Pulse Inhibition of Histone Deacetylases Induces Complete Resistance to Oxidative Death in Cortical Neurons without Toxicity and Reveals a Role for Cytoplasmic p21^waf1/cip1in Cell Cycle-Independent Neuroprotection

Abstract

is sufficient for neuroprotection, it is not necessary for HDAC inhibitor neuroprotection, because these agents can completely protect neurons cultured from p21 waf1/cip1 -null mice. Together these findings demonstrate (1) that pulse inhibition of HDACs in cortical neurons can induce neuroprotection without apparent toxicity; (2) that p21 waf1/cip1 is sufficient but not necessary to mimic the protective effects of HDAC inhibition; and (3) that oxidative stress in this model induces neuronal cell death via cell cycle-independent pathways that can be inhibited by a cytosolic, noncanonical action of p21 waf1/cip1 .

Epigenetic Mechanisms in Cerebral Ischemia

“…In and around the ischemic core, a general decrease of histone H3 acetylation [46][47][48][49][50] as well as of H4 acetylation levels [51][52][53][54] was identified in multiple studies. Vast deacetylation processes occur quickly upon an ischemic insult and induce a fatal course of events.…”

“…However, in an in vitro model of oxidative stress, p21-deficient neurons show a comparable protection to wild-type cells upon HDACi administration, which suggests that p21 is not an essential component of oxidative stress-induced cell death and hints at possible compensatory mechanisms. 51 Inflammation Post stroke inflammation is one of the more delayed mechanisms and yet a major cause of damage (for reviews, see Dirnagl et al, 4 Priller and Dirnagl, 96 and Price et al 97 ). Many different cell types with their characteristic gene expression patterns are involved in the inflammatory response.…”

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…In addition, toxicity not only depends on the inhibition of HDAC class I isoforms but it is also influenced by the compound's kinetic properties that are crucial to maintain cell viability (Lauffer et al, 2013). It has been hypothesized that a short exposure of neurons to HDACis may be sufficient to provide neuroprotection while avoiding toxicity (Langley et al, 2008). In fact, HDACi with fast dissociation kinetics rates (such as hydroxamates) limit the overexpression of genes involved in cell cycle regulation and thus cytotoxicity (Lauffer et al, 2013).…”

Novel Protective Effects of Histone Deacetylase Inhibition on Stroke and White Matter Ischemic Injury

“…It was shown that pulsed exposure of cultured embryonic cortical neurons to HDAC inhibitors blocked cell death induced by oxidative stress [43], and that protection was associated with transcriptional activation of the cell cycle inhibitor, p21. Overexpression of p21 in neurons mimicked the protective effect of HDAC inhibitors against oxidative stress-induced toxicity, including death induced by glutathione depletion or peroxide addition.…”

“…Overexpression of p21 in neurons mimicked the protective effect of HDAC inhibitors against oxidative stress-induced toxicity, including death induced by glutathione depletion or peroxide addition. However, despite p21 induction being sufficient to promote neuronal survival in embryonic neurons subjected to oxidative stress, it was not necessary, as HDAC inhibitors conferred protection on neurons from p21-deficient mice [43].…”