Hsp90 inhibition attenuates the 1, 2-Dichloroethane-induced cognitive impairment by blocking NLRP3 inflammasome activation in mice.

1,2-Dichloroethane (1,2-DCE) is a widely used industrial solvent known to exert neurotoxic effects upon exposure. Hsp90 inhibition has emerged as a potential therapeutic strategy to mitigate neuroinflammation by targeting the NLRP3 inflammasome. However, its role in mitigating 1,2-DCE-induced neurotoxicity remains unclear. This study aimed to elucidate the neuroprotective effect of the Hsp90 inhibitor 17-AAG against 1,2-DCE-induced neurotoxicity and to elucidate the underlying mechanism involving NLRP3 inflammasome activation. Forty male CD-1 mice were exposed to 1,2-DCE (0, 100, 350, 700 mg/m(3))via inhalation for 28 days, followed by treatment with 17-AAG. Cognitive function was assessed using the Morris water maze, novel object recognition, and Y-maze tests. Inflammatory cytokines and NLRP3 inflammasome proteins were measured in whole brain homogenates, while hippocampal tissue was analyzed for region-specific neuroinflammation and apoptosis. In vitro, BV2 microglial cells were transfected with si-NLRP3 or control siRNA and treated with 1,2-DCE and/or 17-AAG. The 28-day repeated inhalation exposure to 1,2-DCE significantly impaired cognitive functions in mice, induced cerebral inflammation and apoptosis, and upregulated NLRP3 inflammasome components. Treatment with 17-AAG alleviated these effects by inhibiting NLRP3 inflammasome activation. Notably, NLRP3 knockdown abolished the anti-inflammatory and anti-apoptotic effects of 17-AAG in BV2 cells, confirming the critical role of NLRP3 in mediating these protective effects. Collectively, these findings demonstrate that Hsp90 inhibition by 17-AAG effectively attenuates 1,2-DCE-induced neurotoxicity via suppression of the NLRP3 inflammasome activation, supporting its potential as a therapeutic target against environmental neurotoxicants.