PMID:25366476

Citation	Qi, J, Han, X, Liu, HT, Chen, T, Zhang, JL, Yang, P, Bo, SH, Lu, XT and Zhang, J (2014) 17-Dimethylaminoethylamino-17-demethoxygeldanamycin Attenuates Inflammatory Responses in Experimental Stroke. Biol. Pharm. Bull. 37:1713-8
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.
Links	PubMed
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
DANRE:H90A1		GO:0006950: response to stress	ECO:0000314:		P		Figure 1 HSP90 reduced infarct size shows inflammatory response signalling pathway inhibited by 17-DMAG in TCC-stained mouse brain section	complete CACAO 10293
MOUSE:E9Q3D6		GO:0031098: stress-activated protein kinase signaling cascade	ECO:0000315:		P		Fig. 2A and 2B: HSP 90 inhibition with 17-DMAG results in a reduced number of active microglia/macrophages in the peri-infarct region within the ipsilateral ischemic cortex	complete CACAO 10348

References

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