神经活性甾体化合物阿尔法羟孕酮和 CDNC24 是有效的催眠药和 GABA 电流增强剂，但对发育中的大鼠大脑没有神经毒性。
Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABA currents, but are not neurotoxic to the developing rat brain.
机构信息
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
出版信息
Br J Anaesth. 2020 May;124(5):603-613. doi: 10.1016/j.bja.2020.01.013. Epub 2020 Mar 6.
BACKGROUND
The most currently used general anaesthetics are potent potentiators of γ-aminobutyric acid A (GABA) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABA potentiation and anaesthetic-induced developmental neurotoxicity has not been established, the question remains whether GABAergic activity is crucial for promoting/enhancing neurotoxicity. Using the neurosteroid analogue, (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABA receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development.
METHODS
The neurotoxic potential of CDNC24 was examined vis-à-vis propofol (2,6-diisopropylphenol) and alphaxalone (5α-pregnan-3α-ol-11,20-dione) at the peak of rat synaptogenesis. In addition to the morphological neurotoxicity studies of the subiculum and medial prefrontal cortex (mPFC), we assessed the extra-, pre-, and postsynaptic effects of these agents on GABAergic neurotransmission in acute subicular slices from rat pups.
RESULTS
CDNC24, like alphaxalone and propofol, caused dose-dependent hypnosis in vivo, with a higher therapeutic index. CDNC24 and alphaxalone, unlike propofol, did not cause developmental neuroapoptosis in the subiculum and mPFC. Propofol potentiated post- and extrasynaptic GABA currents as evidenced by increased spontaneous inhibitory postsynaptic current (sIPSC) decay time and prominent tonic currents, respectively. CDNC24 and alphaxalone had a similar postsynaptic effect, but also displayed a strong presynaptic effect as evidenced by decreased frequency of sIPSCs and induced moderate tonic currents.
CONCLUSIONS
The lack of neurotoxicity of CDNC24 and alphaxalone may be at least partly related to suppression of presynaptic GABA release in the developing brain.
背景
目前最常用的全身麻醉剂是γ-氨基丁酸 A (GABA) 受体的有效增强剂，在临床前动物模型中，在大脑发育的早期阶段，它们始终具有神经毒性。由于 GABA 增强与麻醉诱导的发育性神经毒性之间的因果关系尚未确定，因此仍存在疑问，即 GABA 能活性是否对促进/增强神经毒性至关重要。本研究使用神经甾体类似物（3α,5α）-3-羟基-13,24-环-18,21-二降胆烷-22-烯-24-醇（CDNC24），该物质可增强重组 GABA 受体，研究了这种增强是否是诱导发育过程中神经毒性的驱动力。
方法
在大鼠突触发生高峰期，研究 CDNC24 的神经毒性潜力与丙泊酚（2,6-二异丙基苯酚）和阿尔法羟酮（5α-孕烷-3α-醇-11,20-二酮）的关系。除了对 subiculum 和内侧前额叶皮层（mPFC）的形态神经毒性研究外，还评估了这些药物在急性大鼠海马切片中对 GABA 能神经传递的突触外、突触前和突触后效应。
结果
CDNC24 与阿尔法羟酮和丙泊酚一样，在体内引起剂量依赖性催眠作用，且治疗指数较高。与丙泊酚不同，CDNC24 和阿尔法羟酮在 subiculum 和 mPFC 中不会引起发育性神经细胞凋亡。丙泊酚增强了突触后和突触外 GABA 电流，表现为自发抑制性突触后电流（sIPSC）衰减时间延长和明显的紧张电流。CDNC24 和阿尔法羟酮具有相似的突触后效应，但也表现出强烈的突触前效应，表现为 sIPSC 频率降低和诱导适度的紧张电流。
结论
CDNC24 和阿尔法羟酮无神经毒性，这至少部分与抑制发育中大脑的突触前 GABA 释放有关。
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