Anesthesia-Induced Developmental Neuroapoptosis in non-Human Primates

非人灵长类动物麻醉诱导的发育性神经细胞凋亡

• 批准号: 8043662
• 负责人: JOHN W OLNEY
• 金额: $ 38.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2012-03-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8043662
• 关键词: Age; Agonist; Anatomy; Anesthesia procedures; Anesthetics; Anticonvulsants; Apoptosis; Apoptotic; Attention; Biological; Birth; Brain; Brain Injuries; Categories; Childhood; Clinical Medicine; Development; Discipline of obstetrics; Dose; Drug Combinations; Ethanol; Excitatory Amino Acid Antagonists; Fetal Alcohol Syndrome; Fetus; Future; General Anesthesia; General anesthetic drugs; Goals; Growth; Heart; Hour; Human; Individual; Infant; Injury; Isoflurane; Life; Light; Medicine; Midazolam; Monkeys; Mus; N-Methylaspartate; Nerve Degeneration; Neurons; Nitrous Oxide; Pain; Patients; Pattern; Perinatal Exposure; Pharmaceutical Preparations; Predisposition; Pregnancy; Primates; Process; Property; Propofol; Protocols documentation; Rattus; Request for Applications; Research; Resolution; Risk; Rodent; Saimiri; Series; Sodium Channel Blockers; Staging; Synapses; Time; Unconscious State; accomplished suicide; base; critical period; fetal; in utero; killings; neonate; neurobehavioral; neuron development; nonhuman primate; postnatal; programs; research study; synaptogenesis

DESCRIPTION (provided by applicant): This is a revised competing RO1 application requesting support for studies pertaining to the ability of anesthetic drugs to trigger apoptotic neurodegeneration in the developing monkey brain. In a series of recent studies, the applicants have shown that brief exposure of infant rats or mice to certain classes of drugs, including NMDA glutamate antagonists, GABAA agonists or ethanol, during the developmental period of synaptogenesis, triggers widespread neuroapoptosis in the developing brain. The period of synaptogenesis, also known as the brain growth spurt period, in rats and mice occurs during the first two weeks of postnatal life, but in humans, begins in mid-gestation and extends until approximately 3 years after birth. At the heart of the developmental neuroapoptosis mechanism is the biological fact that neurons in the developing brain are programmed to kill themselves if they fail to make appropriate synaptic connections. Although normally, only a small percentage of neurons commit suicide due to faulty synaptogenesis, our findings from rodent experiments suggest that if neuronal activity is abnormally suppressed for a period of only several hours this disrupts the synaptogenesis process sufficiently to cause large numbers of neurons to commit suicide. These findings are of potential concern in an anesthesia context because most, if not all, general anesthetics have either NMDA antagonist or GABAmimetic properties, and when used in concentrations or doses sufficient to render patients unconscious and insentient to pain, they profoundly suppress neuronal activity. While anesthesia-induced developmental neuroapoptosis (AIDNA) is a readily demonstrable phenomenon in rodent brain, only limited information is available pertaining to susceptibility of other species. In very limited pilot experiments we have observed that fetal monkeys appear to be sensitive to the apoptogenic properties of either ethanol or anesthetic drugs. To further evaluate susceptibility of the developing primate brain to AIDNA injury, we will expose squirrel monkeys to anesthesia during the brain growth spurt period, which in this species occurs primarily prenatally (last two trimesters of gestation). In Aim #1, we will expose monkey fetuses in utero to a triple anesthetic cocktail (isoflurane, nitrous oxide, midazolam) at one of three time points during the brain growth spurt period, and study the brains for evidence of AIDNA. In Aim #2, at the age of peak sensitivity (as determined in Aim #1 experiments), we will expose squirrel monkey fetuses to individual anesthetic agents (isoflurane or propofol), or to double combinations (isoflurane + nitrous oxide, or propofol + nitrous oxide), to help clarify the degree of risk posed by each agent or combination of agents.

描述（由申请人提供）：这是一项经过修订的竞争性RO1应用程序，要求支持与麻醉药物触发发育中猴子大脑中凋亡神经变性的能力有关的研究。在一系列最近的研究中，申请人表明，在突触发生的发育生成期间，婴儿大鼠或小鼠短暂暴露于某些类别的药物，包括NMDA谷氨酸拮抗剂，GABAA激动剂或乙醇，触发性的大脑中广泛的神经脑刺发生。在大鼠和小鼠中，突触发生的时期（也称为大脑生长时期）发生在产后的前两周，但在人类中，开始于妊娠中期，一直延伸至出生后大约3年。发育神经凋亡机制的核心是生物学事实，即发育中的大脑中的神经元在无法建立适当的突触连接时被编程为自杀。尽管通常，由于突触发生故障，只有一小部分神经元会自杀，但我们来自啮齿动物实验的发现表明，如果仅在几个小时的时间内将神经元活性异常抑制，这会充分破坏突触发生的过程，以引起大量神经元自杀。这些发现在麻醉背景下引起了潜在的关注，因为大多数（如果不是全部）全身麻醉药具有NMDA拮抗剂或gabamimetic特性，并且当用于浓度或剂量以使患者失去知觉且无情地疼痛时，它们会深深地抑制神经元活性。虽然麻醉引起的发育神经凋亡（AIDNA）是啮齿动物大脑中很容易证明的现象，但只有有限的信息与其他物种的敏感性有关。在非常有限的试验实验中，我们观察到胎儿猴子似乎对乙醇或麻醉药物的凋亡特性敏感。为了进一步评估发展灵长类动物大脑对AIDNA损伤的敏感性，我们将在大脑生长爆发时暴露于松鼠猴中麻醉，这在该物种中主要发生在产前（妊娠的最后两个三个妊娠剂）。在AIM＃1中，我们将在大脑生长时期的三个时间点之一中，将子宫内的猴子胎儿暴露于三重麻醉鸡尾酒（异氟烷，一氧化二氮，咪达唑仑），并研究大脑以获取AIDNA的证据。在AIM＃2中，在峰值敏感性的时代（在AIM＃1实验中确定），我们将使松鼠猴子胎儿暴露于单个麻醉剂（异氟烷或丙啉代剂）或双重组合（异氟烷 +硝酸氧化物 +硝酸盐氧化物，或抗丙烯氧化物 +丙烯 +氧化物），以帮助脱离剂量或构成剂量。