Nuances in the molecular controls of gene expression underlying preconditioning against cerebral ischemia

The molecular mechanisms underpinning neuroprotection afforded by preconditioning against cerebral ischemia have been a topic of interest since the first reports detailing that an endogenous induction of protective responses can occur. This review serves to update several modulators of gene expression that contribute to the induction of tolerance by various preconditioning stimuli. We focus here on updated information regarding key transcription factors, including HIF1-alpha, NFkappaB, and NRF2, as well as the more recently explored topic of microRNAs. Pittsburgh Institute of Brain Diseases and Recovery and the Department of Neurology, University of Pittsburgh, Pittsburgh PA 15213. National Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China Correspondence should be addressed to Dr. Anne R. Stetler (stetler@pitt.edu). Conditioning Medicine 2018 | Volume 1 | Issue 3 | April 2018 Introduction Mechanistic studies of brain conditioning that confers tolerance to noxious stimuli are very important for the development of various therapies. Therapies considered “conditioning” confer protection by invoking a “tolerant” state when, if a subsequent stronger challenge occurs, the organism incurs less deleterious outcomes than if the stronger challenge had occurred alone. Harnessing the endogenous programs that biological systems employ could not only uncover new therapeutic targets and timing strategies, but also may elicit fewer side effects to the organism. Induction of a tolerant state is often viewed as biphasic, wherein distinct mechanisms are implicated in rapid and delayed tolerance windows. Delayed tolerance hinges on new protein synthesis and engenders neuronal protection days after the preconditioning stimulus. In contrast, rapid ischemic tolerance produces neuroprotection within minutes to hours, seemingly independent of new gene expression. The mechanisms of both types of brain tolerance involve a large number of molecular and signaling pathways. As the topic of this review centers around alterations in gene expression, we will focus primarily on the induction of delayed preconditioning, but will also draw into literature exploring related mechanisms in the rapid preconditioning window. In addition, given the number of substantial reviews, this article will focus on more recent findings, with references to more seminal papers and articles where relevant. The definition of “conditioning” itself has yielded a generous amount of discussion, some of which certainly goes beyond the scope of this review. For the purposes of this review, we will focus primarily on stimuli that have been widely reported in the literature as conditioning (e.g., mild ischemia, sevoflurane, resveratrol, or mild inflammatory agents), and discuss newer aspects of the regulation of mechanisms underlying these paradigms that appear to be components of exerting tolerance in relation to the regulation of gene expression. Alteration of gene expression as a key to understanding the tolerant state One of the major themes in the molecular adaptive state that confers robust tolerance is the alteration of protein expression. Under classical molecular biology dogma, this process can be specifically controlled at the genome level, with activation or suppression of gene transcription via transcriptional factors or chromatin rearrangement, often controlled by posttranslational modifications on regulatory proteins. However, the recent discovery of the role of non-coding RNAs including microRNAs (miRNA) has revealed that genomic control of protein expression is only a part of the equation. We will discuss updates to the major mechanisms of genome-level transcriptional contribution to tolerance as well as more recent discussion on the potential involvement of miRNAs. Genetic reprogramming Early hypotheses regarding the molecular mechanisms of ischemic preconditioning suggested that alterations in gene/ protein expression may be critical, particularly in the socalled “delayed” window of ischemic tolerance (Chen et al., 1997; Truettner et al., 2002; Gidday, 2006). Multiple studies