Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D Pathway

Abstract

Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide. Previous studies have reported that sevoflurane, a frequently used anesthetic, can induce cognitive impairment in preclinical and clinical settings. However, the mechanism underlying the development of this neurotoxicity is currently unclear.Methods: Seven-month-old APP/PS1 mice were placed in an anesthesia induction box containing 3% sevoflurane in 100% O2 for 6 h, while BV2 cells were cultured with 4% sevoflurane for 6 h. Pyroptosis and tau protein expression in excised hippocampus tissues and cells were measured using Western blotting and immunofluorescence assay. Caspase-1 and NLRP3 were knocked out in BV2 microglia using CRISPR/Cas9 technology to determine whether they mediate the effects induced by sevoflurane.Results: Sevoflurane directly activated caspase-1 to induce pyroptosis in the mouse model of AD via NLRP3 and AIM2 activation. In addition, sevoflurane mediated cleavage of gasdermin D (GSDMD) but not gasdermin E (GSDME), promoted the biosynthesis of downstream interleukin-1β and interleukin-18, and increased β-amyloid (Aβ) deposition and tau phosphorylation. The nontoxic caspase-1 small-molecule inhibitor VX-765 significantly inhibited this activation process in microglia, while NLRP3 deletion suppressed sevoflurane-induced caspase-1 cleavage and subsequently pyroptosis, as well as tau pathology. Furthermore, silencing caspase-1 alleviated the sevoflurane-induced release of IL-1β and IL-18 and inhibited tau-related enzymes in microglia.Conclusion: This study is the first to report that clinical doses of sevoflurane aggravate the progression of AD via the NLRP3/caspase-1/GSDMD axis. Collectively, our findings elucidate the crucial mechanisms of NLRP3/caspase-1 in pyroptosis and tau pathogenesis induced by sevoflurane and suggest that VX-765 could represent a novel therapeutic intervention for treating AD.

Knockdown of UAF1 alleviates sevoflurane-induced cognitive impairment and neurotoxicity in rats by inhibiting pro-inflammatory signaling and oxidative stress

“…SEV exposure translocates NF-κB from the cell cytoplasm to the nucleus, resulting in the activation of NF-κB signaling and the expression of pro-inflammatory factors, such as IL-1β, IL-6, IL-18 and TNF-α (Tian et al, 2022). In addition, SEV exposure causes excessive oxidative stress, leading to long-term injury (Gao et al, 2020).…”

Role of pyroptosis in the pathogenesis and treatment of diseases

“…306 In AD models, the NLRP3 inhibitor mefenamic acid was shown to have no effect on pyroptosis, but inhibition or caspase-1 deficiency protected neuroinflammation and memory deficits in rat models of Aβ-induced AD. 307 Tian et al 308 findings elucidate the crucial mechanisms of NLRP3/caspase-1 in pyroptosis and tau pathogenesis induced by sevoflurane. Salidroside (Sal) can not only reduce and inhibit pyroptosis through accumulation of Aβ and phosphorylation of Tau through downregulation of IL-1β and IL-18 expression, in addition, Sal reversed the increase in the protein expression of TLR4, NF-κB, NLRP3, ASC, cleaved caspase-1, cleaved GSDMD, IL-1β, and IL-18 in AD mouse model.…”

“… 307 Tian et al. 308 findings elucidate the crucial mechanisms of NLRP3/caspase‐1 in pyroptosis and tau pathogenesis induced by sevoflurane. Salidroside (Sal) can not only reduce and inhibit pyroptosis through accumulation of Aβ and phosphorylation of Tau through downregulation of IL‐1β and IL‐18 expression, in addition, Sal reversed the increase in the protein expression of TLR4, NF‐κB, NLRP3, ASC, cleaved caspase‐1, cleaved GSDMD, IL‐1β, and IL‐18 in AD mouse model.…”

Microglia Pyroptosis: A Candidate Target for Neurological Diseases Treatment

“…Clinical doses of sevoflurane exacerbated AD progression via the NLRP3/caspase-1/GSDMD axis. VX-765 significantly inhibited the activation of microglia pyroptosis-related pathways and attenuated sevoflurane-induced release of IL-1, IL-18 and tau-related kinases and phosphatases (Xu et al, 2019b;Tian et al, 2021a). Paeoniflorin (PF) exerted antidepressant effects by inhibiting caspase-11-dependent pyroptosis signaling induced by hyperactivation of hippocampal microglia in ricin-treated mice, and attenuated neuroinflammatory responses (Tian et al, 2021b).…”