Frontiers in Immunology
·
2022
·
IF 8.786
Lieliang Zhang,Xifeng Wang,Wen Yu,Jun Ying,Pu Fang,Qingcui Zheng,Xiaojin Feng,Jialing Hu,Fan Xiao,Shoulin Chen,Gen Wei,Yue Lin,Xing Liu,Danying Yang,Yang Fang,Guohai Xu,Fuzhou Hua
Evidence suggests that the accumulation of lipid drots (LDs) accelerates damage to mitochondria and increases the release of inflammatory factors. These have been implicated as a mechanism underlying neurodegenerative diseases or tumors and aging-related diseases such as postoperative cognitive dysfunction (POCD), nevertheless, accumulation of lipid droplets has not been extensively studied in the central nervous system (CNS). Here, we found that after surgery, there was activation of astrocytes and lipid accumulation in the hippocampus. However, cannabinoid receptor type II (CB2R) activation significantly reduced lipid accumulation in astrocytes and change the expression of genes related to lipid metabolism. CB2R reduces the release of the inflammatory factors interleukin-1 beta (IL-1β) and interleukin 6 (IL-6) in peripheral serum and simultaneously improves cognitive ability in mice with POCD. Further research on mechanisms indicates that CB2R activation promotes the nuclear entry of the bHLH-leucine zipper transcription factor, the transcription factor EB (TFEB), and which is a master transcription factor of the autophagy–lysosomal pathway, also reduces TFEB-S211 phosphorylation. When CB2R promotes TFEB into the nucleus, TFEB binds at two sites within promoter region of PGC1α, promoting PGC1α transcription and accelerating downstream lipid metabolism. The aforementioned process leads to autophagy activation and decreases cellular lipid content. This study uncovers a new mechanism allowing CB2R to regulate lipid metabolism and inflammation in POCD.
研究领域:
神经科学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
BRAIN RESEARCH
·
2024
·
IF 2.7
Zhu Wang,Bowen Li,Jingrui Yang,Ying Gao,Liu Gao,Qiang Jia,Li Yu,Yunzhi Ling
The aim of this study was to examine the effects of ML365, a two-pore potassium channel (K2P) inhibitor, on postoperative cognitive impairment (POCD). A mouse model of POCD was constructed by subjecting aged C57BL/6 mice to exploratory laparotomy. Changes in cognitive function were assessed using the Morris water maze test. Western blotting and qPCR were used to detect hippocampal NLRP3, Caspase-1 and IL-1β expression levels on days 3 and 7 post-surgery. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) expression level was also assessed by western blotting. Pathological changes and nerve damage in the hippocampal CA1 and CA3 regions were detected by H&E staining, while the concentration of malondialdehyde (MDA) in the plasma was measured. We found that pretreatment with ML365 (administered intraperitoneally at a dose of 10 mg/kg) 30 min prior to exploratory laparotomy effectively ameliorated POCD in mice. ML365 pretreatment also reduced NLRP3, Caspase-1, ASC and IL-1β expression levels in the hippocampus, improved POCD-induced pathological changes in the hippocampal CA1 and CA3 areas of aged mice, and decreased levels of plasma MDA and oxidative stress. Together, our findings indicate that ML365 can alleviate POCD in mice by inhibiting NLRP3 inflammasome activation in the hippocampus.
研究领域:
神经科学
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药理学
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外科手术
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炎症
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认知障碍
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产品关联
DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
·
2017
·Vol. 32
·期 3
·789-798
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IF 2.297
Wu Xiang,Chen Huixin,Huang Chunhui,Gu Xinmei,Wang Jialing,Xu Dilin,Yu Xin,Shuai Chu,Chen Liping,Li Shun,Xu Yiguo,Gao Tao,Ye Mingrui,Su Wei,Liu Haixiong,Zhang Jinrong,Wang Chuang,Chen Junping,Wang Qinwen,Cui Wei
Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa , ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.
研究领域:
神经科学
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药理学
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老年学
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2022
·Vol. 48
·期 2
·393-403
·
IF 4.414
Ma Zijian,Ma Yang,Cao Xuefeng,Zhang Yunpeng,Song Tieying
Postoperative neurocognitive impairment (POCD) is a common complication after surgery and anesthesia, especially in elderly patients. Avenanthramide-C (AVC) test is a vascular endothelial cell adhesion molecule inhibitor with strong anti-inflammatory and antioxidant effects. The aim of this study was to investigate the effect and mechanism of AVC on POCD in aged rats to clarify the effect of AVC on POCD in aged rats. The aging rat model was established by continuous 200 mg/kg propofol anesthesia. Repeated propofol anesthesia could severely impair spatial learning ability, memory and cognitive function, and could promote hippocampal apoptosis, oxidative stress injury, neuroinflammation and ferroptosis in aging rats. In addition, AVC not only improved cognitive dysfunction, but also significantly inhibited apoptosis, neuroinflammatory response, ferroptosis and oxidative stress level in the hippocampus of aging rats induced by repeated anesthesia. Further mechanistic studies manifested that the above protective effects of AVC on aging rats induced by repeated propofol anesthesia may be achieved by activating Nrf2/ARE pathway activity. AVC pretreatment has a preventive effect on cognitive dysfunction induced by repeated propofol anesthesia in aging rats, and the preventive effect of AVC may be realized by activating the Nrf2/ARE signaling pathway activity. Our results demonstrate that AVC preconditioning reduces postoperative neuronal loss and neuroinflammation, activates the Nrf2/ARE pathway, reduces oxidative stress injury, and improves POCD in aged rats.
研究领域:
神经科学
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药理学
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老年医学
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麻醉学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Yuan Chen,Yi Zhou,Jinhan Cai,Jiayi Xu,Chenwei Hu,Huiyue Chen,Yirui Hong,Nanyi Pan,Yujie Jiang,Chenhui Zhou,Hua Wei,Zhipeng Xu,Lin Liu,Xiang Wu,Wei Cui
Post-operative cognitive dysfunction (POCD) is a multi-etiological symptom mainly occurred in elderly people after surgery. The activation of retinoic acid receptor α (RARα), a transcriptional factor, was previously predicated to be negatively associated with the occurrence of POCD. However, the mechanisms underlying anti-POCD effects of RARα were still unclear. In this study, AM580, a selective agonist of RARα, and all-trans-retinoic acid (ATRA), a pan agonist of RAR, significantly alleviated cognitive dysfunction and increased the expression of RARα in elderly mice after surgery, which was decreased by RO41-5253, an antagonist of RARα. A bioinformatic study further predicted that the activation of RARα might produce anti-POCD effects via the restoration of synaptic proteins. Both agonists inhibited the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and the phosphorylation of nuclear factor kappa-B (NF-κB), leading to the prevention of microglial over-activation and pro-inflammatory cytokines secretion in the hippocampal regions of elderly mice after surgery. Moreover, AM580 and ATRA increased the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and the phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element binding protein (CREB). All these results suggested that the activation of RARα prevented surgery-induced cognitive impairments via the inhibition of neuroinflammation by the reduction of the TLR4/Myd88/NF-κB pathway and the restoration of synaptic proteins by the activation of the BDNF/ERK/CREB pathway, providing a further support that RARα could be developed as a therapeutic target for POCD.
研究领域:
神经科学
·
药理学
·
老年医学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）