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: 10017289
• 负责人: Vesna Jevtovic-Todorovic
• 金额: $ 62.31万
• 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/10017289
• 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; 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 在医学中，幼儿暴露于全身麻醉药（GAS）是常见的；但是，新兴数据 表明这种做法可能对大脑发育有害，导致长期认知 障碍。由于目前使用的气体已知为神经毒性用于未成熟大脑，从而通过 调节两个主要的受体系统 - GABA和NMDA - 我们建议了一个新的假设 具有不同细胞靶标的麻醉药可能是安全的，并且有望替代。一个这样的选择 是一个神经活性类固醇家族，在低压激活的T型钙通道上具有阻塞作用已知 对于神经元令人兴奋和突触传播很重要。我们的长期目标是开发新型气体 这将提供与当前可用的相同的可靠性和易度性，但没有毁灭性的长期 结果。由于T通道阻滞神经活性类固醇不仅是 强大的止痛药，也有效的催眠药。最重要的是，与其他注射剂相比 吸入）麻醉剂，它们似乎对发展的大脑有害于我们 初步的病原体和功能性发现。我们的理由是安全设计 当前对机制的理解应指导儿童使用麻醉剂 负责开发当前使用的气体的神经毒性。为此，我们将使用Ex Vivo和In Vivo GA诱导的发育神经毒性的大鼠模型，以解决新颖的假设 与临床使用的气体不同，神经活性类固醇对T通道的阻塞作用是有效且安全的 在大脑发育的关键阶段使用麻醉剂。目标＃1：表征的麻醉特性 新型神经活​​性类固醇类似物是T通道阻滞剂（例如3-OH和ECN）和GABAA激动剂 （例如ACN，CDNC24和字母酮），并将其在大鼠和小鼠中的麻醉分布与通常 使用的可注射麻醉，建议。初步数据表明3-OH是安全有效的，并且比较 使用氯胺酮，当给大鼠幼崽施用时，它表现出更高的效率和效力（在产后第7天）。目的 ＃2：检查神经活性类固醇类似物的神经毒性潜力（已知会引起明显的 发育神经毒性）通过专注于GA诱导的损伤的形态和功能特征 突触发生（例如，急性凋亡细胞死亡，突触形成/维持的延迟损伤， 线粒体的完整性，神经元存活和突触传播中的损害）。目标＃3：仔细检查长期 早期暴露于新型神经活​​性类固醇类似物的术语功能结果，特别关注 海马外体内片制剂的神经元通信和认知的体内评估 发展。我们的初步发现表明，早期暴露于3-- 哦。目标＃4：通过检查A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 在婴儿非人类隐私中选择神经活性类固醇（如目标1-3中确定）。