背景:葡萄糖转运蛋白1(GLUT1)对于葡萄糖转运到大脑中至关重要,并且主要在脑微脉管系统中表达。GLUT1的下调先于神经退行性疾病中认知障碍的发展。手术创伤引起血脑屏障(BBB)破坏,神经炎症,神经元线粒体功能障碍,和急性认知障碍。我们假设手术减少了GLUT1在BBB中的表达,这反过来破坏了其完整性,并导致大脑中的代谢失调,最终导致术后认知障碍。
方法:使用老年WT小鼠的腹部手术模型,我们评估了围手术期认知能力的变化,紧密连接蛋白表达,GLUT1表达式,以及海马中相关的代谢作用。此后,我们评估了这些参数在有条件过表达GLUT1的老年小鼠中的作用,然后在有或没有事先暴露于GLUT1抑制剂ST-31的有条件过表达GLUT1的老年小鼠中的作用.
结果:我们发现认知能力显著下降,随着GLUT1的减少和葡萄糖代谢的减少,特别是与对照组相比,术后小鼠的ATP水平。GLUT1的过表达减轻了术后认知功能下降和改善了代谢谱,尤其是腺苷,但没有直接将ATP生成恢复到对照水平。GLUT1抑制改善了GLUT1过表达的术后有益作用。
结论:手术诱导的GLUT1减少通过影响大脑中的葡萄糖代谢来显著促进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。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.