Liu Huiqin, Jiang Yanhua, Cong Lianhui, Zhang Xinyue, Zhou Yongjian, Pan Xue, Liu Sidan, Wang Renyi, Cao Xuezhao
Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China.
Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China.
Free Radic Biol Med. 2025 Feb 16;228:240-250. doi: 10.1016/j.freeradbiomed.2025.01.006. Epub 2025 Jan 4.
Perioperative neurocognitive disorders (PND) are common complications following surgery and anesthesia, especially in the elderly. These disorders are associated with disruptions in neuronal energy metabolism and mitochondrial function. This study explores the potential of intranasal insulin administration as a therapeutic strategy to prevent PND by targeting the calcium transport protein complex IP3R/GRP75/VDAC1 on mitochondria-associated endoplasmic reticulum membranes (MAMs).
Male C57BL/6J mice underwent partial hepatectomy to induce PND and were subsequently treated with either intranasal insulin or saline. Cognitive function was evaluated using the Morris water maze test, and hippocampal tissue was analyzed for calcium transport protein complex IP3R/GRP75/VDAC1 expression and apoptosis markers. In vitro, HT22 and BV2 cell co-cultures were utilized to simulate surgical injury, with IP3R knockdown employed to assess its effects on oxidative stress and apoptosis.
Intranasal insulin effectively alleviated cognitive impairment as demonstrated by improved performance in the Morris water maze. It significantly reduced neuronal apoptosis and modulated the expression of the IP3R/GRP75/VDAC1 complex, enhancing mitochondrial ATP production and stabilizing MAMs. Furthermore, insulin administration also increased PI3K/AKT signaling, counteracting the impact of surgical stress. In vitro experiments confirmed that IP3R knockdown mitigated inflammation-induced oxidative stress and neuronal apoptosis, while insulin's beneficial effects were blocked by inhibition of the PI3K/AKT pathway.
Intranasal insulin mitigates PND by modulating the IP3R/GRP75/VDAC1 complex and enhancing mitochondrial function through the PI3K/AKT signaling pathway. This study supports the potential of intranasal insulin as a promising therapeutic strategy for preventing and managing PND, potentially leading to improved surgical outcomes for elderly patients.
围手术期神经认知障碍（PND）是手术和麻醉后常见的并发症，尤其是在老年人中。这些障碍与神经元能量代谢和线粒体功能的破坏有关。本研究探讨了鼻内给予胰岛素作为一种治疗策略的潜力，该策略通过靶向线粒体相关内质网膜（MAM）上的钙转运蛋白复合物IP3R/GRP75/VDAC1来预防PND。
雄性C57BL/6J小鼠接受部分肝切除术以诱导PND，随后接受鼻内胰岛素或生理盐水治疗。使用莫里斯水迷宫试验评估认知功能，并分析海马组织中钙转运蛋白复合物IP3R/GRP75/VDAC1的表达和凋亡标志物。在体外，利用HT22和BV2细胞共培养来模拟手术损伤，采用IP3R基因敲低来评估其对氧化应激和凋亡的影响。
鼻内胰岛素有效减轻了认知障碍，莫里斯水迷宫中的表现改善证明了这一点。它显著减少了神经元凋亡，并调节了IP3R/GRP75/VDAC1复合物的表达，增强了线粒体ATP的产生并稳定了MAM。此外，给予胰岛素还增加了PI3K/AKT信号传导，抵消了手术应激的影响。体外实验证实，IP3R基因敲低减轻了炎症诱导的氧化应激和神经元凋亡，而胰岛素的有益作用被PI3K/AKT途径的抑制所阻断。
鼻内胰岛素通过调节IP3R/GRP75/VDAC复合物并通过PI3K/AKT信号通路增强线粒体功能来减轻PND。本研究支持鼻内胰岛素作为预防和管理PND的一种有前景的治疗策略的潜力，这可能会改善老年患者的手术结局。
