Title

Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21(waf1/cip1) in cell cycle-independent neuroprotection

UMMS Affiliation

Department of Neurology

Publication Date

2008-01-04

Document Type

Article

Subjects

Analysis of Variance; Animals; Cell Cycle; Cell Death; Cells, Cultured; Cerebral Cortex; Cyclin-Dependent Kinase Inhibitor p21; Drug Interactions; Embryo, Mammalian; Enzyme Inhibitors; Glutamic Acid; Green Fluorescent Proteins; Hippocampus; Histone Deacetylase Inhibitors; Histone Deacetylases; Infarction, Middle Cerebral Artery; Neurons; Oxidative Stress; Rats; Rats, Sprague-Dawley; Transfection

Disciplines

Neurology | Neuroscience and Neurobiology

Abstract

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, p21(waf1/cip1), both in this model and in an in vivo model of permanent ischemia. Transgenic overexpression of p21(waf1/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 p21(waf1/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 p21(waf1/cip1) 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).

DOI of Published Version

10.1523/JNEUROSCI.3200-07.2008

Source

J Neurosci. 2008 Jan 2;28(1):163-76. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

Related Resources

Link to Article in PubMed

PubMed ID

18171934

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