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学问题，在美国每年导致50,000人死亡，是长期发病的重要原因。在目前的应用中，我们提出探索tPA突变体（tPA- s481a）的作用机制，该突变体缺乏纤溶活性，不能阻止血脑屏障（BBB）通透性的丧失，但具有强大的神经保护作用。我们的数据通过显示维持血脑屏障通透性的有益作用来帮助解释这一看似矛盾的结果：1)加速神经毒性氨基酸的清除，2)促进tPA- s481a向脑实质的传递，在脑实质中，tPA- s481a与内源性tPA竞争NMDA受体的激活，从而防止神经元凋亡。这些研究为脑外伤后血脑屏障通透性的功能提供了新的基础见解，并确定了一种新的神经保护机制。

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.