Wu R (1980) Terminal transferase-catalyzed addition of nucleotides to the 3’ termini of DNA. Methods Enzymol 65: 43–62PubMedCrossRefGoogle Scholar
  23. 23.
    Simon RP, Cho H, Gwinn R, Lowenstein DH (1991) The temporal profile of 72-kDa heatshock protein expression following global ischemia. J Neurosci 11: 881–889PubMedGoogle Scholar
  24. 24.
    Thilmann R, Xie Y, Kleihues P, Kiessling M (1986) Persistent inhibition of protein synthesis precedes delayed neuronal death in postischemic gerbil hippocampus. Acta Neuropathol (Berl) 71: 88–93CrossRefGoogle Scholar
  25. 25.
    Vass K, Welch WJ, Nowak TS Jr (1988) Localization of 70kDa stress protein induction in gerbil brain after ischemia. Acta Neuropathol (Berl) 77: 128–135Google Scholar
  26. 26.
    Welsh FA, Harris VA (1991) Postischemic hypothermia fails to reduce ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab 11: 617–620PubMedCrossRefGoogle Scholar
  27. 27.
    Widmann R, Kuroiwa T, Bonnekoh P, Hossmann K-A (1991) [14C]Leucine incorporation into brain proteins in gerbils after transient ischemia: relationship to selective vulnerability of hippocampus. J Neurochem 56: 789–796Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • S. Suga
    • 1
    • 2
  • T. S. NowakJr
    • 1
    • 3
  1. 1.Stroke Branch, National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA
  2. 2.Department of NeurosurgeryKeio University School of MedicineShinjuku-ku, TokyoJapan
  3. 3.Department of NeurologyUniversity of Tennessee College of MedicineMemphisUSA

Personalised recommendations