Department of Anaesthesiology, LKS Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Room K424, 4Th Floor, K Block, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China.
Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, L4-49, Laboratory Block, Faculty of Medicine Building, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
J Neuroinflammation. 2023 Oct 19;20(1):237. doi: 10.1186/s12974-023-02905-8.
Glucose transporter 1 (GLUT1) is essential for glucose transport into the brain and is predominantly expressed in the cerebral microvasculature. Downregulation of GLUT1 precedes the development of cognitive impairment in neurodegenerative conditions. Surgical trauma induces blood-brain barrier (BBB) disruption, neuroinflammation, neuronal mitochondria dysfunction, and acute cognitive impairment. We hypothesized that surgery reduces the expression of GLUT1 in the BBB that in turn disrupts its integrity and contributes to metabolic dysregulation in the brain that culminates in postoperative cognitive impairment.
Using an abdominal surgery model in aged WT mice, we assessed the perioperative changes in cognitive performance, tight junction proteins expression, GLUT1 expression, and the associated metabolic effects in the hippocampus. Thereafter, we evaluated the effects of these parameters in aged mice with conditional overexpression of GLUT1, and then again in aged mice with conditional overexpression of GLUT1 with or without prior exposure to the GLUT1 inhibitor ST-31.
We showed a significant decline in cognitive performance, along with GLUT1 reduction and diminished glucose metabolism, especially in the ATP level in the postoperative mice compared with controls. Overexpression of GLUT1 expression alleviated postoperative cognitive decline and improved metabolic profiles, especially in adenosine, but did not directly restore ATP generation to control levels. GLUT1 inhibition ameliorated the postoperative beneficial effects of GLUT1 overexpression.
Surgery-induced GLUT1 reduction significantly contributes to postoperative cognitive deficits in aged mice by affecting glucose metabolism in the brain. It indicates the potential of targeting GLUT1 to ameliorate perioperative neurocognitive disorders.
葡萄糖转运蛋白 1（GLUT1）对于葡萄糖向大脑的转运至关重要，主要在脑微血管中表达。在神经退行性疾病中，GLUT1 的下调先于认知障碍的发展。手术创伤会引起血脑屏障（BBB）破坏、神经炎症、神经元线粒体功能障碍和急性认知障碍。我们假设手术会降低 BBB 中 GLUT1 的表达，进而破坏其完整性，并导致大脑代谢失调，最终导致术后认知障碍。
我们使用老年 WT 小鼠的腹部手术模型，评估了认知表现、紧密连接蛋白表达、GLUT1 表达以及海马体中相关代谢变化的围手术期变化。此后，我们评估了在 GLUT1 条件过表达的老年小鼠中这些参数的影响，然后再次评估了在 GLUT1 条件过表达的老年小鼠中，以及在 GLUT1 抑制剂 ST-31 暴露前后这些参数的影响。
与对照组相比，术后小鼠的认知表现显著下降，同时 GLUT1 减少和葡萄糖代谢减少，尤其是 ATP 水平降低。与对照组相比，GLUT1 过表达可减轻术后认知障碍，并改善代谢谱，尤其是腺苷，但不能直接将 ATP 生成恢复至对照水平。GLUT1 抑制可改善 GLUT1 过表达的术后有益作用。
手术诱导的 GLUT1 减少通过影响大脑中的葡萄糖代谢，显著导致老年小鼠术后认知缺陷。这表明靶向 GLUT1 改善围手术期神经认知障碍的潜力。
