title: 17-Dimethylaminoethylamino-17-demethoxygeldanamycin attenuates inflammatory responses in experimental stroke.
abstract: Heat shock protein 90 (HSP90) is a ubiquitous molecular chaperone involved in the proper conformation of many proteins. HSP90 inhibitors (17-dimethyl aminoethylamino-17-demethoxygeldanamycin hydrochloride [17-DMAG]) bind to and inactivate HSP90, suppressing some key signaling pathways involved in the inflammatory process. Since considerable evidence suggests that inflammation accounts for the progression of cerebral ischemic injury, we investigated whether 17-DMAG can modulate inflammatory responses in middle cerebral artery occluded (MCAO) mice. Male C57/BL6 mice were pretreated with 17-DMAG or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Mice were evaluated at 24 h after MCAO for neurological deficit scoring. Moreover, the mechanism of the anti-inflammatory effect of 17-DMAG was investigated with a focus on nuclear factor kappa B (NF-κB) pathway. 17-DMAG significantly reduced cerebral infarction and improved neurological outcome. 17-DMAG suppressed activation of microglia and decreased phosphorylation of inhibitory (I)κB and subsequent nuclear translocation of p65, which eventually downregulated expression of NF-κB-regulated genes. These results suggest that 17-DMAG has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism.
authors.affiliation: Department of Pharmacy, Xinhua Hospital, Shanghai Jiaotong University.
authors.forename: Jia
authors.initials: J
authors.lastname: Qi
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.forename: Hai Tao
authors.initials: HT
authors.lastname: Liu
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Jin Lian
authors.initials: JL
authors.lastname: Zhang
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Shu Hong
authors.initials: SH
authors.lastname: Bo
authors.forename: Xiao Tong
authors.initials: XT
authors.lastname: Lu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin