Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats
Abstract Aims/introduction As a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevo...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-01-01
|
| Series: | BMC Neuroscience |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12868-023-00777-5 |
| _version_ | 1797818153317695488 |
|---|---|
| author | Junjie Zhou Chao Zhang Xu Fang Naixin Zhang Xiaoxi Zhang Zhaoqiong Zhu |
| author_facet | Junjie Zhou Chao Zhang Xu Fang Naixin Zhang Xiaoxi Zhang Zhaoqiong Zhu |
| author_sort | Junjie Zhou |
| collection | DOAJ |
| description | Abstract Aims/introduction As a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats. Method Before the experiment, D-galactose was diluted with normal saline into a liquid with a concentration of 125 mg/kg and injected subcutaneously into the neck and back of rats for 42 days to establish the aging rat model. Morris water maze experiments were performed, including positioning navigation (5 days) and space exploration (1 day). The POCD model was established by 3.2% sevoflurane inhalation. The rats were treated with or without MCC950, a potent and selective nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) inhibitor, followed by autophagy agonists and autophagy inhibitors. The expression levels of inflammasome-related protein NLRP3 and autophagy-related proteins LC3B and P62 were detected to test the behavior of rats with a water maze. Results We found that sevoflurane exposure affected learning and working memory ability in aged rats. We also observed microglia activation in the prefrontal cortex. NLRP3 protein expression was significantly upregulated after sevoflurane inhalation. NLRP3 inflammasome activation induced increased expression and mRNA expression of cleaved Caspase-1 and inflammatory cytokines IL-1β and IL-18, and increased secretion of peripheral proinflammatory cytokines. The inhibitor MCC950 was used to improve cognitive ability and inflammation in rats and inhibit the secretion of cytokines. In addition, we demonstrated that significant inhibition of autophagy (decreased LC3-II/I and increased P62) was accompanied by increased activation of NLRP3 inflammasomes and more severe neural cell damage. However, autophagy inhibitor rapamycin administration to activate autophagy resulted in the inhibition of NLRP3 inflammasomes, ultimately attenuating neuronal injury. Conclusions The activation of autophagy suppressed the formation of NLRP3 inflammasomes. It also alleviated cognitive impairment in aged rats. |
| first_indexed | 2024-03-13T09:03:46Z |
| format | Article |
| id | doaj.art-8a137825a41f437394422606216ef564 |
| institution | Directory Open Access Journal |
| issn | 1471-2202 |
| language | English |
| last_indexed | 2024-03-13T09:03:46Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Neuroscience |
| spelling | doaj.art-8a137825a41f437394422606216ef5642023-05-28T11:09:23ZengBMCBMC Neuroscience1471-22022023-01-0124111410.1186/s12868-023-00777-5Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly ratsJunjie Zhou0Chao Zhang1Xu Fang2Naixin Zhang3Xiaoxi Zhang4Zhaoqiong Zhu5Affiliated Hospital of Zunyi Medical UniversityAffiliated Hospital of Zunyi Medical UniversityAffiliated Hospital of Zunyi Medical UniversityAffiliated Hospital of Zunyi Medical UniversityAffiliated Hospital of Zunyi Medical UniversityAffiliated Hospital of Zunyi Medical UniversityAbstract Aims/introduction As a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats. Method Before the experiment, D-galactose was diluted with normal saline into a liquid with a concentration of 125 mg/kg and injected subcutaneously into the neck and back of rats for 42 days to establish the aging rat model. Morris water maze experiments were performed, including positioning navigation (5 days) and space exploration (1 day). The POCD model was established by 3.2% sevoflurane inhalation. The rats were treated with or without MCC950, a potent and selective nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) inhibitor, followed by autophagy agonists and autophagy inhibitors. The expression levels of inflammasome-related protein NLRP3 and autophagy-related proteins LC3B and P62 were detected to test the behavior of rats with a water maze. Results We found that sevoflurane exposure affected learning and working memory ability in aged rats. We also observed microglia activation in the prefrontal cortex. NLRP3 protein expression was significantly upregulated after sevoflurane inhalation. NLRP3 inflammasome activation induced increased expression and mRNA expression of cleaved Caspase-1 and inflammatory cytokines IL-1β and IL-18, and increased secretion of peripheral proinflammatory cytokines. The inhibitor MCC950 was used to improve cognitive ability and inflammation in rats and inhibit the secretion of cytokines. In addition, we demonstrated that significant inhibition of autophagy (decreased LC3-II/I and increased P62) was accompanied by increased activation of NLRP3 inflammasomes and more severe neural cell damage. However, autophagy inhibitor rapamycin administration to activate autophagy resulted in the inhibition of NLRP3 inflammasomes, ultimately attenuating neuronal injury. Conclusions The activation of autophagy suppressed the formation of NLRP3 inflammasomes. It also alleviated cognitive impairment in aged rats.https://doi.org/10.1186/s12868-023-00777-5AutophagyElderly ratNucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasomeSevoflurane |
| spellingShingle | Junjie Zhou Chao Zhang Xu Fang Naixin Zhang Xiaoxi Zhang Zhaoqiong Zhu Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats BMC Neuroscience Autophagy Elderly rat Nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome Sevoflurane |
| title | Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats |
| title_full | Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats |
| title_fullStr | Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats |
| title_full_unstemmed | Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats |
| title_short | Activation of autophagy inhibits the activation of NLRP3 inflammasome and alleviates sevoflurane-induced cognitive dysfunction in elderly rats |
| title_sort | activation of autophagy inhibits the activation of nlrp3 inflammasome and alleviates sevoflurane induced cognitive dysfunction in elderly rats |
| topic | Autophagy Elderly rat Nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome Sevoflurane |
| url | https://doi.org/10.1186/s12868-023-00777-5 |
| work_keys_str_mv | AT junjiezhou activationofautophagyinhibitstheactivationofnlrp3inflammasomeandalleviatessevofluraneinducedcognitivedysfunctioninelderlyrats AT chaozhang activationofautophagyinhibitstheactivationofnlrp3inflammasomeandalleviatessevofluraneinducedcognitivedysfunctioninelderlyrats AT xufang activationofautophagyinhibitstheactivationofnlrp3inflammasomeandalleviatessevofluraneinducedcognitivedysfunctioninelderlyrats AT naixinzhang activationofautophagyinhibitstheactivationofnlrp3inflammasomeandalleviatessevofluraneinducedcognitivedysfunctioninelderlyrats AT xiaoxizhang activationofautophagyinhibitstheactivationofnlrp3inflammasomeandalleviatessevofluraneinducedcognitivedysfunctioninelderlyrats AT zhaoqiongzhu activationofautophagyinhibitstheactivationofnlrp3inflammasomeandalleviatessevofluraneinducedcognitivedysfunctioninelderlyrats |