A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain
A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain
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DOI：
10.1016/j.bja.2017.12.039
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发表时间：
2018-04-01
影响因子：
9.8
通讯作者：
Jevtovic-Todorovic, V.
中科院分区：
文献类型：
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作者：
Atluri, N.;Joksimovic, S. M.;Jevtovic-Todorovic, V.
背景：仅在美国，每年就有400多万儿童接触镇静剂和全身麻醉剂（GA）。最近的数据表明，常见的GA可能对大脑发育有害，导致神经退行性变和长期认知障碍。最近美国食品和药物管理局（FDA）警告说，GA对儿童有潜在的神经毒性作用，因此迫切需要开发更安全的GA。出生后第7天（P7），两种性别的大鼠幼仔暴露于6种（每2小时重复一次）注射等效催眠剂量的氯胺酮或神经活性类固醇（3 β，5 β，17 β）-3-羟基雄甾烷-17-腈（3 β-OH）12小时。翻正反射的丧失用于评估催眠特性和治疗指数;定量半胱天冬酶-3免疫组织化学用于评估发育性神经细胞凋亡;急性脑切片中的膜片钳记录用于评估3 β-OH对神经元兴奋性和突触传递的影响。暴露于氯胺酮，3 β-OH，或车辆在P7的大鼠的认知能力进行了评估，在年轻的成年使用的径向臂迷宫.Results：神经活性类固醇3 β-OH具有类似于氯胺酮，一种常用的临床GA的治疗指数。我们报告说，3 β-OH是安全的，不像氯胺酮，不会导致神经细胞凋亡或损害认知发育时，给予P7大鼠幼崽。有趣的是，3 β-OH块T-型钙通道和突触前抑制突触传递hyperglycemic相关的大脑concentrations，但它缺乏对g-氨基丁酸A或谷氨酸门控离子channels.Conclusions的直接影响：神经甾体3 β-OH是一种相对安全的催眠药，值得进一步考虑儿科麻醉。
Background: More than 4 million children are exposed annually to sedatives and general anaesthetics (GAs) in the USA alone. Recent data suggest that common GAs can be detrimental to brain development causing neurodegeneration and long-term cognitive impairments. Challenged by a recent US Food and Drug Administration (FDA) warning about potentially neurotoxic effects of GAs in children, there is an urgent need to develop safer GAs.Methods: Postnatal Day 7 (P7) rat pups of both sexes were exposed to six (repeated every 2 h) injections of equipotent hypnotic doses of ketamine or the neuroactive steroid (3 beta, 5 beta, 17 beta)-3-hydroxyandrostane-17-carbonitrile (3 beta-OH) for 12 h. Loss of righting reflex was used to assess hypnotic properties and therapeutic index; quantitative caspase-3 immunohistochemistry was used to assess developmental neuroapoptosis; patch-clamp recordings in acute brain slices were used to assess the effects of 3 beta-OH on neuronal excitability and synaptic transmission. Cognitive abilities of rats exposed to ketamine, 3 beta-OH, or vehicle at P7 were assessed in young adulthood using the radial arm maze.Results: The neuroactive steroid 3 beta-OH has a therapeutic index similar to ketamine, a commonly used clinical GA. We report that 3 beta-OH is safe and, unlike ketamine, does not cause neuroapoptosis or impair cognitive development when administered to P7 rat pups. Interestingly, 3 beta-OH blocks T-type calcium channels and presynaptically dampens synaptic transmission at hypnotically-relevant brain concentrations, but it lacks a direct effect on g-aminobutyric acid A or glutamate-gated ion channels.Conclusions: The neurosteroid 3 beta-OH is a relatively safe hypnotic that warrants further consideration for paediatric anaesthesia.