Skip to main content
NCBI home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2012 Jul 11;28(3):316–320. doi: 10.1007/s12264-012-1222-x

Hypoxic preconditioning in an autohypoxic animal model

Guo Shao 1,2,4, Guo-Wei Lu 2,3,✉
PMCID: PMC5560319  PMID: 22622832

Abstract

Hypoxic preconditioning refers to the exposure of organisms, systems, organs, tissues or cells to moderate hypoxia/ischemia that results in increased resistance to a subsequent episode of severe hypoxia/ischemia. In this article, we review recent research based on a mouse model of repeated exposure to autohypoxia. Pre-exposure markedly increases the tolerance to or protection against hypoxic insult, and preserves the cellular structure of the brain. Furthermore, the hippocampal activity amplitude and frequency of electroencephalogram, latency of cortical somatosensory-evoked potential and spinal somatosensory-evoked potential progressively decrease, while spatial learning and memory improve. In the brain, detrimental neurochemicals such as free radicals are down-regulated, while beneficial ones such as adenosine are upregulated. Also, antihypoxia factor(s) and gene(s) are activated. We propose that the tolerance and protective effects depend on energy conservation and plasticity triggered by exposure to hypoxia via oxygen-sensing transduction pathways and hypoxia-inducible factor-initiated cascades. A potential path for further research is the development of devices and pharmaceuticals acting on antihypoxia factor(s) and gene(s) for the prevention and treatment of hypoxia and related syndromes.

Keywords: hypoxia, hypoxic preconditioning, adaptive medicine

References

  • [1].Lu G.W. Tissue-cell adaptation to hypoxia. Adv Pathophysiol. 1963;1:197–239. [Google Scholar]
  • [2].Janoff A. Alterations in lysosomes (intracellular enzymes) during shock; effects of preconditioning (tolerance) and protective drugs. Int Anesthesiol Clin. 1964;2:251–269. doi: 10.1097/00004311-196402000-00008. [DOI] [PubMed] [Google Scholar]
  • [3].Murry C.E., Jennings R.B., Reimer K.A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136. doi: 10.1161/01.CIR.74.5.1124. [DOI] [PubMed] [Google Scholar]
  • [4].Schurr A., Reid K.H., Tseng M.T., West C., Rigor B.M. Adaptation of adult brain tissue to anoxia and hypoxia in vitro. Brain Res. 1986;374:244–248. doi: 10.1016/0006-8993(86)90418-X. [DOI] [PubMed] [Google Scholar]
  • [5].Tang Y.L., Zhu W., Cheng M., Chen L., Zhang J., Sun T., et al. Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression. Circ Res. 2009;104:1209–1216. doi: 10.1161/CIRCRESAHA.109.197723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Giusti S., Fiszer de Plazas S. Neuroprotection by hypoxic preconditioning involves upregulation of hypoxia-inducible factor-1 in a prenatal model of acute hypoxia. J Neurosci Res. 2012;90(2):468–478. doi: 10.1002/jnr.22766. [DOI] [PubMed] [Google Scholar]
  • [7].Miller B.A., Perez R.S., Shah A.R., Gonzales E.R., Park T.S., Gidday J.M. Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion. Neuroreport. 2001;12:1663–1669. doi: 10.1097/00001756-200106130-00030. [DOI] [PubMed] [Google Scholar]
  • [8].Kitagawa K., Matsumoto M., Tagaya M., Hata R., Ueda H., Niinobe M., et al. ’Ischemic tolerance’ phenomenon found in the brain. Brain Res. 1990;528:21–24. doi: 10.1016/0006-8993(90)90189-I. [DOI] [PubMed] [Google Scholar]
  • [9].Marshall J.M., Metcalfe J.D. Analysis of the cardiovascular changes induced in the rat by graded levels of systemic hypoxia. J Physiol. 1988;407:385–403. doi: 10.1113/jphysiol.1988.sp017422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Hu X., Wei L., Taylor T.M., Wei J., Zhou X., Wang J.A., et al. Hypoxic preconditioning enhances bone marrow mesenchymal stem cell migration via Kv2.1 channel and FAK activation. Am J Physiol Cell Physiol. 2011;301:C362–372. doi: 10.1152/ajpcell.00013.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Ara J., Fekete S., Frank M., Golden J.A., Pleasure D., Valencia I. Hypoxic-preconditioning induces neuroprotection against hypoxiaischemia in newborn piglet brain. Neurobiol Dis. 2011;43:473–485. doi: 10.1016/j.nbd.2011.04.021. [DOI] [PubMed] [Google Scholar]
  • [12].Lu G., Ding D., Shi M. Acute adaptation of mice to hypoxic hypoxia. Biol Signals Recept. 1999;8:247–255. doi: 10.1159/000014594. [DOI] [PubMed] [Google Scholar]
  • [13].Lu G.W., Shi M.T., Li L. Effects of acute repetitive exposure to hypoxia on hypoxic tolerance. Chin J Pathophysiol. 1992;8:425–429. [Google Scholar]
  • [14].Dong C.Z., Lu G.W. Effects of brain homogenate extract of hypoxic preconditioned mice on PC12 cells. J Capital Univ Med Sci. 2001;22:97–99. [Google Scholar]
  • [15].Liu L., Lu G.W. Protective effect of brain homogenate of hypoxic preconditioned mice on rat cortical synaptosomes. Chin J Neurosci. 2001;17:373–375. [Google Scholar]
  • [16].Zhang J.B., Zhang Z.S., Lu G.W. Light microscopic observation on hippocampal neurons of mice acutely and repetitively exposed to hypoxia. J Armed Policeman Med. 1996;6:313–316. [Google Scholar]
  • [17].Li J., Lu G.W. Study of ultrastructure of cerebral cortex neuron in acute repeated hypoxia mice. J N China Coal Med Coll. 2002;4:548–549. [Google Scholar]
  • [18].Liang Y.J., Lu G.W. The expression of hypoxia inducible factor-1 and eNOS in hypoxia preconditioned mice. Acta Anat Sin. 2002;33:420–423. [Google Scholar]
  • [19].Li H.T., Lu G.W. Effects of acute and repetitive hypoxia on electrical activity of hippocampus. Chin J Appl Physiol. 1996;12:124–128. [Google Scholar]
  • [20].Shao G., Zhang R., Wang Z.L., Gao C.Y., Huo X., Lu G.W. Hypoxic preconditioning improves spatial cognitive ability in mice. Neurosignals. 2006;15:314–321. doi: 10.1159/000121368. [DOI] [PubMed] [Google Scholar]
  • [21].Li J.F., Han S., Zhu P.Y., Lu G.W. Membrane translocation of protein kinase C is increased by hypoxic preconditioning in mice. Basic Med Clin. 2003;23:382–382. [Google Scholar]
  • [22].Cui X.Y., Li L., An Y.Y., Lu G.W. Changes in the contents of glycogen and lactate in the brain and blood during hypoxic preconditioning. Acta Physiol Sin. 2001;53:325–328. [PubMed] [Google Scholar]
  • [23].Duan C., Yan F., Song X., Lu G.W. Changes of superoxide dismutase, glutathione perioxidase and lipid peroxides in the brain of mice preconditioned by hypoxia. Biol Signals Recept. 1999;8:256–260. doi: 10.1159/000014595. [DOI] [PubMed] [Google Scholar]
  • [24].Duan C.L., Liu H.Y., Lu G.W. Role of reactive oxygen species in hypoxic preconditioning. Chin J Neuroanat. 1999;17:377–379. [Google Scholar]
  • [25].Hou Y.Z., Jiao X.H., Lu G.W., Gao C.Y. Effects of repetitive hypoxia on NPY like immunity in the brain of mice. Chin J Pathophysiol. 2001;17:1016–1018. [Google Scholar]
  • [26].Hou Y.Z., Jiao X.H., Lu G.W., Gao C.Y. Changes of contents of CGRP and Ang II in the brain of mice during hypoxic preconditioning. Basic Med Clin. 2002;22:524–526. [Google Scholar]
  • [27].Liu H.Y., Wu D., Lu G.W. Role of excitatory amino acids in formation of hypoxic preconditioning. Chin J Appl Physiol. 2000;16:342–344. [Google Scholar]
  • [28].Lu G.W., Liu H.Y. Downregulation of nitric oxide in the brain of mice during their hypoxic preconditioning. J Appl Physiol. 2001;91:1193–1198. doi: 10.1152/jappl.2001.91.3.1193. [DOI] [PubMed] [Google Scholar]
  • [29].Wang Y.S., Li J.F., Han S., Lu G.W. Phosphorylation level of JNK1 increased by hypoxic preconditioning. Nerv Dis Mental Health. 2003;3:334–337. [Google Scholar]
  • [30].Xie J., Lu G.W., Hou Y.Z. Role of excitatory amino acids in hypoxic preconditioning. Biol Signals Recept. 1999;8:267–274. doi: 10.1159/000014597. [DOI] [PubMed] [Google Scholar]
  • [31].Zhang J.N., Yan S.L., Liu Y.L., Lu G.W., Gan W.J. Changes of Na-KATPase and Ca-ATPase activity during repetitive exposure to hypoxia in mice. Chin J Appl Physiol. 1994;10:237–239. [Google Scholar]
  • [32].Zhao G., Cui X.Y., Lu G.W. Effects of repeated hypoxia and H2O2 on lactate production in brain and synaptome. Chin J Appl Physiol. 1999;15:70–73. [Google Scholar]
  • [33].Zhao G., Liu H.Y., Lu G.W. Role of calcium ion in cerebral hypoxic preconditioning. Chin J Neuroanat. 2001;37:136–140. [Google Scholar]
  • [34].Zhang W.L., Lu G.W. Effects of acute repeated hypoxia on adenosine and its A1 receptor in mouse brain of mice. Chin J Appl Physiol. 1997;13:114–117. [PubMed] [Google Scholar]
  • [35].Zhang Y.B., Lu G.W., Yang M.F., Niu J.Z., Sun B.L. Changes in Bcl-2 and Caspase-3 expressions in cortex of hypoxic preconditioning mice. Acta Physiol Sin. 2008;60:249–253. [PubMed] [Google Scholar]
  • [36].Shao G., Gong K.R., Li J., Xu X.J., Gao C.Y., Zeng X.Z., et al. Antihypoxic effects of neuroglobin in hypoxia-preconditioned mice and SH-SY5Y cells. Neurosignals. 2009;17:196–202. doi: 10.1159/000209867. [DOI] [PubMed] [Google Scholar]
  • [37].Shao G., Gao C.Y., Lu G.W. Alterations of hypoxia-inducible factor-1 alpha in the hippocampus of mice acutely and repeatedly exposed to hypoxia. Neurosignals. 2005;14:255–261. doi: 10.1159/000088641. [DOI] [PubMed] [Google Scholar]
  • [38].Zhang X.F., Lu G.W. Effect of brain extract of hypoxic preconditioned mice on activity of ATP sensitive potassium channel in hippocampal neurons. Natl Med J. 2002;82:108–110. [PubMed] [Google Scholar]
  • [39].Lu G.W., Cui X.Y., Gao C.Y., Shao G. Hypoxic Preconditioning: A Novel Principle and Strategy for Prevention and Treatment of Hypoxia. Beijing: Peking University Medical Press; 2005. pp. 276–293. [Google Scholar]
  • [40].Lu G.W. Pathways of hypoxic responses. Progr Physiol Sci. 2001;32:65–67. [PubMed] [Google Scholar]
  • [41].Lu G.W. Hypoxic tolerant strategy of cells of hypoxic tolerant animals. J High Altitude Med. 2001;11:65–67. [Google Scholar]
  • [42].Lu G.W. Progresses of/prospects for hypoxic preconditioning. Prog Physiol Sci. 2007;32:32–36. [PubMed] [Google Scholar]
  • [43].Lu G.W., Yu S., Li R.H., Cui X.Y., Gao C.Y. Hypoxic preconditioning: a novel intrinsic cytoprotective strategy. Mol Neurobiol. 2005;31:255–271. doi: 10.1385/MN:31:1-3:255. [DOI] [PubMed] [Google Scholar]
  • [44].Abu-Amara M., Yang S.Y., Quaglia A., Rowley P., Tapuria N., Seifalian A.M., et al. Effect of remote ischemic preconditioning on liver ischemia/reperfusion injury using a new mouse model. Liver Transpl. 2011;17:70–82. doi: 10.1002/lt.22204. [DOI] [PubMed] [Google Scholar]
  • [45].Hong D.M., Mint J.J., Kim J.H., Sohn I.S., Lim T.W., Lim Y.J., et al. The effect of remote ischaemic preconditioning on myocardial injury in patients undergoing off-pump coronary artery bypass graft surgery. Anaesth Intensive Care. 2010;38:924–929. doi: 10.1177/0310057X1003800518. [DOI] [PubMed] [Google Scholar]
  • [46].Jean-St-Michel E., Manlhiot C., Li J., Tropak M., Michelsen M.M., Schmidt M.R., et al. Remote preconditioning improves maximal performance in highly trained athletes. Med Sci Sports Exerc. 2011;43:1280–1286. doi: 10.1249/MSS.0b013e318206845d. [DOI] [PubMed] [Google Scholar]
  • [47].Hu S., Dong H.L., Li Y.Z., Luo Z.J., Sun L., Yang Q.Z., et al. Effects of remote ischemic preconditioning on biochemical markers and neurologic outcomes in patients undergoing elective cervical decompression surgery: a prospective randomized controlled trial. J Neurosurg Anesthesiol. 2010;22:46–52. doi: 10.1097/ANA.0b013e3181c572bd. [DOI] [PubMed] [Google Scholar]
  • [48].Murphy T., Walsh P.M., Doran P.P., Mulhall K.J. Transcriptional responses in the adaptation to ischaemia-reperfusion injury: a study of the effect of ischaemic preconditioning in total knee arthroplasty patients. J Transl Med. 2010;8:46. doi: 10.1186/1479-5876-8-46. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES