Cellular Mechanisms of General Anesthetic Mediated Neurotoxicity

全身麻醉介导的神经毒性的细胞机制

• 批准号: 7024826
• 负责人: DEBORAH J CULLEY
• 金额: $ 12.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024826
• 关键词: anesthesia complication; cell age; cell death; cell differentiation; cytotoxicity; developmental neurobiology; drug adverse effect; general anesthesia; immunocytochemistry; laboratory rat; nerve stem cell; neural plasticity; neurotoxicology; neurotrophic factors; tissue /cell culture

DESCRIPTION (provided by applicant): General anesthesia is one of the great advances of medicine but is not without risks. Subtle central nervous toxicity may be one of them. In neonatal animals, several general anesthetic agents have been implicated in neurodegeneration, hippocampal dysfunction, synaptic abnormalities, and learning impairment, with the period of the brain growth spurt and synaptogenesis being especially vulnerable. The mature brain, like the developing brain, contains immature cells that develop into neurons and get incorporated into functional neuronal circuits and has regions constantly remodeling synaptic connections in a rapid, highly dynamic process known as synaptic plasticity. Our central hypothesis, therefore, is that general anesthetic-mediated neurotoxicity is as much a function of the state of neural cellular development as it is the age of the animal. This implies that mitotically competent, immature-undifferentiated and immature-differentiating neural progenitors-whether they are in neonatal brain or "plastic" areas of mature brain-are targets of general anesthetic-mediated neurotoxicity. To test this hypothesis, we will use a few selected general anesthetic agents (ketamine, propofol, isoflurane) and a cell culture model that permits the maturity and differentiation state of the cells to be regulated and included as an independent variable. Immunocytochemically characterized immature-undifferentiated and immature-differentiating neural progenitors as well as terminally differentiated cells will be exposed to the anesthetics in vitro and various measures of cell death and injury used to assess survival, capacity for growth / replication, and differentiation / synaptogenesis. Furthermore, we will investigate mechanism of cell death and the role of neurotrophic support in neurotoxicity, as well as examine opportunities to modify or mitigate it with neurotrophins or other protective compounds that can be used in vivo. As such, this work will elucidate the neurotoxic properties of general anesthetics in neural cells at different stages of development and lead potentially to novel mechanism-directed therapies to mitigate it. Accordingly, this research has implications for understanding anesthetic-related neurotoxicity and behavioral impairments in the young as well as the old.

描述（由申请人提供）： 全身麻醉是医学的巨大进步之一，但并非没有风险。微妙的中枢神经毒性可能是其中之一。在新生动物中，几种全身麻醉剂与神经退行性抗体有关，海马功能障碍，突触异常和学习障碍与大脑生长的时期和突触发生时期有关。像发育中的大脑一样，成熟的大脑包含不成熟的细胞，这些细胞会形成神经元，并掺入功能性神经元回路中，并在快速，高度动态的突触可塑性中不断地重塑突触连接。因此，我们的中心假设是全一麻醉介导的神经毒性与神经细胞发育状态的函数一样多，而不是动物的时代。 这意味着有丝分裂的，不成熟的，不成熟的和不成熟的差异神经祖细胞 - 无论是在新生儿大脑中还是一般麻醉介导的神经毒性的成熟脑ARE靶标的“塑性”区域。为了检验这一假设，我们将使用一些选定的一般麻醉剂（氯胺酮，丙泊酚，异氟烷）和一个细胞培养模型，该模型允许调节细胞的成熟度和分化状态，并将其作为独立变量包括在内。免疫细胞化学表征的未成熟差异和未成熟分化的神经祖细胞以及末端分化的细胞将在体外暴露于麻醉剂以及用于评估生存能力，生长 /复制能力以及分化 /突触发生的能力的细胞死亡和损伤的各种措施。此外，我们将研究细胞死亡的机制以及神经营养支持在神经毒性中的作用，并检查使用可在体内使用的神经营养蛋白或其他保护性化合物来修饰或减轻它的机会。因此，这项工作将阐明在发育的不同阶段，神经细胞中全身麻醉药的神经毒性特性，并可能导致新型机制导向疗法来减轻它。因此，这项研究对了解年轻人和年轻人中与麻醉相关的神经毒性和行为障碍具有意义。