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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 25, 2007, 27(17):4562-4571; doi:10.1523/JNEUROSCI.5110-06.2007

This Article Full Text Full Text (PDF) Supplemental Data 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 Harms, C. Articles by Hörtnagl, H. Search for Related Content PubMed PubMed Citation Articles by Harms, C. Articles by Hörtnagl, H.

 Previous Article  |  Next Article 

Neurobiology of Disease
Phosphatidylinositol 3-Akt-Kinase-Dependent Phosphorylation of p21^Waf1/Cip1 as a Novel Mechanism of Neuroprotection by Glucocorticoids

Christoph Harms,^1,2 Katharina Albrecht,³ Ulrike Harms,¹ Kerstin Seidel,³ Ludger Hauck,⁴  Tina Baldinger,^1,2 Denise Hübner,^1,2 Golo Kronenberg,^1,5 Junfeng An,⁴ Karsten Ruscher,¹ Andreas Meisel,¹ Ulrich Dirnagl,⁶ Rüdiger von Harsdorf,⁴  Matthias Endres,^1,2 and Heide Hörtnagl³

¹Klinik und Poliklinik für Neurologie, ²Neurowissenschaftliches Forschungszentrum, and ³Institut für Pharmakologie und Toxikologie, Charité Campus Mitte, Charité–Universitätsmedizin Berlin, D-10117 Berlin, Germany, ⁴Max Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany, ⁵Klinik und Poliklinik für Psychiatrie, Charité Campus Benjamin Franklin, D-14050 Berlin, Germany, and ⁶Abteilung für Experimentelle Neurologie, Charité–Universitätsmedizin Berlin, D-10117 Berlin, Germany

Correspondence should be addressed to either of the following: Dr. Matthias Endres, Klinik und Poliklinik für Neurologie, Charitéplatz 1, D-10117 Berlin, Germany, Email: matthias.endres{at}charite.de; or Dr. Heide Hörtnagl, Institut für Pharmakologie und Toxikologie, Charité, Dorotheenstrasse 94, D-10117 Berlin, Germany, Email: heide.hoertnagl{at}charite.de

The role of glucocorticoids in the regulation of apoptosis remains incongruous. Here, we demonstrate that corticosterone protects neurons from apoptosis by a mechanism involving the cyclin-dependent kinase inhibitor p21^Waf1/Cip1. In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21^Waf1/Cip1 at Thr 145. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21^Waf1/Cip1 preceding apoptosis in neurons. These effects of AF64A are reversed by pretreatment with corticosterone. Corticosterone-mediated upregulation of p21^Waf1/Cip1 and neuroprotection are completely abolished by glucocorticoid and mineralocorticoid receptor antagonists as well as inhibitors of PI3- and Akt-kinase. Both germline and somatically induced p21^Waf1/Cip1 deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21^Waf1/Cip1 suffices to protect neurons from apoptosis. We identify p21^Waf1/Cip1 as a novel antiapoptotic factor for postmitotic neurons and implicate p21^Waf1/Cip1 as the molecular target of neuroprotection by high-dose glucocorticoids.

Key words: apoptosis; neuroprotection; cortical neurons; p21^Waf1/Cip1; glucocorticoid; Akt-kinase

---

Received July 19, 2006; revised March 6, 2007; accepted March 19, 2007.

Correspondence should be addressed to either of the following: Dr. Matthias Endres, Klinik und Poliklinik für Neurologie, Charitéplatz 1, D-10117 Berlin, Germany, Email: matthias.endres{at}charite.de; or Dr. Heide Hörtnagl, Institut für Pharmakologie und Toxikologie, Charité, Dorotheenstrasse 94, D-10117 Berlin, Germany, Email: heide.hoertnagl{at}charite.de

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help