Dexmedetomidine reduces hippocampal microglia inflammatory response induced by surgical injury through inhibiting NLRP3

Abstract

Purpose To investigate whether dexmedetomidine (Dex) can reduce the production of inflammatory factor IL-1β by inhibiting the activation of NLRP3 inflammasome in hippocampal microglia, thereby alleviating the inflammatory response of the central nervous system induced by surgical injury. Methods Exploratory laparotomy was used in experimental models in this study. Totally 48 Sprague Dawley male rats were randomly divided into 4 groups ( n = 12 for each), respectively sham control (group A), laparotomy only (group B); and Dex treatment with different doses of 5 μg/kg (group D1) or 10 μg/kg (group D2). Rats in groups D1 and D2 were intraperitoneally injected with corresponding doses of Dex every 6 h. The rats were sacrificed 12 h after operation; the hippocampus tissues were isolated, and frozen sections were made. The microglia activation was estimated by immunohistochemistry. The protein expression of NLRP3, caspase-1, ASC and IL-1β were detected by immunoblotting. All data were presented as mean ± standard deviation, and independent sample t test was used to analyze the statistical difference between groups. Results The activated microglia in the hippocampus of the rats significantly increased after laparotomy (group B vs. sham control, p < 0.01). After Dex treatment, the number was decreased in a dose-dependent way (group D1 vs. D2, p < 0.05), however the activated microglia in both groups were still higher than that of sham controls (both p < 0.05). Further Western blot analysis showed that the protein expression levels of NLRP3, caspase-1, ASC and downstream cytokine IL-1β in the hippocampus from the laparotomy group were significantly higher than those of the sham control group (all p < 0.01). The elevated expression of these proteins was relieved after Dex treatment, also in a dose-dependent way (D2 vs. D1 group, p < 0.05). Conclusion Dex can inhibit the activation of microglia and NLRP3 inflammasome in the hippocampus of rats after operation, and the synthesis and secretion of IL-1β are also reduced in a dose-dependent manner by using Dex. Hence, Dex can alleviate inflammation activation on the central nervous system induced by surgical injury.

Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice

“…Assembly of the NLRP3 inflammasome triggers cleavage of caspase-1 and induces maturation of the proinflammatory cytokines IL-1β and IL-18, and subsequent cleavage of GSDMD and pyroptotic cell death (Man et al, 2017 ; Shi et al, 2017 ; Voet et al, 2019 ). Our results showed that surgery-induced upregulation of NLRP3 and cleaved caspase-1, and secretion of IL-1β and IL-18, in the hippocampus in aged mice, in agreement with the results of previous studies (Peng et al, 2019 ; Fu et al, 2020 ). Furthermore, surgery-induced upregulation of the GSDMD N domain, the key biomarker of pyroptosis, and the surgery group exhibited more ruptured and TUNEL-positive neurons, a morphological characteristic of pyroptosis.…”

Elevated Level of Serum C-reactive Protein Predicts Postoperative Delirium among Patients Receiving Cervical or Lumbar Surgery

“…(4) The application of dexmedetomidine in some cases of anesthesia in this study could be another compromise. It is believed that dexmedetomidine could reduce the inflammatory response [ 38 – 40 ] and the incidence of postoperative delirium [ 41 ]. And (5) we did not exclude younger patients (under 65 years old) from this study considering that the inflammation response to the same surgical wound could be the same in young people and the elderly.…”

Dexmedetomidine protects aged rats from postoperative cognitive dysfunction by alleviating hippocampal inflammation

“…Microglia can be activated by infection, trauma and ischemia, and perform innate immune functions, including the induction of inflammation, cytotoxic effects and modulation of T cell responses via antigen presentation (37). Activated microglia can release inflammatory factors, including TNF-α, IL-1β, IL-6, nitric oxide and prostaglandin E2 (38). These inflammatory factors exhibit a strong toxic effect on neurons and reactivate microglia, aggravating or expanding the inflammatory response of the CNS (39).…”