Repeated propofol exposure-induced neuronal damage and cognitive impairment in aged rats by activation of NF-κB pathway and NLRP3 inflammasome

•200 mg/kg propofol treatment (intraperitoneal injection, i.p.) every 9 days, with a total of 6 times did not affect the cognition of the aged rats.•200 mg/kg propofol treatment i.p.) every day, with a total of 6 times impaired the cognition of the aged rats.•Propofol induced cognitive dysfunction p...

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Vydáno v:	Neuroscience letters Ročník 740; s. 135461
Hlavní autoři:	Liu, Peng-fei, Gao, Teng, Li, Tian-zuo, Yang, Yi-tian, Xu, Yong-xing, Xu, Zhi-peng, Mi, Wei-dong
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Ireland Elsevier B.V 01.01.2021
Témata:	Aging Aging - psychology Anesthetics, Intravenous - toxicity Animals Apoptosis Cognition - drug effects Cognition Disorders - chemically induced Cognition Disorders - psychology Conditioning, Operant - drug effects Hippocampus - metabolism Inflammasomes - drug effects Male Maze Learning - drug effects Memory - drug effects Neuroinflammation Neurons - pathology NF-kappa B - antagonists & inhibitors NF-kappa B - drug effects NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors NLR Family, Pyrin Domain-Containing 3 Protein - drug effects NOD-like receptor protein 3 inflammasome Postoperative cognitive dysfunction Propofol Propofol - toxicity Rats Rats, Sprague-Dawley PaCO2 dUTP POCD DMSO WB Pro Postoperative cognitive dysfunction p-NF-κB NF-κB Aβ SE CA1 TUNEL CA3 ANOVA Pro+Bay pH Aging NLRP3 Propofol IκBa Con+Bay PBS MWM Con IKK-β Neuroinflammation i.p IL-1β IL-6 Bay 11-7082 PaO2 TNF-α FCT NOD-like receptor protein 3 inflammasome GAPDH ELISA Apoptosis
ISSN:	0304-3940, 1872-7972, 1872-7972
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Abstract	•200 mg/kg propofol treatment (intraperitoneal injection, i.p.) every 9 days, with a total of 6 times did not affect the cognition of the aged rats.•200 mg/kg propofol treatment i.p.) every day, with a total of 6 times impaired the cognition of the aged rats.•Propofol induced cognitive dysfunction partly through the activation of NF-κB pathway and NLRP3 inflammasome.•Bay 11-7082, an inhibitor of NF-κB, could attenuate the neuroinflammation and cognition injury caused by daily propofol treatment. Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition. The study included two parts. In the first part, aged (18–20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, NLRP3, caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1β, IL-6, and TNF-α were evaluated using ELISA. There were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the NLRP3 inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/NLRP3 inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment. Intermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and NLRP3 inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients.
AbstractList	•200 mg/kg propofol treatment (intraperitoneal injection, i.p.) every 9 days, with a total of 6 times did not affect the cognition of the aged rats.•200 mg/kg propofol treatment i.p.) every day, with a total of 6 times impaired the cognition of the aged rats.•Propofol induced cognitive dysfunction partly through the activation of NF-κB pathway and NLRP3 inflammasome.•Bay 11-7082, an inhibitor of NF-κB, could attenuate the neuroinflammation and cognition injury caused by daily propofol treatment. Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition. The study included two parts. In the first part, aged (18–20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, NLRP3, caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1β, IL-6, and TNF-α were evaluated using ELISA. There were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the NLRP3 inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/NLRP3 inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment. Intermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and NLRP3 inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients. Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition. The study included two parts. In the first part, aged (18-20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, NLRP3, caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1β, IL-6, and TNF-α were evaluated using ELISA. There were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the NLRP3 inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/NLRP3 inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment. Intermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and NLRP3 inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients. Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition.BACKGROUNDElderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition.The study included two parts. In the first part, aged (18-20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, NLRP3, caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1β, IL-6, and TNF-α were evaluated using ELISA.METHODSThe study included two parts. In the first part, aged (18-20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, NLRP3, caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1β, IL-6, and TNF-α were evaluated using ELISA.There were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the NLRP3 inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/NLRP3 inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment.RESULTSThere were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the NLRP3 inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/NLRP3 inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment.Intermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and NLRP3 inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients.CONCLUSIONSIntermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and NLRP3 inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients.
ArticleNumber	135461
Author	Xu, Yong-xing Xu, Zhi-peng Gao, Teng Yang, Yi-tian Liu, Peng-fei Li, Tian-zuo Mi, Wei-dong
Author_xml	– sequence: 1 givenname: Peng-fei surname: Liu fullname: Liu, Peng-fei organization: Anesthesia and Operation Center, the First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing 100853, China – sequence: 2 givenname: Teng surname: Gao fullname: Gao, Teng organization: Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, 10th Tieyi Road, Haidian District, Beijing, 100038, China – sequence: 3 givenname: Tian-zuo surname: Li fullname: Li, Tian-zuo organization: Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, 10th Tieyi Road, Haidian District, Beijing, 100038, China – sequence: 4 givenname: Yi-tian surname: Yang fullname: Yang, Yi-tian organization: Anesthesia and Operation Center, the First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing 100853, China – sequence: 5 givenname: Yong-xing surname: Xu fullname: Xu, Yong-xing organization: Department of Nephrology, Chinese PLA Strategic Support Force Characteristic Medical Center, 9th AnXiangBeiLi Road, Beijing, 100101, China – sequence: 6 givenname: Zhi-peng surname: Xu fullname: Xu, Zhi-peng email: xuzhipeng20@163.com organization: Anesthesia and Operation Center, the First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing 100853, China – sequence: 7 givenname: Wei-dong surname: Mi fullname: Mi, Wei-dong email: wwdd1962@aliyun.com organization: Anesthesia and Operation Center, the First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing 100853, China
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Keywords	PaCO2 dUTP POCD DMSO WB Pro Postoperative cognitive dysfunction p-NF-κB NF-κB Aβ SE CA1 TUNEL CA3 ANOVA Pro+Bay pH Aging NLRP3 Propofol IκBa Con+Bay PBS MWM Con IKK-β Neuroinflammation i.p IL-1β IL-6 Bay 11-7082 PaO2 TNF-α FCT NOD-like receptor protein 3 inflammasome GAPDH ELISA Apoptosis
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Snippet	•200 mg/kg propofol treatment (intraperitoneal injection, i.p.) every 9 days, with a total of 6 times did not affect the cognition of the aged rats.•200 mg/kg... Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent...
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SubjectTerms	Aging Aging - psychology Anesthetics, Intravenous - toxicity Animals Apoptosis Cognition - drug effects Cognition Disorders - chemically induced Cognition Disorders - psychology Conditioning, Operant - drug effects Hippocampus - metabolism Inflammasomes - drug effects Male Maze Learning - drug effects Memory - drug effects Neuroinflammation Neurons - pathology NF-kappa B - antagonists & inhibitors NF-kappa B - drug effects NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors NLR Family, Pyrin Domain-Containing 3 Protein - drug effects NOD-like receptor protein 3 inflammasome Postoperative cognitive dysfunction Propofol Propofol - toxicity Rats Rats, Sprague-Dawley
Title	Repeated propofol exposure-induced neuronal damage and cognitive impairment in aged rats by activation of NF-κB pathway and NLRP3 inflammasome
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