Low-dose Esketamine suppresses NLRP3-mediated apoptotic and pyroptotic cell death in microglial cells to ameliorate LPS-induced depression via ablating GSK-3

Esketamine is verified as a potential therapeutic drug for the treatment of depression, but it is still unclear the detailed underlying mechanisms by which Esketamine ameliorates depression-related symptoms, which seriously limits the utilization of this drug in clinical practices. In this study, the C57BL6/J mice and mouse primary microglial cells were subjected to lipopolysaccharide (LPS)-induced depressive models in vivo and in vitro, and our results confirmed that LPS-induced neuroinflammation, pyroptotic and apoptotic death contributed to the development of LPS-induced depressive symptoms. Then, the following experiments verified that low-dose Esketamine treatment decreased the expression levels of IL-6, TNF-alpha and IL-18 to restrain cellular inflammation, downregulated NLRP3, cleaved Caspase-1, IL-1 beta and GSDMD-N to hamper pyroptotic cell death, and inhibited cleaved caspase-3 and Bax, but upregulated Bcl-2 to restrict apoptotic cell death in the LPS-treated mice hippocampus tissues and mouse microglial cells, leading to the suppression of depression development. However, high-dose Esketamine did not have those effects. Next, by conducting mechanical experiments, we verified that low-dose Esketamine downregulated GSK-3 beta to inactivate NLRP3 inflammasome, and the effects of low-dose Esketamine on cell pyroptosis, neuroinflammation and apoptosis in the LPS-treated microglial cells were all abrogated by overexpressing GSK-3 beta and NLRP3. Taken together, low-dose Esketamine ameliorated LPS-induced depressive symptoms in mice through regulating the GSK-3 beta/NLRP3 pathway, and our work suggested that appropriate doses of Esketamine were essential for the treatment of depression in clinic.