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

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.

The Interventional Effect of Remote Ischemic Preconditioning on Cerebral Small Vessel Disease: A Pilot Randomized Clinical Trial

“…The reason why RIPC can mitigate brain injuries attributed to SVD remains unclear, but ischemia resulting from narrowed or occluded small vessels is assumed to be the major mechanism underlying SVD-related brain injury initiated by endothelial damage. Mechanisms such as neural pathways [41] , humoral pathways [42,43] and genetic expression [44] have been proposed while many molecules and substances involved in inflammatory responses including heat shock proteins, adenosine, nitric oxide and opioid receptors have been suggested to mediate the neuroprotective function of RIPC [45,46] .…”

Intralesional Patterns of MRI ADC Maps Predict Outcome in Experimental Stroke

“…Several explanations for this diversity in functional outcome have been brought forward and include individual variability in collateral circulation, preconditioning, and microcirculation response after ischemic insult [10,11]. However, the relation between heterogeneous patterns in ADC maps and functional outcome has not yet been addressed in the clinical setting.…”

Forebrain Ischemic Stroke and the Phenomenon of Ischemic Tolerance: Is Homocysteine Foe or Friend?

“…In the clinical setings of human stroke, which is hardly predicted, a novel algorithm of postconditioning may have a very high therapeutic value. Remarkably, it could be used afterward of ictus to stimulate protective and regenerative pathways or as a precaution against stroke recurrence [1,12,1 ]. Clinical studies are needed to test the safety and eicacy of these novel strategies in humans [ , ].…”

“…However, a bit surprisingly, the experimental results, which are focused on the mutual inluence of the comorbid hyperhomocysteinemia to ischemic damage on the animal models of human stroke, are only limited [12,2,7]. Ischemic insult/reperfusion insult in the animal models is followed by the degeneration of majority more than 6 % of hippocampal neurons [ , ].…”