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.Key words heat shock protein 90 (HSP90); stroke; inflammation Acute ischemic stroke is one of the most frequent causes of death and permanent disability in adults worldwide.1) Although various mechanisms are involved in the pathogenesis of stroke, recent work has demonstrated that inflammatory responses accompanying necrotic brain injury contribute to ischemic pathology, and anti-inflammatory strategies have become popular.2) Nuclear factor-kappa B (NF-κB) is a central regulator of inflammatory response in ischemic stroke, whose activation is required for the transcriptional induction of many proinflammatory mediators involved in innate immunity, such as cellular adhesion molecules, cytokines, and growth factors.3) Indeed, it has been evidenced that factors that modulate the activity of NF-κB could potentially regulate inflammatory processes in ischemic stroke. 4)Heat shock protein 90 (HSP90) is a ubiquitous molecular chaperone which plays essential roles in the folding, activation, and assembly of client proteins. Blocking the ATP-binding site of HSP90 by inhibitors, results in degradation of some client proteins (e.g. inhibitory (I)κB kinase (IKK)) via an ubiquitin-proteasome-dependent pathway.6) Previous studies showed that inhibition of HSP90 by injections of geldanamycin (GA, an HSP90 inhibitor) into the cerebral ventricles protects ischemic stroke through stimulation of heat shock gene transcription (such as HSP70 and HSF1).7) 17-Dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG) is a more water soluble HSP90 inhibitor and can be administered orally. However little is known about anti-inflammatory effect of HSP90 inhibitor during ischemic stroke and whether 17...

Inhibition of Heat Shock Protein 90 by 17-AAG Reduces Inflammation via P2X7 Receptor/NLRP3 Inflammasome Pathway and Increases Neurogenesis After Subarachnoid Hemorrhage in Mice

“…However, we only focused on neurogenesis in the hippocampus. Third, a previous study reported that inhibition of HSP90 alleviated IκB/NF-κB-mediated inflammation (Qi et al, 2014 ). Therefore, it is possible that other pathways may also contribute to the reduction of inflammation and enhancement of neurogenesis induced by the inhibition of HSP90.…”

“…It has been suggested that inhibition of HSP90 exerts neuroprotective effects, including attenuation of the inflammatory response, protection of BBB integrity, prevention of neuronal cell death, and preservation of NPCs in various diseases, such as traumatic brain injury and ischemic stroke (Kim et al, 2012 ; Bradley et al, 2014 ; Qi et al, 2014 ; Tukaj and Wegrzyn, 2016 ; Wang et al, 2018 ). As a potent inhibitor of HSP90, 17-AAG binds HSP90 and inhibits its function, which eventually results in the degradation of the HSP90 client proteins.…”

“…Heat shock protein 90 (HSP90) mediates protein folding and maturation and is thus considered to maintain cellular protein homeostasis (Wang et al, 2018 ). Numerous studies have shown that HSP90 inhibition exerts neuroprotective effects by attenuating necroptosis and inflammation and by preserving the BBB after ischemic stroke (Qi et al, 2014 , 2015 ; Wang et al, 2018 ). Interestingly, a recent study showed HSP90 to be essential for P2X7R stabilization and function (Migita et al, 2016 ).…”

Heat shock protein signaling in brain ischemia and injury

“…17-(2-dimethylaminoethyl) amino-17-demethoxygeldanamycin (17-DMAG), also a GA derivative, is thought to have wider tissue distribution, and was studied in an experimental stroke model where it was shown to improve neurological outcome through HSP70 induction. The beneficial effect was also correlated to reduced inflammation through inhibition of microglial activation and phosphorylation NF-kB's inhibitor protein IkB [97].…”

17-DMAG, an HSP90 Inhibitor, Ameliorates Multiple Organ Dysfunction Syndrome via Induction of HSP70 in Endotoxemic Rats

“…17-DMAG is a geldanamycin analog, reported to have less hepatic and renal toxicity compared with the original geldanamycin [ 12 ]. It has been shown that 17-DMAG attenuates the inflammatory responses in macrophage cells [ 23 ], hemorrhage-induced intestinal injury [ 24 ], and experimental animal model-induced stroke [ 25 ]. 17-DMAG induces HSP70 protein expression via activating HSF-1, an HSP70 transcription factor, and interferes the binding of NF-κB to the TNF-α transcription element to inhibit the TNF-α transcription, leading to amelioration of liver injury caused by LPS [ 11 ].…”