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Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

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Neurotherapeutics

Abstract

Ischemic preconditioning is an innate neuroprotective mechanism in which a sub-injurious ischemic exposure increases the brain’s ability to withstand a subsequent, normally injurious ischemic insult. Part of ischemic preconditioning neuroprotection stems from an epigenetic reprogramming of the brain to a phenotype of ischemic tolerance, which results in a gene expression profile different from that observed in the non-injured and ischemia-injured brains. Such neuroprotective reprograming, activated by ischemic preconditioning, requires specific changes in DNA accessibility coordinated with activation of transcriptional activator and repressor proteins, which allows for expression of specific neuroprotective proteins despite a general repression of gene expression. In this review we examine the effects of injurious ischemia and ischemic preconditioning on the regulation of DNA methylation, histone post-translational modifications, and non-coding RNA expression. There is increasing interest in the role of epigenetics in disease pathobiology, and whether and how pharmacological manipulation of epigenetic processes may allow for ischemic neuroprotection. Therefore, a better understanding of the epigenomic determinants underlying the modulation of gene expression that lead to ischemic tolerance or cell death offers the promise of novel neuroprotective therapies that target global reprograming of genomic activity versus individual cellular signaling pathways.

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Acknowledgments

This work was supported by National Institutes of Health grants NS45676, NS054147 and NS34773 (to M.A.P.P), and NS073779 (to K.R.D.) and by a Postdoctoral award from the American Heart Association, Greater Southeast Affiliate (to J.W.T). The authors declare no competing financial interests. Full conflict of interest disclosures are available in the electronic supplementary materials for this article.

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  1. Cerebral Vascular Disease Research Laboratories, Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA

    John W. Thompson, Kunjan R. Dave & Miguel A. Perez-Pinzon

  2. John P. Hussman Institute for Human Genomics and Dr. John T. Macdonald Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA

    Juan I. Young

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  1. John W. Thompson
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Correspondence to John W. Thompson.

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Thompson, J.W., Dave, K.R., Young, J.I. et al. Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance. Neurotherapeutics 10, 789–797 (2013). https://doi.org/10.1007/s13311-013-0202-9

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