MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on December 22, 2008; DOI: 10.1124/mol.108.052183

0026-895X/09/7503-667-676$20.00
Mol Pharmacol 75:667-676, 2009

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.108.052183v1
75/3/667    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Humar, M.
Right arrow Articles by Pannen, B. H. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Humar, M.
Right arrow Articles by Pannen, B. H. J.

Heterocyclic Thioureylenes Protect from Calcium-Dependent Neuronal Cell Death

Matjaz Humar, Christine Graetz, Martin Roesslein, Ulrich Goebel, Klaus K. Geiger, Bernd Heimrich, and Benedikt H. J. Pannen

Center for Clinical Research, Department of Anesthesiology and Critical Care Medicine, University Hospital Freiburg, Freiburg, Germany (M.H., C.G., U.G., K.K.G.); Clinic for Anesthesiology, Ludwig-Maximilians-University Munich, Munich, Germany (M.R.); Institute of Anatomy and Cell Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany (B.H.); and Department of Anesthesiology, University Hospital Duesseldorf, Duesseldorf, Germany (B.H.J.P.)

Calcium-dependent cell death occurs in neurodegenerative diseases and ischemic or traumatic brain injury. We analyzed whether thioureylenes can act in a neuroprotective manner by pharmacological suppression of calcium-dependent pathological pathways. In human neuroblastoma (SK-N-SH) cells, thioureylenes (thiopental, carbimazole) inhibited the calcium-dependent neuronal protein phosphatase (PP)-2B, the activation of the proapoptotic transcription factor nuclear factor of activated T-cells, BAD-induced initiation of caspase-3, and poly-(ADP-ribose)-polymerase cleavage. Caspase-3-independent cell death was attenuated by carbimazole and the protein kinase C (PKC) {delta} inhibitor rottlerin by a PP-2B-independent mechanism. Neuroprotective effects were mediated by the redox-active sulfur of thioureylenes. Furthermore, we observed that the route of calcium mobilization was differentially linked to caspase-dependent or independent cell death and that BAD dephosphorylation did not necessarily induce intrinsic caspase activation. In addition, a new 30- to 35-kDa caspase-3 fragment with an unknown function was identified. In organotypic hippocampal slice cultures, thioureylenes inhibited caspase-3 activation or reduced N-methyl-D-aspartate and kainic acid receptor-mediated cell death that was independent of caspase-3. Because prolonged inhibition of caspase-3 resulted in caspase-independent cellular damage, different types of cell death must be taken under therapeutic consideration. Here we show that thioureylenes in combination with PKC{delta} inhibitors might represent a promising therapeutic approach to attenuate neuronal damage.

Received for publication September 23, 2008.

Accepted for publication December 22, 2008.

Address correspondence to: Dr. Matjaz Humar, Center for Clinical Research, Department of Anesthesiology and Critical Care Medicine, University Hospital Freiburg, Breisacherstrasse 66, D-79106 Freiburg, Germany. E-mail: humar{at}ana1.ukl.uni-freiburg.de






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2009 by the American Society for Pharmacology and Experimental Therapeutics