RT Journal Article SR Electronic T1 Pulse Inhibition of Histone Deacetylases Induces Complete Resistance to Oxidative Death in Cortical Neurons without Toxicity and Reveals a Role for Cytoplasmic p21waf1/cip1 in Cell Cycle-Independent Neuroprotection JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 163 OP 176 DO 10.1523/JNEUROSCI.3200-07.2008 VO 28 IS 1 A1 Brett Langley A1 Melissa A. D'Annibale A1 Kyungsun Suh A1 Issam Ayoub A1 Aaron Tolhurst A1 Birgül Bastan A1 Lichuan Yang A1 Brian Ko A1 Marc Fisher A1 Sunghee Cho A1 M. Flint Beal A1 Rajiv R. Ratan YR 2008 UL http://www.jneurosci.org/content/28/1/163.abstract AB Histone deacetylase (HDAC) inhibitors are currently in human clinical trials as antitumor drugs because of their ability to induce cell dysfunction and death in cancer cells. The toxic effects of HDAC inhibitors are also apparent in cortical neurons in vitro, despite the ability of these agents to induce significant protection in the cells they do not kill. Here we demonstrate that pulse exposure of cortical neurons (2 h) in an in vitro model of oxidative stress results in durable neuroprotection without toxicity. Protection was associated with transcriptional upregulation of the cell cycle inhibitor, p21waf1/cip1, both in this model and in an in vivo model of permanent ischemia. Transgenic overexpression of p21waf1/cip1 in neurons can mimic the protective effect of HDAC inhibitors against oxidative stress-induced toxicity, including death induced by glutathione depletion or peroxide addition. The protective effect of p21waf1/cip1 in the context of oxidative stress appears to be unrelated to its ability to act in the nucleus to inhibit cell cycle progression. However, although p21waf1/cip1 is sufficient for neuroprotection, it is not necessary for HDAC inhibitor neuroprotection, because these agents can completely protect neurons cultured from p21waf1/cip1-null mice. Together these findings demonstrate (1) that pulse inhibition of HDACs in cortical neurons can induce neuroprotection without apparent toxicity; (2) that p21waf1/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 p21waf1/cip1.