Novel approaches for neuroprotection

神经保护的新方法

• 批准号: 8054407
• 负责人: Abd Alroof HIGAZI
• 金额: $ 19.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054407
• 关键词: Alteplase; Amino Acids; Animal Model; Apoptosis; Area; Binding; Blood - brain barrier anatomy; Brain; Brain Injuries; Cessation of life; Data; Generations; Glutamate Receptor; Glutamates; Injury; Measures; Medical; Microdialysis; Modeling; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurological outcome; Outcome; Peptides; Permeability; Radiolabeled; Receptor Activation; Traumatic Brain Injury; Work; insight; mutant; neuron apoptosis; neuroprotection; neurotoxic; neurotoxicity; new therapeutic target; novel; novel strategies; prevent; public health relevance; radiotracer; receptor

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) remains a major medical problem, resulting in 50,000 deaths/year in the US and is an important cause of long-term morbidity. In the present application we propose to explore the mechanism of action of a tPA mutant (tPA-S481A) that lacks fibrinolytic activity and does not prevent loss of blood-brain-barrier (BBB) permeability exerts a powerful neuroprotective effect. Our data help explain this seemingly paradoxical outcome by showing the beneficial effects of maintaining BBB permeability by 1) accelerating the clearance of neurotoxic amino acids and 2) promoting the delivery of tPA-S481A to brain parenchyma where it competes with endogenous tPA for activation of the NMDA receptor and thereby prevents neuronal apoptosis. These studies provide both fundamental new insights into the function of BBB permeability post-TBI and identify a novel mechanism of neuroprotection. PUBLIC HEALTH RELEVANCE: We will explore the mechanism of action of a tPA mutant that exerts a powerful neuroprotective effect against traumatic brain injury (TBI) in the absence of fibrinolytic activity and without preventing loss blood-brain-barrier integrity. We will explore this seemingly paradoxical outcome by showing how opening of the BBB during brain injury provides neuroprotection by clearing neurotoxic agents and ameliorating apoptosis by preventing NMDA receptor activation.

描述（由申请人提供）：创伤性脑损伤（TBI）仍然是一个主要的医学问题，在美国每年50,000例死亡，这是长期发病率的重要原因。在本应用中，我们建议探索缺乏纤维蛋白溶解活性的TPA突变体（TPA-S481A）的作用机理，并且不能防止血脑栓塞（BBB）渗透率丧失产生强大的神经保护作用。我们的数据有助于解释这种看似矛盾的结果，通过显示通过1）加速神经毒性氨基酸的清除和2）促进TPA-S481A到脑部实质性的递送的有益作用，并与内源性TPA竞争NMDA受体的NMDA受体Neuronal Neuronal Neuronal竞争。这些研究既提供了对TBI后BBB渗透率功能的基本新见解，并确定了一种新颖的神经保护机制。 公共卫生相关性：我们将探索TPA突变体的作用机理，该突变体在没有纤维蛋白水解活性并且而不会防止血脑屏障完整性的情况下对创伤性脑损伤（TBI）发挥强大的神经保护作用。我们将通过展示BBB在脑损伤期间的开放如何通过清除神经毒性剂并通过防止NMDA受体激活来改善凋亡来探索这种看似自相矛盾的结果。