Manzella Francesca M, Covey Douglas F, Jevtovic-Todorovic Vesna, Todorovic Slobodan M
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
J Neuroendocrinol. 2022 Feb;34(2):e13086. doi: 10.1111/jne.13086. Epub 2022 Jan 10.
Since the 1990s, there has been waning interest in researching general anaesthetics (anaesthetics). Although currently used anaesthetics are mostly safe and effective, they are not without fault. In paediatric populations and neonatal animal models, they are associated with learning impairments and neurotoxicity. In an effort to research safer anaesthetics, we have gone back to re-examine neuroactive steroids as anaesthetics. Neuroactive steroids are steroids that have direct, local effects in the central nervous system. Since the discovery of their anaesthetic effects, neuroactive steroids have been consistently used in human or veterinary clinics as preferred anaesthetic agents. Although briefly abandoned for clinical use due to unwanted vehicle side effects, there has since been renewed interest in their therapeutic value. Neuroactive steroids are safe sedative/hypnotic and anaesthetic agents across various animal species. Importantly, unlike traditional anaesthetics, they do not cause extensive neurotoxicity in the developing rodent brain. Similar to traditional anaesthetics, neuroactive steroids are modulators of synaptic and extrasynaptic γ-aminobutyric acid type A (GABA ) receptors and their interactions at the GABA receptor are stereo- and enantioselective. Recent work has also shown that these agents act on other ion channels, such as high- and low-voltage-activated calcium channels. Through these mechanisms of action, neuroactive steroids modulate neuronal excitability, which results in characteristic burst suppression of the electroencephalogram, and a surgical plane of anaesthesia. However, in addition to their interactions with voltage and ligand gated ions channels, neuroactive steroids interact with membrane bound metabotropic receptors and xenobiotic receptors to facilitate signaling of prosurvival, antiapoptotic pathways. These pathways play a role in their neuroprotective effects in neuronal injury and may also prevent extensive apoptosis in the developing brain during anaesthesia. The current review explores the history of neuroactive steroids as anaesthetics in humans and animal models, their diverse mechanisms of action, and their neuroprotective properties.
自20世纪90年代以来，对全身麻醉药（麻醉剂）的研究兴趣一直在下降。尽管目前使用的麻醉剂大多安全有效，但并非没有缺陷。在儿科人群和新生动物模型中，它们与学习障碍和神经毒性有关。为了研究更安全的麻醉剂，我们回过头来重新审视神经活性甾体作为麻醉剂的情况。神经活性甾体是在中枢神经系统中具有直接局部作用的甾体。自发现其麻醉作用以来，神经活性甾体一直作为首选麻醉剂在人类或兽医临床中持续使用。尽管由于不良的载体副作用曾一度被放弃用于临床，但此后人们对其治疗价值重新产生了兴趣。神经活性甾体在各种动物物种中都是安全的镇静/催眠和麻醉剂。重要的是，与传统麻醉剂不同，它们不会在发育中的啮齿动物大脑中引起广泛的神经毒性。与传统麻醉剂类似，神经活性甾体是突触和突触外A型γ-氨基丁酸（GABA）受体的调节剂，它们在GABA受体上的相互作用具有立体和对映体选择性。最近的研究还表明，这些药物作用于其他离子通道，如高电压和低电压激活的钙通道。通过这些作用机制，神经活性甾体调节神经元兴奋性，从而导致脑电图特征性的爆发抑制和手术麻醉平面。然而，除了与电压门控和配体门控离子通道相互作用外，神经活性甾体还与膜结合的代谢型受体和外源性受体相互作用，以促进促生存、抗凋亡途径的信号传导。这些途径在其对神经元损伤的神经保护作用中发挥作用，也可能在麻醉期间预防发育中大脑的广泛凋亡。本综述探讨了神经活性甾体在人类和动物模型中作为麻醉剂的历史、其多样的作用机制及其神经保护特性。
