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: 7626844
• 负责人: Melissa Hernandez
• 金额: $ 4.12万
• 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/7626844
• 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; Time; deprivation; effective therapy; excitotoxicity; experience; functional decline; gamma-Aminobutyric Acid; in vivo; interest; neuroprotection; neurosteroids; 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(申请人提供)：中风或心脏骤停期间经历的全球脑缺血仍然是美国的主要杀手，那些在急性发作中幸存下来的人经历了许多神经缺陷。目前，还没有预防心脏骤停或中风造成的神经损伤的治疗方法。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什么死亡的了解。兴奋性毒性，即CMS中谷氨酸的过度释放，是一种在缺血期间发生的病理生理事件，被认为是细胞死亡的主要罪魁祸首。然而，使用谷氨酸受体拮抗剂来阻断兴奋性毒性的治疗在人类中会产生许多有害的副作用。或者，增加抑制性音调的水平可能会防止兴奋性毒性。使用GABA受体激动剂阻断兴奋性毒性的研究结果不一致，导致人们对GABA激活化合物作为治疗剂失去了兴趣。最近的研究揭示了这些发现的一个可能的解释，这些研究表明，缺血后GABAA受体蛋白减少，可能降低了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，特别容易受到缺血的影响。使用电生理记录来评估GABAA受体的功能活性，结合分子生物学和组织学技术，我计划表征缺血后GABAA受体活性的功能下降，并确定神经类固醇别孕酮的神经保护机制。