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

精氨酸治疗脑外伤后脑血流量减少

• 批准号: 6224760
• 负责人: CLAUDIA S ROBERTSON
• 金额: $ 20.36万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-26 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6224760
• 关键词: arginine; behavior test; brain injury; cardiovascular disorder chemotherapy; cerebral ischemia /hypoxia; disease /disorder model; intracranial pressure; isozymes; laboratory mouse; laboratory rat; medical complication; nitric oxide synthase; nonhuman therapy evaluation; stereoisomer; vascular endothelium

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.

创伤性脑损伤(TBI)导致大脑容易受到二次侮辱。我们开发的二次损伤模型直接模拟了轻度颅脑损伤患者的情况，该患者可能有全身损伤，可能导致低血压或缺氧。二次伤害模型也代表了中、重度颅脑损伤患者的情况，他们的大脑中有受伤的区域，容易受到二次伤害，但如果处理得当，可能是可以挽救的。受创伤的大脑对二次伤害的易感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的血管扩张机制受损，特别是一氧化氮。另一个可能的原因是血管收缩物质的创伤释放，这些物质阻止了血管扩张。我们有初步证据表明，一氧化氮功能的改变在局部脑血流量的减少中发挥了作用，而L精氨酸治疗逆转了这些发现，并改善了严重皮质撞击伤后的预后。有趣的是，L-精氨酸输注引起的脑血流量增加与颅内压升高无关；事实上，L-精氨酸治疗组的颅内压低于生理盐水对照组。这不是血管扩张剂的特征，如硝普钠和硝酸甘油。这通常会导致受伤大脑中的颅内压升高。我们在这个项目中提出的研究将把这些研究扩展到二次伤害模型，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。1.研究L-精氨酸和D-精氨酸对3m/s撞击伤合并二次损伤后生理、组织和行为学指标的影响。2.探讨颅脑损伤后脑血流量减少的机制及L-精氨酸对脑血流量减少的影响。3.研究L精氨酸给药时机对大鼠行为学和组织学结果的影响。4.研究L精氨酸对脑外伤后血管内皮细胞和神经元一氧化氮合酶亚型的影响。