Neuroprotection by Allopregnanolone through Modulation of GABAA Receptors

Allopregnanolone 通过调节 GABAA 受体实现神经保护

• 批准号: 7486518
• 负责人: Melissa Hernandez
• 金额: $ 4.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486518
• 关键词: Acute; Adverse effects; Allopregnanolone; Asses; Cell Death; Cerebral Ischemia; Dependence; Dose; Effectiveness; Event; Excitatory Amino Acid Antagonists; GABA Agonists; GABA Receptor; Glucose; Glutamates; Grant; Heart Arrest; Histology; Human; In Vitro; Ischemia; Molecular Biology; Nervous System Trauma; Neurologic; Neurons; Oxygen; Pharmaceutical Preparations; Protein Subunits; Purkinje Cells; Rattus; Stroke; Techniques; Testing; Therapeutic Agents; Thinking; Time; deprivation; excitotoxicity; experience; functional decline; gamma-Aminobutyric Acid; in vivo; interest; neuroprotection; prevent; receptor; receptor coupling

DESCRIPTION (provided by applicant): Global cerebral ischemia, as experienced during stroke or cardiac arrest, continues to be a major killer in the US and those who survive the acute attack experience many neurological deficits. Currently, there are no therapies to prevent neurological damage from cardiac arrest or stroke. One of the major obstacles for developing effective treatments is the lack of understanding how and why neurons die when deprived of oxygen. Excitotoxicity, excessive release of glutamate in the CMS, is a pathophysiological event that occurs during ischemia and is thought to be a major culprit in cell death. However, therapies using glutamate receptor antagonists to block excitotoxicity result in many detrimental side effects in humans. Alternatively, increasing the level of inhibitory tone may prevent excitotoxicity. Studies using GABA receptor agonists to block excitotoxicity have yielded inconsistent results, resulting in a loss of interest in GABA activating compounds as therapeutic agents. A possible explanation for these findings was unveiled in more recent studies which show that GABAA receptor protein is decreased following ischemia, possibly decreasing the effectiveness of GABA potentiating drugs. Our lab has been able to reaffirm these findings in Purkinje cells in culture, which receive robust excitatory and inhibitory drive and are particularly susceptible to ischemia. Using electrophysiological recordings to asses the functional activity of GABAA receptors, coupled with molecular biology and histology techniques, I plan to characterize the functional decline in GABAA receptor activity following ischemia and determine the mechanism of neuroprotection granted by the neurosteroid allopregnanolone.

描述（由申请人提供）：中风或心脏骤停期间经历的全身脑缺血仍然是美国的主要杀手，并且那些在急性发作中幸存下来的人会经历许多神经功能缺损。目前，没有任何疗法可以预防心脏骤停或中风造成的神经损伤。开发有效治疗方法的主要障碍之一是缺乏对神经元在缺氧时如何以及为何死亡的了解。兴奋性毒性（CMS 中谷氨酸的过量释放）是缺血期间发生的病理生理事件，被认为是细胞死亡的主要原因。然而，使用谷氨酸受体拮抗剂来阻断兴奋性毒性的疗法会对人类产生许多有害的副作用。或者，增加抑制音水平可以防止兴奋性毒性。使用 GABA 受体激动剂阻断兴奋性毒性的研究产生了不一致的结果，导致人们失去了对 GABA 激活化合物作为治疗剂的兴趣。最近的研究揭示了对这些发现的可能解释，这些研究表明缺血后 GABAA 受体蛋白减少，可能降低 GABA 增强药物的有效性。我们的实验室已经能够在培养的浦肯野细胞中重申这些发现，这些细胞受到强大的兴奋和抑制驱动，并且特别容易发生缺血。我计划利用电生理记录评估 GABAA 受体的功能活性，结合分子生物学和组织学技术，描述缺血后 GABAA 受体活性功能下降的特征，并确定神经类固醇四氢孕酮提供的神经保护机制。