Lu Dihan, Zhang Wen, Chen Keyu, Feng Xia
Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
Neural Regen Res. 2024 Dec 7;21(1):81-95. doi: 10.4103/NRR.NRR-D-24-00828.
Debates regarding the specific effects of general anesthesia on developing brains have persisted for over 30 years. A consensus has been reached that prolonged, repeated, high-dose exposure to anesthetics is associated with a higher incidence of deficits in behavior and executive function, while single exposure has a relatively minor effect on long-term neurological function. In this review, we summarize the dose-dependent neuroprotective or neurotoxic effects of gamma-aminobutyric acid type A receptor agonists, a representative group of sedatives, on developing brains or central nervous system diseases. Most preclinical research indicates that anesthetics have neurotoxic effects on the developing brain through various signal pathways. However, recent studies on low-dose anesthetics suggest that they may promote neurodevelopment during this critical period. These findings are incomprehensible for the general "dose-effect" principles of pharmacological research, which has attracted researchers' interest and led to the following questions: What is the threshold for the dual effects exerted by anesthetics such as propofol and sevoflurane on the developing brain? To what extent can their protective effects be maximized? What are the underlying mechanisms involved in these effects? Consequently, this issue has essentially become a "mathematical problem." After summarizing the dose-dependent effects of gamma-aminobutyric acid type A receptor agonist sedatives in both the developing brain and the brains of patients with central nervous system diseases, we believe that all such anesthetics exhibit specific threshold effects unique to each drug. These effects range from neuroprotection to neurotoxicity, depending on different brain functional states. However, the exact values of the specific thresholds for different drugs in various brain states, as well as the underlying mechanisms explaining why these thresholds exist, remain unclear. Further in-depth exploration of these issues could significantly enhance the therapeutic translational value of these anesthetics.
关于全身麻醉对发育中大脑的具体影响的争论已经持续了30多年。目前已达成共识，即长期、反复、高剂量接触麻醉剂与行为和执行功能缺陷的发生率较高有关，而单次接触对长期神经功能的影响相对较小。在这篇综述中，我们总结了γ-氨基丁酸A型受体激动剂（一类具有代表性的镇静剂）对发育中大脑或中枢神经系统疾病的剂量依赖性神经保护或神经毒性作用。大多数临床前研究表明，麻醉剂通过各种信号通路对发育中的大脑具有神经毒性作用。然而，最近关于低剂量麻醉剂的研究表明，它们可能在这个关键时期促进神经发育。这些发现不符合药理学研究的一般“剂量-效应”原则，这引起了研究人员的兴趣，并引发了以下问题：丙泊酚和七氟醚等麻醉剂对发育中大脑产生双重作用的阈值是多少？它们的保护作用能在多大程度上最大化？这些作用涉及的潜在机制是什么？因此，这个问题本质上已经变成了一个“数学问题”。在总结了γ-氨基丁酸A型受体激动剂镇静剂在发育中大脑和中枢神经系统疾病患者大脑中的剂量依赖性作用后，我们认为所有这类麻醉剂都表现出每种药物特有的特定阈值效应。这些效应从神经保护到神经毒性不等，具体取决于不同的脑功能状态。然而，不同药物在各种脑状态下的具体阈值的确切值，以及解释这些阈值为何存在的潜在机制，仍然不清楚。对这些问题进行进一步深入探索可能会显著提高这些麻醉剂的治疗转化价值。
