Dexmedetomidine Inhibits Gasdermin D-Induced Pyroptosis via the PI3K/AKT/GSK3β Pathway to Attenuate Neuroinflammation in Early Brain Injury After Subarachnoid Hemorrhage in Rats

Wei, Boyang; Li, Wenchao; Jin, Lei; Guo, Shenquan; Fan, Haiyan; Jin, Fa; Wei, Chengcong; Fang, Dazhao; Zhang, Xin; Su, Shixing

doi:10.3389/fncel.2022.899484

Cited by 17 publications

(4 citation statements)

References 57 publications

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“…As indicated by our results, DEX decreased the levels of NLRP3, cleaved Caspase-1, GSDMD-N, IL-1β, and IL-18 in SK-N-SH cells. In agreement with our results, DEX inhibits lipopolysaccharide (LPS)-induced release of nuclear factor-kappaB and pro-inflammatory factors from BV2 microglia, thus ameliorating neuroinflammation (Bao et al, 2019), and DEX pretreatment ameliorates GSDMD-induced microglia pyroptosis via the PI3K/ AKT/GSK3β pathway in subarachnoid hemorrhage (Wei et al, 2022). Altogether, our findings initially demonstrated that DEX attenuates Ropi-induced neuronal pyroptosis to alleviate neurotoxicity.…”

Section: Discussionsupporting

confidence: 91%

Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway

Wang

Liu

et al. 2023

J. Toxicol. Sci.

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Dexmedetomidine (DEX) has been demonstrated to protect against ropivacaine (Ropi)induced neuronal damages. This study was conducted to explore the protective role of DEX in Ropiinduced neuronal pyroptosis and provide a strategy to eliminate Ropi-induced neurotoxicity. The impacts of different concentrations of Ropi and DEX on neurotoxicity in SK-N-SH cells were evaluated by cell counting kit-8 assay and lactic dehydrogenase assay kits. Levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), NLR family pyrin domain containing 3 (NLRP3), cleaved Caspase-1, cleaved N-terminal gasdermin D, interleukin (IL)-1β, and IL-18 were measured by real-time quantitative PCR, Western blotting, and enzyme linked immunosorbent assay. The Nrf2 level after nuclear/cytoplasmic separation was quantified. SK-N-SH cells were treated with si-Nrf2, Nigericin (NLRP3 activator), and Zinc Protoporphyrin (HO-1 inhibitor) to validate the mechanism. Ropi reduced SK-N-SH cell viability in a concentration-and time-dependent manner. DEX treatment alleviated Ropi-induced toxicity and inhibited pyroptosis. Ropi increased the expression levels of Nrf2 and HO-1, and DEX further enhanced the increases and promoted Nrf2 nuclear translocation. Nrf2/HO-1 inhibition or NLRP3 activation both neutralized the inhibitory role of DEX in Ropi-induced pyroptosis of SK-N-SH cells. Overall, DEX promoted the Nrf2/HO-1 pathway to inhibit NLRP3 expression, thus alleviating Ropi-induced neuronal pyroptosis.

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Section: Discussionsupporting

confidence: 91%

Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway

Wang

Liu

et al. 2023

J. Toxicol. Sci.

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“…In the first 24 h after SAH, hyperactivated microglial and several brain blood immune cells (T cells, macrophages, and neutrophils) were significantly reduced by DEX, potentially providing neuroprotection for brain injury ( 290 , 320 ). DEX relieves microglial pyroction in post-SAH EBI by activating the PI3K/Akt/GSK3β pathway and inhibits SAH-induced release of pro-inflammatory cytokines ( 321 ). In terms of neuroprotection, this study also showed that DEX alleviated SAH-induced neuroinflammation in the context of the NLRP3 inflammasome and inhibited the TLR4/NF-κB pathway.…”

Section: Multiple Treatment Strategies For Sahmentioning

confidence: 99%

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

Jin

Duan

et al. 2022

Front. Immunol.

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Intracranial aneurysm subarachnoid hemorrhage (SAH) is a cerebrovascular disorder associated with high overall mortality. Currently, the underlying mechanisms of pathological reaction after aneurysm rupture are still unclear, especially in the immune microenvironment, inflammation, and relevant signaling pathways. SAH-induced immune cell population alteration, immune inflammatory signaling pathway activation, and active substance generation are associated with pro-inflammatory cytokines, immunosuppression, and brain injury. Crosstalk between immune disorders and hyperactivation of inflammatory signals aggravated the devastating consequences of brain injury and cerebral vasospasm and increased the risk of infection. In this review, we discussed the role of inflammation and immune cell responses in the occurrence and development of aneurysm SAH, as well as the most relevant immune inflammatory signaling pathways [PI3K/Akt, extracellular signal-regulated kinase (ERK), hypoxia-inducible factor-1α (HIF-1α), STAT, SIRT, mammalian target of rapamycin (mTOR), NLRP3, TLR4/nuclear factor-κB (NF-κB), and Keap1/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/ARE cascades] and biomarkers in aneurysm SAH. In addition, we also summarized potential therapeutic drugs targeting the aneurysm SAH immune inflammatory responses, such as nimodipine, dexmedetomidine (DEX), fingolimod, and genomic variation-related aneurysm prophylactic agent sunitinib. The intervention of immune inflammatory responses and immune microenvironment significantly reduces the secondary brain injury, thereby improving the prognosis of patients admitted to SAH. Future studies should focus on exploring potential immune inflammatory mechanisms and developing additional therapeutic strategies for precise aneurysm SAH immune inflammatory regulation and genomic variants associated with aneurysm formation.

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“…We verified the mechanical role of Dex in intracellular Akt, ERK, and NF-κB signaling in RA-FLSs [ 27 , 28 , 29 ]. We determined the levels of intracellular signaling proteins in multiple-input-stimulated RA-FLSs ( Figure 2 a–l).…”

Section: Resultsmentioning

confidence: 67%

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine

Lee

Hong

2023

IJMS

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Dexmedetomidine (Dex) has analgesic and sedative properties and anti-inflammatory functions. Although the effects of Dex on arthritis have been revealed, the physiological mechanism underlying the interaction between Dex and rheumatoid arthritis (RA)-mediated inflammatory cytokines has not been fully studied. Inflamed and migrated fibroblast-like synoviocytes (FLSs) are involved in RA severity. Thus, we aimed to determine the effects of Dex on RA-FLSs treated with inflammatory cytokines and a growth factor as multiple stimulating inputs. TNF-α, IL-6, and EGF as multiple stimulating inputs increased the cAMP concentration of RA-FLSs, while Dex treatment reduced cAMP concentration. Dex reduced electroneutral sodium-bicarbonate cotransporter 1 (NBCn1) expression, NBC activity, and subsequent RA-FLS migration. The mRNA expression levels of RA-related factors, such as inflammatory cytokines and osteoclastogenesis factors, were enhanced by multiple-input treatment. Notably, Dex effectively reduced these expression levels in RA-FLSs. These results indicate that multiple inflammatory or stimulating inputs enhance RA-FLS migration, and treatment with Dex relieves activated RA-FLSs, suggesting that Dex is a potential therapeutic drug for RA.

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Dexmedetomidine Inhibits Gasdermin D-Induced Pyroptosis via the PI3K/AKT/GSK3β Pathway to Attenuate Neuroinflammation in Early Brain Injury After Subarachnoid Hemorrhage in Rats

Cited by 17 publications

References 57 publications

Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway

Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway

Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine

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