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

Abstract

Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease that usually has a poor prognosis. Heat shock proteins (HSPs) have been implicated in the mechanisms of SAH-associated damage, including increased inflammation and reduced neurogenesis. The aim of this study was to investigate the effects of HSP90 inhibition on inflammation and neurogenesis in a mouse model of experimental SAH induced by endovascular surgery. Western blotting showed HSP90 levels to be decreased, while neurogenesis, evaluated by 5-bromo-2’-deoxyuridine (BrdU) immunohistochemistry, was decreased in the hippocampuses of SAH mice. SAH also induced pro-inflammatory factors such as interleukin-1β (IL-1β), capase-1 and the NLRP3 inflammasome. However, intraperitoneal administration of the specific HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) reduced the levels of HSP90, NLRP3, ASC, caspase-1 and IL-1β, while increasing the levels of brain-derived neurotrophic factor and doublecortin (DCX), as well as the number of BrdU-positive cells in SAH mice. In addition, 17-AGG improved short- and long-term neurobehavioral outcomes. The neuroprotective and anti-inflammatory effects of 17-AGG were reversed by recombinant HSP90 (rHSP90); this detrimental effect of HSP90 was inhibited by the specific P2X7 receptor (P2X7R) inhibitor A438079, indicating that SAH-induced inflammation and inhibition of neurogenesis were likely mediated by HSP90 and the P2X7R/NLRP3 inflammasome pathway. HSP90 inhibition by 17-AAG may be a promising therapeutic strategy for the treatment of SAH.

α-Cyperone Confers Antidepressant-Like Effects in Mice via Neuroplasticity Enhancement by SIRT3/ROS Mediated NLRP3 Inflammasome Deactivation

“…The NLRP3 inflammasome has been proposed as a regulator of neuroplasticity. The declines in protein expression of NLRP3, ASC, Caspase-1, and IL-1βincreased BDNF and doublecortin (DCX) expressions, as well as BrdU+ cells in the hippocampuses of mice ( Zuo et al, 2018 ). Spatial training reduced the production of NLRP3, Caspase-1, and IL-1β in PR5 mice, which upregulated the expression of synaptophysin, PSD-93, and PSD-95, and enhanced dendritic spine number ( Ren et al, 2019 ).…”

Inhibition of HSP90 and Activation of HSF1 Diminish Macrophage NLRP3 Inflammasome Activity in Alcohol‐Associated Liver Injury

“…Studies from our group have shown the significance of proteostasis chaperones, HSP90 and HSP70/HSPA1A, and transcription factor, heat shock factor 1 (HSF1), in alcohol‐mediated effects on immune cells and liver injury (Ambade et al, 2014; Muralidharan et al, 2014). Recent studies have identified a link between HSP90 and NLRP3 in macular degeneration (Piippo et al, 2018), cerebrovascular disease (Zuo et al, 2018), and HSV infection (Li et al, 2019). Previous studies showed that the NLRP3‐SGT1 (suppressor of the G2 allele of skp1) complex interacts with HSP90 and is important for inflammasome activation (Mayor et al, 2007).…”

DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

“…Previous studies have demonstrated that Hsp90 was involved in apoptosis as well as inflammation in cardiac muscle and neuron cells 29,30 . Recent studies demonstrated that inhibition of Hsp90 by the 17-allylamino-17-demethoxygeldanamycin (17-AAG) or 17-DMAG attenuated UUO, indoxyl sulfate (IS), and high salt-diet-induced renal fibrosis 20,24,31 .…”