QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 2, 2008, 28(1):163-176; doi:10.1523/JNEUROSCI.3200-07.2008

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Langley, B. Articles by Ratan, R. R. Search for Related Content PubMed PubMed Citation Articles by Langley, B. Articles by Ratan, R. R.

 Previous Article  |  Next Article 

Neurobiology of Disease
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

Brett Langley,^1,2 Melissa A. D'Annibale,¹ Kyungsun Suh,^1,2 Issam Ayoub,³ Aaron Tolhurst,¹ Birgül Bastan,⁴ Lichuan Yang,² Brian Ko,¹ Marc Fisher,⁴ Sunghee Cho,^1,2 M. Flint Beal,² and Rajiv R. Ratan^1,2

¹Burke Medical Research Institute, White Plains, New York 10605, ²Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, ³Department of Neurology, Harvard Medical School and the Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and ⁴Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Correspondence should be addressed to Dr. Brett Langley, Burke/Cornell Medical Research Institute, 785 Mamaroneck Road, White Plains, NY 10605. Email: bcl2002{at}med.cornell.edu

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.

Key words: oxidative stress; histone deacetylase inhibitors; HDAC; cell cycle; apoptosis; neuron(s); cyclin-dependent kinase; Cdk

---

Received Jan. 31, 2007; revised Nov. 9, 2007; accepted Nov. 11, 2007.

Correspondence should be addressed to Dr. Brett Langley, Burke/Cornell Medical Research Institute, 785 Mamaroneck Road, White Plains, NY 10605. Email: bcl2002{at}med.cornell.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help