Jinquan Chen1, Qian Ding2, Xiangxue Jiao1, Binrong Wang2, Zhenzhong Sun3, Yutao Zhang2, Juan Zhao4. 1. Anesthesia Operation Center, The First Peoples Hospital of Xianyang, Xianyang, 712000, People's Republic of China. 2. Anesthesia Operation Center, Xi´an International Medical Center Hospital, No. 777, Xitai Road, 710100, Xi´an, People's Republic of China. 3. Department of Anesthesiology, Guangdong Armed Police Corps Hospital, Guangzhou, 510507, People's Republic of China. 4. Anesthesia Operation Center, Xi´an International Medical Center Hospital, No. 777, Xitai Road, 710100, Xi´an, People's Republic of China. juanzhao0011@163.com.
Abstract
RATIONALE: Due to its anti-inflammatory effect, dexmedetomidine (DEX) can confer neuroprotection in postoperative neurocognitive disorders (NCD). Here, the mechanism responsible for this effect of DEX is rarely ascertained. OBJECTIVES: Our research was implemented to figure out mechanism governing the protection of DEX against hippocampal neuroinflammation in postoperative NCD. METHODS: Exploratory laparotomy was applied for generating a postoperative NCD mouse model before bilateral hippocampal injection with microRNA (miR)-329-3p-agomir and intraperitoneal injection with DEX. Cognitive function of mice was evaluated by water maze test and fear conditioning test. Immunofluorescence was performed to assess microglial activation in hippocampus. After cell transfection and DEX treatment, mouse microglial cells (BV-2) were stimulated by lipopolysaccharide (LPS). IL-1β, IL-6, and TNF-α levels and the number of phagocytes were assessed by ELISA and flow cytometry. Dual-luciferase reporter assay was adopted to assess the relationship between miR-329-3p and CREB1. RESULTS: miR-329-3p expression was reduced in the postoperative NCD mice after DEX treatment. DEX treatment or miR-329-3p downregulation caused attenuated cognitive dysfunction and microglia activation as well as reduced IL-1β, IL-6, and TNF-α levels in the hippocampus of the postoperative NCD mice. Mechanistically, miR-329-3p inversely targeted CREB1 that activated IL1RA in LPS-induced BV-2 cells. DEX treatment, miR-329-3p inhibition, or CREB1 or IL1RA upregulation curtailed the release of proinflammatory proteins and the number of phagocytes in LPS-induced BV-2 cells. CONCLUSIONS: Collectively, our data provided the novel insight of the neuroprotective mechanism of DEX in postoperative NCD pertaining to the miR-329-3p/CREB1/IL1RA axis.
RATIONALE: Due to its anti-inflammatory effect, dexmedetomidine (DEX) can confer neuroprotection in postoperative neurocognitive disorders (NCD). Here, the mechanism responsible for this effect of DEX is rarely ascertained. OBJECTIVES: Our research was implemented to figure out mechanism governing the protection of DEX against hippocampal neuroinflammation in postoperative NCD. METHODS: Exploratory laparotomy was applied for generating a postoperative NCD mouse model before bilateral hippocampal injection with microRNA (miR)-329-3p-agomir and intraperitoneal injection with DEX. Cognitive function of mice was evaluated by water maze test and fear conditioning test. Immunofluorescence was performed to assess microglial activation in hippocampus. After cell transfection and DEX treatment, mouse microglial cells (BV-2) were stimulated by lipopolysaccharide (LPS). IL-1β, IL-6, and TNF-α levels and the number of phagocytes were assessed by ELISA and flow cytometry. Dual-luciferase reporter assay was adopted to assess the relationship between miR-329-3p and CREB1. RESULTS: miR-329-3p expression was reduced in the postoperative NCD mice after DEX treatment. DEX treatment or miR-329-3p downregulation caused attenuated cognitive dysfunction and microglia activation as well as reduced IL-1β, IL-6, and TNF-α levels in the hippocampus of the postoperative NCD mice. Mechanistically, miR-329-3p inversely targeted CREB1 that activated IL1RA in LPS-induced BV-2 cells. DEX treatment, miR-329-3p inhibition, or CREB1 or IL1RA upregulation curtailed the release of proinflammatory proteins and the number of phagocytes in LPS-induced BV-2 cells. CONCLUSIONS: Collectively, our data provided the novel insight of the neuroprotective mechanism of DEX in postoperative NCD pertaining to the miR-329-3p/CREB1/IL1RA axis.
Authors: L Evered; B Silbert; D S Knopman; D A Scott; S T DeKosky; L S Rasmussen; E S Oh; G Crosby; M Berger; R G Eckenhoff Journal: Anesthesiology Date: 2018-11 Impact factor: 7.892