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Heat shock protein 90 inhibitors exhibit anti‐inflammatory response and differential cytoprotection pattern from oxidative stress‐ induced injury.
Author(s) -
Kacimi Rachid,
Yenari Midori
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.489.4
Subject(s) - cytoprotection , geldanamycin , oxidative stress , pharmacology , chemistry , viability assay , heat shock protein , microglia , inflammation , programmed cell death , hsp90 , microbiology and biotechnology , apoptosis , immunology , biology , biochemistry , gene
Geldanamycin have emerged as promising therapeutic agents in cancer. Accordingly, we tested the role of GA, 17AAG and radicicol in LPS‐ activated microglia. BV2 cells were treated with LPS with or without GA analogs. 24hr later, media and cell extracts were assayedfor NO and iNOS protein; in parallel injury was examined by viability assays. Pretreatment with GA and its analogs markedly prevent iNOS/NO accumulation elicited by LPS. Conversely, GA and its analogs prevented LPS ‐induced subsequent BV2 death. In addition, treatment of astrocytes with GA for 24hr induces increase of HSP70i expression. Moreover, we found that GA protect from oxidative stress induced by H2O2 in glial cells. To examine the mechanisms of delayed protection in LPS induced injury, cells were incubated with GA and analogs for 1 day, thereafter, cells were subjected to LPS for another 24hr. GA and to lesser extend 17AAG but not radicicol showed a partial blunting in pro‐inflammatory induction of iNOS/NO accumulation and display protection in the delayed window from LPS ‐induced BV2 cell death. Our data together, showed that GA and its analogs exhibit dual protection in brain resident cells: acutely by blocking the signaling that drive inflammatory response elicited by endotoxin or TLR3 agonist, and a delayed protection against oxidative stress. These data support usefulness of the HSP90 targeting to protect from neuro‐inflammatory disease.