Discovery of molecular mechanisms of neuroprotection using cell-based bioassays and oligonucleotide arrays

被引:28
作者
Sarang, SS [1 ]
Yoshida, T [1 ]
Cadet, R [1 ]
Valeras, AS [1 ]
Jensen, RV [1 ]
Gullans, SR [1 ]
机构
[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis,Biotechnol Ctr, Cambridge, MA 02139 USA
关键词
oxidative stress; galanin;
D O I
10.1152/physiolgenomics.00064.2002
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:45 / 52
页数:8
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