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Physiol. Genomics (September 17, 2002). doi:10.1152/physiolgenomics.00064.2002
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Articles in PresS, published online ahead of print September 17, 2002
Physiol Genomics, 10.1152/physiolgenomics.00064.2002
Submitted on May 28, 2002
Accepted on September 13, 2002

Discovery of Molecular Mechanisms of Neuroprotection Using Cell Based Bioassays and Oligonucleotide Arrays

Satinder S Sarang1, Takumi Yoshida1, Rudolphe Cadet1, Andrew S Valeras1, Roderick V Jensen1, and Steven R Gullans1*

1 Biotechnology Center, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA

* To whom correspondence should be addressed. E-mail: sgullans{at}rics.bwh.harvard.edu.

Oxidative injury and the resulting death of neurons is a major pathological factor involved in numerous neurodegenerative diseases. However, the development of drugs that target this mechanism remains limited. The goal of this study was to test a compound library of approved Food and Drug Administration drugs against a hydrogen peroxide induced oxidant injury model in neuroblastoma cells. We identified 26 neuroprotective compounds, of which megestrol, meclizine, verapamil, methazolamide, sulindac, and retinol were examined in greater detail. Using large-scale oligonucleotide microarray analysis we identified genes modulated by these drugs that might underlie the cytoprotection. Five key genes were either uniformly upregulated or downregulated by all six drug treatments, namely tissue inhibitor of matrix metalloproteinase (TIMP1), ret-proto-oncogene, clusterin, galanin, and growth associated protein (GAP43). Exogenous addition of the neuropeptide galanin alone conferred survival to oxidant stressed cells, comparable to that seen with the drugs. Our approach, which we term "interventional profiling" represents a general and powerful strategy for identifying new bioactive agents for any biological process, as well as identifying key downstream genes and pathways that are involved.




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