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艾司氯胺酮通过AMPK/SIRT1/PGC-1α信号通路改善髋部骨折大鼠术后认知功能障碍的机制
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| 篇名： | 艾司氯胺酮通过AMPK/SIRT1/PGC-1α信号通路改善髋部骨折大鼠术后认知功能障碍的机制 |
| TITLE： | Mechanism by which esketamine improves postoperative cognitive impairment in rats with hip fracture through AMPK/SIRT1/PGC-1α signaling pathway |
| 摘要： | 目的 基于AMP活化蛋白激酶（AMPK）/沉默信息调节因子1（SIRT1）/过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）信号通路，探讨艾司氯胺酮改善髋部骨折大鼠术后认知功能障碍的机制。方法将髋部骨折术后大鼠分为模型组、艾司氯胺酮组（10mg/kg）、抑制剂组（250μg/mLAMPK抑制剂CompoundC）、艾司氯胺酮+抑制剂组（10mg/kg艾司氯胺酮+250μg/mLCompoundC），并将执行假手术的大鼠作为对照组，每组12只。采用新物体识别及巴恩斯迷宫实验评估大鼠认知功能；检测血清肿瘤坏死因子α（TNF-α）、白细胞介素1β（IL-1β）、超氧化物歧化酶（SOD）、丙二醛（MDA）、γ-氨基丁酸（GABA）、多巴胺（DA）、谷氨酸（Glu）水平以及海马神经元细胞凋亡情况；观察海马组织病理形态和线粒体超微结构的变化；检测海马组织中B细胞淋巴瘤-2（Bcl-2）、Bcl-2相关X蛋白（Bax）mRNA表达水平，AMPK、SIRT1和PGC-1α的mRNA和蛋白表达以及磷酸化（p）-AMPK的蛋白表达。结果与对照组比较，模型组大鼠海马神经元排列较乱，较多神经元坏死，且线粒体肿胀；新物体识别指数，SOD、GABA、DA水平，Bcl-2、AMPK、SIRT1、PGC-1αmRNA表达水平以及p-AMPK、SIRT1、PGC-1α蛋白表达水平均显著降低，而寻找未知洞的潜伏期、错误次数，TNF-α、IL-1β、MDA、Glu水平，神经元细胞凋亡率以及BaxmRNA表达水平均显著升高/延长（P＜0.05）；与模型组比较，艾司氯胺酮组大鼠海马组织病理损伤减轻；新物体识别指数，SOD、GABA、DA水平，Bcl-2、AMPK、SIRT1、PGC-1αmRNA表达水平以及p-AMPK、SIRT1、PGC-1α蛋白表达水平均显著升高，而寻找未知洞的潜伏期、错误次数，TNF-α、IL-1β、MDA、Glu水平，神经元细胞凋亡率以及BaxmRNA表达水平均显著下降（P＜0.05）；抑制剂组上述指标变化趋势则与艾司氯胺酮组相反（P＜0.05）。AMPK抑制剂可逆转艾司氯胺酮对大鼠髋部骨折术后上述指标的改善作用（P＜0.05）。结论艾司氯胺酮可能通过激活AMPK/SIRT1/PGC-1α信号通路改善大鼠髋部骨折术后炎症反应和氧化应激水平，抑制神经元细胞凋亡，改善线粒体结构，促进术后认知功能恢复。 |
| ABSTRACT： | OBJECTIVE To investigate the mechanism by which esketamine improves postoperative cognitive impairment in rats with hip fracture based on the AMP-activated protein kinase （AMPK）/silencing information regulatory factor 1 （SIRT1）/ peroxisome proliferator activated-receptor-γ coactivator-1α （PGC-1α） signaling pathway. METHODS Rats with hip fracture surgery were assigned into model group， esketamine group （10 mg/kg）， inhibitor group （250 μg/mL AMPK inhibitor Compound C）， and esketamine+inhibitor group （10 mg/kg esketamine + 250 μg/mL Compound C）， and rats undergoing sham surgery were used as the control group， with 12 rats in each group. New object recognition and Barnes maze experiments were used to E-mail：448231@163.com evaluate cognitive function in rats. The levels of serum tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β），superoxide dismutase （SOD）， malondialdehyde （MDA）， gamma-aminobutyric acid （GABA）， dopamine （DA） and glutamate （Glu）， and the apoptosis of hippocampal neurons were detected. The pathological morphology of the hippocampal tissue and the ultrastructure of mitochondria were observed. The mRNA expression of B-cell lymphoma-2 （Bcl-2） and Bcl-2-associated X protein （Bax），the mRNA and protein expression of AMPK， SIRT1 and PGC-1α， as well as the expression of phosphorylated （p）-AMPK in hippocampal tissue， were detected. RESULTS Compared with the control group， the hippocampal neurons in the model group of rats were disordered， with more neurons necrotic and swollen mitochondria；the new object recognition index， the SOD， GABA， DA levels， Bcl-2， AMPK， SIRT1 and PGC-1α mRNA expression levels， and p-AMPK， SIRT1， PGC-1α protein expression levels were significantly reduced， while the latency and number of errors for locating unknown holes， the TNF-α， IL-1β， MDA and Glu levels， neuronal cell apoptosis rate， and Bax mRNA expression levels were significantly increased/prolonged （P＜0.05）. Compared with the model group， the esketamine group showed reduced pathological damage to the hippocampal tissue of rats， and the new object recognition index， the SOD， GABA and DA levels， the Bcl-2， AMPK， SIRT1 and PGC-1α mRNA expression levels， and p-AMPK， SIRT1， PGC-1α protein expression levels were significantly increased，while the latency and error frequency for locating unknown holes， TNF-α， IL-1β， MDA and Glu levels， neuronal cell apoptosis rate， and Bax mRNA expression levels were significantly decreased （P＜0.05）；the inhibitor group showed the opposite trend of changes in these indicators compared to the esketamine group （P＜0.05）.AMPK inhibitor could reverse the improvement effect of esketamine on the above indicators after hip fracture surgery in rats （P＜0.05）. CONCLUSIONS Esketamine may improve postoperative inflammatory response and oxidative stress levels in rats with hip fracture by activating the AMPK/SIRT1/PGC-1α signaling pathway， inhibiting neuronal cell apoptosis， improving mitochondrial structure， and promoting postoperative cognitive function recovery. |
| 期刊： | 2025年第36卷第21期 |
| 作者： | 刘璇；张晓敏；刘进婷；郝岩；汪业铭；陈丽星 |
| AUTHORS： | LIU Xuan，ZHANG Xiaomin，LIU Jinting，HAO Yan，WANG Yeming，CHEN Lixing |
| 关键字： | 艾司氯胺酮；AMP活化蛋白激酶；沉默信息调节因子 1；过氧化物酶体增殖物激活受体 γ共激活因子1α；髋部骨折；认知 |
| KEYWORDS： | esketamine； AMP-activated protein kinase； silencing information regulator factor 1； peroxisome proliferator |
| 阅读数： | 1 次 |
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