Arginine treatment of a reduced cerebral blood flow after traumatic brain injury

创伤性脑损伤（TBI）导致大脑容易受到二次损伤。我们开发的二次损伤模型直接模拟了轻度TBI患者的情况，该患者可能具有可能导致低血压或缺氧的全身损伤。二次损伤模型也代表了中度和重度TBI患者的情况，这些患者的大脑中有受伤的区域，易受二次损伤，但如果最佳管理，可能是可以挽救的。创伤后大脑对二次损伤的脆弱性增加的主要机制似乎是血管。这些发现的一个可能原因是正常血管舒张机制的损害，特别是一氧化氮。另一个可能的原因是创伤释放了阻止血管舒张的血管收缩物质。我们有初步证据表明，一氧化氮功能的改变在rCBF的减少中起作用，并且用L-精氨酸治疗逆转了这些发现并改善了严重皮质撞击损伤后的结果。有趣的是，L-精氨酸输注诱导的CBF增加与ICP增加无关;事实上，L-精氨酸治疗的ICP低于盐水对照。这是血管扩张剂（如硝普钠和硝酸甘油）所不具备的特征。这通常会提高受伤大脑的颅内压我们在这个项目中提出的研究将把这些研究扩展到二次损伤模型，并更详细地研究创伤如何改变一氧化氮代谢。以及L-精氨酸如何改善这种情况。该项目的四个具体目标是：1。目的：研究L-精氨酸和D-精氨酸对大鼠3 m/s撞击伤合并二次损伤后生理、组织学和行为学指标的影响。2.目的：探讨脑外伤后脑血流量降低的机制及L-精氨酸对脑外伤后脑血流量的影响。3.研究L-精氨酸给药时机对行为学和组织学结局的影响。4.目的：探讨L-精氨酸对颅脑损伤后内皮细胞和神经细胞一氧化氮合酶（NOS）亚型的影响。

Traumatic brain injury (TBI) causes the brain to susceptible to secondary insults. The secondary insult model that we have developed directly mimics the circumstances of a mild TBI patient who may have systemic injuries that may result in hypotension or hypoxia. The secondary insult model also represent the circumstance in moderate and severe TBI patients who have areas in the brain that are injured and vulnerable to secondary insults, but potentially salvageable if managed optimally. The primary mechanism for the increased vulnerability of traumatized brain to secondary insults appears to be vascular. One possible cause of these findings is impairment of the normal vasodilatory mechanisms, in particular nitric oxide. Another possible cause is release by the trauma of vasoconstrictive substances that prevent vasodilation. We have preliminary evidence that alterations in nitric oxide function play a role in the reduction in rCBF, and treat treatment with L-arginine reverses these findings and improves outcome after severe cortical impact injury. Interestingly, the increase in CBF induced by L-arginine infusion is not associated with an increase in ICP; in fact the ICP is lower with L- arginine treatment than in the saline controls. This is uncharacteristic for vasodilating agents, such as nitroprusside and nitroglycerin. which typically raise ICP in the injured brain. The studies that we propose in this project will extend these studies into the secondary insult model, and examine in more detail how trauma alters nitric oxide metabolism. and how L-arginine ameliorates the situation. The 4 specific aims for the project are: 1. To study the effect of L-arginine and D-arginine on physiological, histological and behavioral measures after the 3m/sec impact injury complicate by a secondary insult. 2. To study the mechanism of the reduced CBF after traumatic brain injury and the L-arginine effect of increasing the reduced CBF. 3. To study the effect of timing of L-arginine dosage on behavior and histological outcome. 4. To study the effect of L-arginine infusion on endothelial and neuronal isoforms of NOS after TBI.