Targeting Histone Deacetylases as a Multifaceted Approach to Treat the Diverse Outcomes of Stroke

Abstract

Abstract-Achieving therapeutic efficacy in ischemic stroke represents one of the biggest challenges in translational neurobiology. Despite extensive efforts, tissue plasminogen activator remains the only available intervention for enhancing functional recovery in humans once a stroke has occurred. To expand the repertoire of therapeutic options in stroke, one must consider and target its diverse pathophysiologies that trigger cell loss in a manner that also permits and enhances neuronal plasticity and repair. Several converging lines of inquiry suggest that histone deacetylase (HDAC) inhibition could be a strategy to achieve these goals. Here, we review evidence that targeting HDACs with low-molecular-weight inhibitors significantly decreases neuronal injury and improves functional outcome in multiple preclinical models of focal ischemia. Key Words: focal ischemia Ⅲ histone deacetylase inhibitors Ⅲ neuroprotection Ⅲ plasticity Ⅲ memory S troke is one of the leading causes of death and adult disability worldwide. The large majority (60% to 80%) of strokes in the Western world are ischemic, which result from an occlusion of a major cerebral artery by a thrombus or embolism. The other major type of stroke is hemorrhagic, which results from a blood vessel rupture either in the brain or on its surface. 1 The consequence of both of these events is a significant reduction in blood flow and nutrients critical for neural function and survival.Despite this common origin, there are numerous factors that impact stroke outcome. For example, whether the occlusion is of large or small vessels, the particular brain region involved, the differing vulnerabilities of cell types within these regions, the patients age, gender, ethnicity, comorbidities, and concurrent medications, all have a considerable impact on stroke outcome. There is also heterogeneity with regard to mechanisms responsible for cell death. Within the focal ischemic core, a rapid excitatory death, characterized by energy failure, membrane depolarization, excitatory glutamate and calcium overload, occurs within minutes to hours after stroke. Alternatively, in the penumbra, the region surrounding the core infarct area that experiences less ischemia and has more energy, a more delayed apoptotic-type of death occurs over days to weeks. 2 The penumbral region is the target for many neuroprotective drugs, as this is where tissue can still be salvaged. However, with the exception of tissue plasminogen activator (tPA), no such compound has yet received U.S. approval for this application. Indeed, the last 2 decades have seen a number of neuroprotective agents and strategies, with good preclinical efficacy, fail to translate to efficacy in human patients. 3 Nevertheless, there is optimism that given a better understanding of the heterogeneity of stroke, and the realization that more complex multi-targeted approaches are required to meet this heterogeneity, a clinical therapeutic intervention for acute stroke can be attained. A second consideration of critical import with re...

LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons

“…However, maintaining acetylation of certain transcription factors (like Stat3, NFkB, and SP1) with HDAC inhibitors can activate genes involved in neuronal survival [41,42]. Several studies have shown that HDAC inhibitors significantly decrease neuronal injury and improve functional outcomes in multiple preclinical models of focal cerebral ischemia (see review by Langley [41]). Therefore, selecting the correct type and dose of HDAC inhibitor could be useful in the treatment of cerebral ischemia following stroke [42].…”

Mechanisms and treatment of ischaemic stroke—insights from genetic associations

“…39 Levels of HDAC9 mRNA expression were found to be elevated above normal levels in carotid athero sclerotic plaques compared with non diseased arterial wall. 38 Interestingly, this elevation was seen to a greater degree in carotid plaques than in athero sclerotic plaques elsewhere in the body.…”

Interplay between histone acetylation/deacetylation and poly(ADP-ribosyl)ation in the development of ischemic tolerance in vitro

“…Numerous studies have demonstrated that in experimental models of cerebral ischemia in vivo there is an imbalance in the acetylation/deacetylation homeostasis that can be prevented by using HDAC inhibitors that restore histone acetylation levels (see for reviews: (Langley et al, 2009;Gibson and Murphy, 2010;Schweizer et al, 2013). Along this line, we have previously demonstrated that in the ischemic brain tissue of rats subjected to middle cerebral artery occlusion for 6 h, histone H3 acetylation levels were drastically reduced, with no evidence for a concomitant change of histone acetyl-transferase or deacetylase activities, and that treatment with the HDAC inhibitor SAHA increased histone acetylation in the normal brain and prevented deacetylation in the ischemic brain (Faraco et al, 2006).…”

“…A number of studies (reviewed in: Langley et al, 2009;Gibson and Murphy, 2010;Schweizer et al, 2013) have shown that histone acetylation is reduced following cerebral ischemia and that class I, II and IV HDAC inhibitors are able to ameliorate neuronal death and cognitive deficits following transient (Endres et al, 2000;Ren et al, 2004;Qi et al, 2004;Faraco et al, 2006;Yildrim et al, 2008;Wang et al, 2012) and permanent Langley et al, 2008;Kim et al, 2009) focal ischemia and in a model of transient global ischemia (Xuan et al, 2012). These effects appear to be due to the maintenance of histone acetylation levels, the expression of cell survival (Bcl-2, Bcl-XL, Hsp70) and regenerative (BDNF) pathways, and the downregulation of pro-inflammatory genes (COX-2, iNOS, TNF-a, IL-b) (Faraco et al, 2006;Kim et al, 2007Kim et al, , 2009.…”