Novel neurosteroid anesthetics and developmental synaptogenesis

新型神经类固醇麻醉剂和发育突触发生

• 批准号: 10456624
• 负责人: Vesna Jevtovic-Todorovic
• 金额: $ 52.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456624
• 关键词: Acute; Address; Age; Agonist; Alphaxolone; Analgesics; Anesthesia procedures; Anesthetics; Animals; Apoptotic; Base of the Brain; Behavioral; Brain; Cell Death; Child; Childhood; Clinical; Communication; Complement; Data; Development; Drug Interactions; Drug Kinetics; Electrophysiology (science); Equilibrium; Exhibits; Exposure to; Family; General Anesthesia; General anesthetic drugs; Goals; Health Professional; Hippocampal Formation; Hippocampus (Brain); Human; Impaired cognition; Impairment; Infant; Inhalation Anesthetics; Injectable; Ketamine; Maintenance; Medicine; Mental Depression; Mitochondria; Modeling; Modernization; Monkeys; Morphology; Mus; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Outcome; Pharmaceutical Preparations; Play; Pregnant Women; Preparation; Property; Propofol; Protective Agents; Rattus; Regimen; Reporting; Risk; Rodent; Role; Safety; Slice; Steroids; Synaptic Transmission; System; T-Type Calcium Channels; Testing; behavioral impairment; cellular targeting; channel blockers; cognitive development; design; developmental neurotoxicity; functional disability; functional outcomes; gamma-Aminobutyric Acid; hypnotic; in vivo; long-term sequelae; neuronal excitability; neuronal survival; neurosteroids; neurotoxic; new therapeutic target; nonhuman primate; novel; postnatal; postsynaptic; presynaptic; pup; receptor; side effect; steroid analog; synaptic function; synaptogenesis; translational study; voltage; young adult

Summary Exposure of young children to general anesthetics (GAs) is common in medicine; however, emerging data suggest that this practice may be detrimental to brain development, resulting in long-term cognitive impairments. Since currently used GAs known to be neurotoxic to the immature brain exert their action by modulating two main receptor systems – GABA and NMDA – we suggest the general hypothesis that novel anesthetics with different cellular targets might be safe and promising alternative. One such alternative is a family of neuroactive steroids with blocking action on low-voltage-activated T-type calcium channels known to be important for neuronal excitability and synaptic transmission. Our long-term goal is to develop novel GAs that will provide the same reliability and efficacy as currently available ones but without devastating long-term consequences. We are off to a promising start since T-channel-blocking neuroactive steroids are not only powerful analgesics but also effective hypnotics. Most importantly, compared with other injectable (and inhaled) anesthetics, they appear to be much less harmful to the developing brain based on our preliminary pathomorphological and functional findings. Our rationale is that the design of safer anesthetics for use in children should be guided by the presently available understanding of the mechanisms responsible for developmental neurotoxicity of currently used GAs. To that end, we will use ex vivo and in vivo rat models of GA-induced developmental neurotoxicity to address the specific hypothesis that novel neuroactive steroids with blocking action on T-channels, unlike clinically-used GAs, are effective and safe anesthetics for use during critical stages of brain development. Aim #1: Characterizes anesthetic properties of novel neuroactive steroid analogs that are T-channel blockers (e.g. 3-OH and ECN) and GABAA agonists (e.g. ACN, CDNC24 and alphaxalone) and compares their anesthesia profile in rats and mice with commonly used injectable anesthetic, propofol. Preliminary data suggest that 3-OH is safe and effective and, compared with ketamine, it exhibits higher efficacy and potency when administered to rat pups (at post-natal day 7). Aim #2: Examines neurotoxic potential of neuroactive steroid analogs vis-à-vis propofol (known to cause significant developmental neurotoxicity) by focusing on morphological and functional features of GA-induced impairments of synaptogenesis (e.g. acute apoptotic cell death, delayed impairment in synapse formation/maintenance, integrity of mitochondria, neuronal survival and impairment in synaptic transmission). Aim #3: Scrutinizes long- term functional outcomes of an early exposure to novel neuroactive steroid analogs with particular focus on neuronal communication in hippocampal ex vivo slice preparation and in vivo assessment of cognitive development. Our preliminary findings suggest a lack of cognitive impairment after an early exposure to 3- OH. Aim #4: Takes rodent studies to the next level by examining the anesthetic properties and safety of a chosen neuroactive steroid (as determined in Aims 1-3) in infant non-human primates.

概括 然而，新出现的数据显示，幼儿接触全身麻醉剂 (GA) 的现象在医学上很常见； 表明这种做法可能会损害大脑发育，导致长期认知能力下降 由于目前使用的 GA 已知对未成熟的大脑具有神经毒性，因此发挥其作用。 调节两个主要受体系统——GABA 和 NMDA——我们提出一般假设： 具有不同细胞靶点的麻醉剂可能是一种安全且有前途的替代方案。 是一类神经活性类固醇，对低电压激活的 T 型钙通道具有阻断作用，已知 对于神经兴奋性和突触传递很重要，我们的长期目标是开发新型 GA。 这将提供与现有产品相同的可靠性和功效，但不会破坏长期效果 我们有了一个充满希望的开始，因为 T 通道阻断神经活性类固醇不仅是一种药物。 与其他注射剂（和）相比，它是强效镇痛药，也是有效的催眠药。 吸入）麻醉剂，根据我们的研究，它们对发育中的大脑的危害似乎要小得多 我们的初步病理形态学和功能发现是设计更安全。 用于儿童的麻醉剂应以目前对机制的了解为指导 为此，我们将使用离体和体内的方法。 GA 诱导的发育神经毒性大鼠模型，以解决新的特定假设 与临床使用的 GA 不同，具有 T 通道阻断作用的神经活性类固醇有效且安全 在大脑发育的关键阶段使用的麻醉剂。目标#1：表征麻醉剂的特性。 新型神经活​​性类固醇类似物，即 T 通道阻滞剂（例如 3-OH 和 ECN）和 GABAA 激动剂 （例如 ACN、CDNC24 和 alphaxalone），并将它们在大鼠和小鼠中的麻醉效果与常见药物进行比较 与注射用麻醉剂异丙酚相比，初步数据表明3-OH是安全有效的。 与氯胺酮相比，当给幼鼠施用时（出生后第 7 天），它表现出更高的功效和效力。 #2：检查神经活性类固醇类似物相对于异丙酚的潜在神经毒性（已知会导致显着的 发育神经毒性），重点关注 GA 引起的损伤的形态和功能特征 突触发生（例如急性细胞凋亡、突触形成/维持的延迟损伤、 目标#3：仔细审视长期 早期接触新型神经活​​性类固醇类似物的长期功能结果，特别关注 海马离体切片制备和体内认知评估中的神经通讯 我们的初步研究结果表明，早期接触 3- 后不会出现认知障碍。 哦。目标#4：通过检查麻醉剂的麻醉特性和安全性，将啮齿动物研究提升到一个新的水平。 在婴儿非人类灵长类动物中选择神经活性类固醇（如目标 1-3 中确定）。