Xia Xiaohui, Li Jiayi, Zhang Mengmeng, Zhang Chunyan, Lu Keliang, Han Huirong
Laboratory of Anesthesia and Critical Care Medicine in Colleges and Universities of Shandong Province School of Anesthesiology, Shandong Second Medical University, Weifang, China.
Department of Anesthesiology, Affiliated Hospital of Shandong Second Medical University, Weifang, China.
Sci Rep. 2025 May 22;15(1):17774. doi: 10.1038/s41598-025-01394-4.
Perioperative neurocognitive disorder (PND) is a long-term perioperative complication that affects elderly surgical patients. As the aging population continues to grow, the prevention and treatment of PND have become important issues to address. Research has shown that ulinastatin significantly reduces the incidence of PND in elderly patients undergoing various types of surgery, including spinal and abdominal surgeries. However, the underlying mechanisms of this effect remain unclear. Transient receptor potential melastatin 4 (TRPM4) is a Ca2 + -activated, monovalent cation channel associated with many neurological diseases. In the present study, we aimed to investigate the relationship between ulinastatin and TRPM4 in PND and to determine its underlying mechanism. Forty eighteen-month-old male Sprague‒Dawley rats were randomly divided into four groups: the sham group, surgery group (internal fixation of tibial fracture), ulinastatin group (ulinastatin + surgery), and 9-phenanthrol group (TRPM4 channel inhibitor 9-phenanthrol + surgery). The neurocognitive function of the rats was detected using the Y-maze and new object recognition (NOR) tests. We used WB, qPCR, and IF to detect the expression levels of TRPM4 in different groups of rats. We also detected the degree of apoptosis in rat hippocampal cells. Surgery under inhaled sevoflurane anesthesia induced cognitive impairments and elevated the expression of TRPM4 in the hippocampus. Downregulation of TRPM4 expression by ulinastatin or 9-phenanthrol alleviated cognitive impairments after anesthesia and surgery. Furthermore, ulinastatin treatment decreased the level of apoptosis in the hippocampus. Ulinastatin downregulates TRPM4 expression and apoptosis to mitigate cognitive dysfunction in aged perioperative neurocognitive disorder rats, and ulinastatin is a promising neuroprotectant against PND.
围手术期神经认知障碍（PND）是一种影响老年外科患者的长期围手术期并发症。随着老龄化人口持续增长，PND的预防和治疗已成为需要解决的重要问题。研究表明，乌司他丁可显著降低接受各种类型手术（包括脊柱和腹部手术）的老年患者PND的发生率。然而，这种作用的潜在机制仍不清楚。瞬时受体电位香草酸亚型4（TRPM4）是一种与许多神经疾病相关的Ca2 +激活的单价阳离子通道。在本研究中，我们旨在探讨乌司他丁与PND中TRPM4的关系，并确定其潜在机制。将40只18月龄雄性Sprague-Dawley大鼠随机分为四组：假手术组、手术组（胫骨骨折内固定）、乌司他丁组（乌司他丁+手术）和菲咯啉组（TRPM4通道抑制剂菲咯啉+手术）。使用Y迷宫和新物体识别（NOR）试验检测大鼠的神经认知功能。我们使用蛋白质免疫印迹法（WB）、实时定量聚合酶链反应（qPCR）和免疫荧光法（IF）检测不同组大鼠中TRPM4的表达水平。我们还检测了大鼠海马细胞的凋亡程度。吸入七氟醚麻醉下的手术诱导了认知障碍，并提高了海马中TRPM4的表达。乌司他丁或菲咯啉下调TRPM4表达可减轻麻醉和手术后的认知障碍。此外，乌司他丁治疗降低了海马中的凋亡水平。乌司他丁下调TRPM4表达和凋亡以减轻老年围手术期神经认知障碍大鼠的认知功能障碍，并且乌司他丁是一种有前景的抗PND神经保护剂。
