Novel approaches for neuroprotection

描述（由申请人提供）：创伤性脑损伤（TBI）仍然是一个主要的医疗问题，在美国每年导致50，000例死亡，并且是长期发病的重要原因。在本申请中，我们提出探索缺乏纤维蛋白溶解活性并且不能防止血脑屏障（BBB）通透性丧失的tPA突变体（tPA-S481 A）发挥强大的神经保护作用的作用机制。我们的数据有助于解释这一看似矛盾的结果，显示了通过1）加速神经毒性氨基酸的清除和2）促进tPA-S481 A向脑实质的递送来维持BBB通透性的有益作用，在脑实质中，它与内源性tPA竞争激活NMDA受体，从而防止神经元凋亡。这些研究为TBI后BBB通透性的功能提供了基本的新见解，并确定了一种新的神经保护机制。 公共卫生相关性：我们将探讨tPA突变体的作用机制，该突变体在缺乏纤溶活性且不阻止血脑屏障完整性丧失的情况下对创伤性脑损伤（TBI）发挥强大的神经保护作用。我们将探讨这一看似矛盾的结果，通过显示脑损伤期间血脑屏障的开放如何通过清除神经毒性药物和通过防止NMDA受体激活来改善细胞凋亡来提供神经保护。

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.